HYPERCHOLESTEROLEMIA 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., 1960Hypercholesterolemia: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00458-5 1. Hypercholesterolemia-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on hypercholesterolemia. 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 HYPERCHOLESTEROLEMIA ....................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Hypercholesterolemia .................................................................... 6 E-Journals: PubMed Central ....................................................................................................... 65 The National Library of Medicine: PubMed ................................................................................ 68 CHAPTER 2. NUTRITION AND HYPERCHOLESTEROLEMIA ........................................................... 117 Overview.................................................................................................................................... 117 Finding Nutrition Studies on Hypercholesterolemia................................................................. 117 Federal Resources on Nutrition ................................................................................................. 119 Additional Web Resources ......................................................................................................... 119 CHAPTER 3. ALTERNATIVE MEDICINE AND HYPERCHOLESTEROLEMIA ..................................... 121 Overview.................................................................................................................................... 121 National Center for Complementary and Alternative Medicine................................................ 121 Additional Web Resources ......................................................................................................... 130 General References ..................................................................................................................... 133 CHAPTER 4. PATENTS ON HYPERCHOLESTEROLEMIA .................................................................. 135 Overview.................................................................................................................................... 135 Patents on Hypercholesterolemia ............................................................................................... 135 Patent Applications on Hypercholesterolemia ........................................................................... 141 Keeping Current ........................................................................................................................ 151 CHAPTER 5. BOOKS ON HYPERCHOLESTEROLEMIA...................................................................... 153 Overview.................................................................................................................................... 153 Book Summaries: Federal Agencies............................................................................................ 153 Book Summaries: Online Booksellers......................................................................................... 154 Chapters on Hypercholesterolemia............................................................................................. 154 CHAPTER 6. PERIODICALS AND NEWS ON HYPERCHOLESTEROLEMIA ........................................ 161 Overview.................................................................................................................................... 161 News Services and Press Releases.............................................................................................. 161 Academic Periodicals covering Hypercholesterolemia ............................................................... 163 CHAPTER 7. RESEARCHING MEDICATIONS .................................................................................. 165 Overview.................................................................................................................................... 165 U.S. Pharmacopeia..................................................................................................................... 165 Commercial Databases ............................................................................................................... 167 Researching Orphan Drugs ....................................................................................................... 168 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 171 Overview.................................................................................................................................... 171 NIH Guidelines.......................................................................................................................... 171 NIH Databases........................................................................................................................... 173 Other Commercial Databases..................................................................................................... 175 APPENDIX B. PATIENT RESOURCES ............................................................................................... 177 Overview.................................................................................................................................... 177 Patient Guideline Sources.......................................................................................................... 177 Finding Associations.................................................................................................................. 180 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 183 Overview.................................................................................................................................... 183 Preparation................................................................................................................................. 183 Finding a Local Medical Library................................................................................................ 183 Medical Libraries in the U.S. and Canada ................................................................................. 183
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ONLINE GLOSSARIES................................................................................................................ 189 Online Dictionary Directories ................................................................................................... 190 HYPERCHOLESTEROLEMIA DICTIONARY ........................................................................ 193 INDEX .............................................................................................................................................. 269
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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 hypercholesterolemia 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 hypercholesterolemia, 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 hypercholesterolemia, 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 hypercholesterolemia. 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 hypercholesterolemia, 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 hypercholesterolemia. 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 HYPERCHOLESTEROLEMIA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on hypercholesterolemia.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and hypercholesterolemia, 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 “hypercholesterolemia” (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: •
Effect of Garlic on Hypercholesterolemia in Renal Transplant Patients Source: Transplantation Proceedings. 30(1): 189-191. February 1998. Contact: Available from Appleton and Lange. P.O. Box 86, Congers, NY 10920-0086. (203) 406-4623. Summary: Hyperlipidemia is a common problem in renal transplant patients and the treatment options have proven difficult. Thus it is desirable to identify safe and effective alternative modalities. This article reports on a study that explored the use of garlic as an herbal medicine to reduce cholesterol levels in renal transplant patients. The study included 35 renal transplant patients with a total serum cholesterol of greater than 240 mg per dL and LDL cholesterol of greater than 160 mg per dL. All participants had
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stable renal allograft function for more than a 6 month period. Patients were instructed in a Step One National Cholesterol Education Program reduction diet and randomized to receive a 12 week course of either placebo or matching garlic tablets at a dose of 680 mg two times a day. Garlic was effective in decreasing both total and LDL cholesterol levels. This benefit was apparent after 6 weeks of therapy and sustained at 12 weeks. In contrast, total cholesterol and LDL cholesterol levels did not change significantly in the placebo group. In general, garlic therapy was well tolerated. The response to garlic was somewhat less than that reported in the metanalysis in which garlic was found to decrease total cholesterol by about 9 percent. However, it is possible that even small decrements in cholesterol may have a long term benefit, particularly in a population that is at higher risk for coronary disease. And, although garlic had significant beneficial effects, treated patients still had hyperlipidemia severe enough to consider the addition of standard pharmacotherapy. 1 figure. 2 tables. 16 references. •
Association Between Hypercholesterolemia, Cardiovascular Disease and Severe Periodontal Disease Source: Journal of Clinical Periodontology. 28(9): 865-868. September 2001. Contact: Available from Munksgaard International Publishers Ltd. Commerce Place, 350 Main Street, Malden, MA 02148-5018. (781) 388-8273. Fax (781) 388-8274. Summary: Premature death in men is known to be significantly associated with coronary heart disease (CHD). More and more studies are pointing toward a possible association between periodontal disease and increased risk of cardiovascular disease. The association of poor oral hygiene and atherosclerosis (hardening of the arteries) can be explained by the effect of chronic inflammatory disease on blood rheology (altered flow and contents). This article reports on a study undertaken to assess the relationship between CHD and periodontal disease. The study population included 1094 Israeli army service men aged 26 to 53 years (mean 39 years plus or minus 5 years). The study group comprised 151 subjects classified as having CHD, i.e., myocardial infarction and or anginal syndrome with angiographic evidence of significant coronary disease, or suffer from atherosclerotic risk factors, i.e., diabetes (fasting glucose) and hypertension (high blood pressure) according to strict, well established criteria. Blood levels of cholesterol and triglycerides were also determined. The severity of periodontal disease was assessed by the aid of CPITN (community periodontal index of treatment need). Statistical analysis showed a significant association of CPITN score 4 with hypercholesterolemia (high levels of cholesterol in the blood) and a possible association with CHD. The authors conclude by proposing the generation of higher cholesterol blood levels as a possible link between chronic periodontal inflammation and atherosclerosis. 3 tables. 28 references.
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Treatment of Hypercholesterolemia and Combined Hyperlipidemia with Simvastatin and Gemfibrozil in Patients with NIDDM: A Multicenter Comparison Study Source: Diabetes Care. 21(4): 477-481. April 1998. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article describes a double-blind, double-dummy study that investigated the lipid-lowering efficacy of simvastatin and gemfibrozil in Finnish patients who had type 2 diabetes and combined hyperlipidemia (CHL) or isolated hypercholesterolemia (IHC). Patients with primary dyslipidemia and type 2 diabetes treated with oral hypoglycemic agents and insulin, alone or in combination, were recruited from 10
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Finnish centers participating in the study. After a 4-week placebo run-in period, they were randomly assigned to simvastatin or gemfibrozil. The 47 patients in the simvastatin group received 10 milligrams (mg) once a night for 8 weeks, 20 mg for the next 8 weeks, and 40 mg for the third 8-week period. The 49 patients in the gemfibrozil group received 600 mg twice a day throughout the 24 weeks. The lipid-lowering efficacy of both drugs was compared in all patients, as well as separately in patients with CHL and IHC. Results show that simvastatin reduced low density lipoprotein (LDL) and total cholesterol and the LDL-to-high density lipoprotein (HDL) cholesterol ratio more effectively in all patients, whereas gemfibrozil was more effective in elevating HDL cholesterol and decreasing triglyceride levels. The effects differed according to lipid phenotype at baseline. Simvastatin decreased LDL cholesterol levels by 30 to 40 percent in both phenotypes. Gemfibrozil caused a 15 percent reduction in LDL cholesterol in IHC but no change in CHL patients. Simvastatin produced 15 to 30 percent reductions in triglyceride levels in CHL but no change in IHC patients. Gemfibrozil caused reductions in triglycerides in CHL and in IHC patients, with 12 to 18 percent increases in HDL cholesterol in these groups. The article concludes that simvastatin is useful both in CHL and IHC patients, whereas gemfibrozil can be used in patients with high triglyceride and low or normal LDL cholesterol levels. 1 appendix. 2 figures. 3 tables. 26 references. (AA-M). •
Hypercholesterolemia in Diabetes and Glucose Intolerance in the U.S. Population Source: Diabetes Care. 14(5): 366-374. May 1991. Summary: This article reports on the prevalence of hypercholesterolemia, according to the guidelines of the National Cholesterol Education Program, which has been determined in a national survey of diabetes and glucose intolerance. Rates of elevated total cholesterol in people with diabetes in the United States are only slightly greater than in those without diabetes after adjusting for age and sex. Nevertheless, high or borderline high total cholesterol is common in diabetes and is present in 70 percent of adults with diagnosed diabetes and 77 percent with undiagnosed diabetes. The authors discuss the findings as they apply to risks for coronary heart disease. The authors conclude that investigation of blood lipid levels and coronary heart disease risk factors should be routine in all patients with diabetes, and treatment strategies should include management of lipid disorders and the multiple other risk factors for coronary heart disease that are highly prevalent in these patients. 2 figures. 7 tables. 50 references. (AAM).
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Effects of Psyllium on Glucose and Serum Lipid Responses in Men with Type 2 Diabetes and Hypercholesterolemia Source: American Journal of Clinical Nutrition. 70(4): 466-473. October 1999. Contact: Available from American Journal of Clinical Nutrition. Production Office, 9650 Rockville Pike, Bethesda, MD 20814. (301) 530-7038. Fax (301) 571-8303. Website: www.ajcn.org. Summary: Water soluble dietary fibers decrease postprandial (after a meal) glucose (sugar) concentrations and decrease serum cholesterol concentrations. This article reports on a study examining the effects of administering psyllium to men with type 2 diabetes. Psyllium is a viscous, mostly water soluble fiber. The objective of the study was to evaluate the safety and effectiveness of psyllium husk fiber used adjunctively to a traditional diet for diabetes. After a 2 week dietary stabilization phase, 34 men with type 2 diabetes and mild to moderate hypercholesterolemia (high cholesterol) were
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randomly assigned to receive 5.1 grams of psyllium or cellulose placebo twice daily for 8 weeks. Serum lipid and glycemic indexes were evaluated biweekly on an outpatient basis and at weeks 0 and 8 in a metabolic ward. The psyllium group showed significant improvement in glucose and lipid values compared with the placebo group. Serum total concentrations were 8.9 percent lower and LDL (low density lipoprotein) cholesterol concentrations were 13.0 percent lower in the psyllium than in the placebo group. All day and postlunch postprandial glucose concentrations were 11 percent and 19.2 percent lower in the psyllium than in the placebo group. Both products were well tolerated, with no serious adverse events related to treatment reported in either group. The authors conclude that the addition of psyllium to a traditional diet for persons with diabetes is safe, is well tolerated, and improves glycemic and lipid control in men with type 2 diabetes and hypercholesterolemia. 1 figure. 3 tables. 45 references.
Federally Funded Research on Hypercholesterolemia The U.S. Government supports a variety of research studies relating to hypercholesterolemia. 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 hypercholesterolemia. 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 hypercholesterolemia. The following is typical of the type of information found when searching the CRISP database for hypercholesterolemia: •
Project Title: ANGIOTENSIN, FIBRINOLYSIS
THE
VASCULAR
ENDOTHELIUM,
AND
Principal Investigator & Institution: Vaughan, Douglas E.; Chief, Division of Cardiovascular Medici; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-JUL-1994; Project End 31-MAR-2006 Summary: (Provided by applicant): The renin-angiotensin system (RAS) plays an integral role in cardiovascular homeostasis through its effects on vascular tone and volume, and pharmacological interruption of this system has found widespread clinical application. Independent of the effects of the RAS on blood pressure, activation of this system has been identified as a risk factor for the development of ischemic heart disease. Although multiple mechanisms may be responsible for this association, we have focused on the effects of the RAS on the plasminogen activator system, which serves as one of the major endogenous defense mechanisms against intravascular thrombosis and also plays an important role in vascular and tissue remodeling. The central hypothesis 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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of this proposal is that a major component of the vascular toxicity brought on by activation of the RAS is derived from the deleterious effects of angiotensin on fibrinolytic balance. A multifaceted research strategy involving in vitro and in vivo experiments is described to test this hypothesis. The specific aims of this proposal are the following: 1) to test the hypothesis that angiotensin land bradykinin modulate fundamental peripheral circadian oscillating mechanisms that regulate PAl-1 production in vitro; 2) to characterize the role of angiotensin and the All receptor in promoting PAl-1 expression in response to chronic nitric oxide synthase inhibition; and 3) to study the effects of angiotensin II alone and in combination with hypercholesterolemia on the development of coronary thrombosis in transgenic mice that over express a stable form of human PAl-1. It is anticipated that these studies will generate important new information regarding the interactions of the RAS, the vascular endothelium, and fibrinolysis. Furthermore, this project may contribute to our understanding of the regulation of two systems that play vital roles in cardiovascular homeostasis, and thus may improve our abililty to prevent and treat atherothrombotic cardiovascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANTIOXIDANT FUNCTIONS OF LIPOIC ACID Principal Investigator & Institution: May, James M.; Associate Professor; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Lipoic acid has been promoted as an antioxidant effective in a variety of conditions in which there is oxidant damage to the vascular bed, including diabetes mellitus and atherosclerosis. An early manifestation of such damage is dysfunction of the vascular endothelium due to deficient generation or excessive destruction of nitric oxide. Whether lipoic acid can spare nitric oxide and thus lessen endothelial dysfunction is an unanswered question with important clinical implications. We have shown that cultured human endothelial cells take up lipoic acid and reduce it to dihydrolipoic acid. The latter protects the cells in a concentration dependent manner against both internal and external oxidant stresses, and this is associated with an increase in nitric oxide generation by the cells. In this proposal we seek to confirm these novel results, to clarify the mechanism by which they occur, and to determine whether they might be relevant to clinical atherosclerosis. In the first aim we will assess the antioxidant efficacy of lipoic acid in endothelial cells in culture. Oxidant stress will be initiated by agents with biological relevance for the cells, including H202 and minimally oxidized human low density lipoprotein (LDL). Cell protection by lipoic acid will be assessed using a fluorescence-based assay of intracellular oxidant stress, by measuring lipid peroxidation as F2-isoprostanes, and by assay of cellular antioxidants. In the second aim, we will determine whether and how these antioxidant effects of lipoic acid can explain its ability to enhance endothelial nitric oxide generation. We will focus on whether intracellular dihydrolipoic acid acts directly or through glutathione, whether it is synergistic with ascorbic acid, and whether it prevents or reverses impaired nitric oxide generation due to oxidized LDL. Showing that lipoic acid enhances endothelial nitric oxide generation and action will form the basis for a small double-blind, placebocontrolled clinical trial of its ability to reverse nitric oxide-dependent endothelial dysfunction (aim 3). Subjects with increased oxidant stress due to hypercholesterolemia will be studied before and after taking lipoic acid or placebo for 8 weeks with regard to changes in plasma and urinary F2-isoprostanes and flow-mediated brachial artery
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dilation. Despite the widespread use of lipoic acid, these studies are necessary to establish the biological basis and rationale for the clinical use of the agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: APO A-1 STRUCTURAL MUTATION AND ATHEROSCLEROSIS Principal Investigator & Institution: Sorci-Thomas, Mary G.; Professor, Department of Pathology; Pathology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 31-JUL-2004 Summary: The incidence of premature coronary atherosclerosis in the human population is highly correlated to decreased concentrations of plasma high density lipoproteins (HDL) and its major apoprotein, apolipoprotein A-I (apo A-I). Transgenic and knockout mouse studies have shown that circulating HDL apo A-I primarily plays a "protective function" in response to high levels of atherogenic lipoproteins through its ability to accept, organize and transport cholesterol out of the artery to the liver for uptake and excretion into bile. This "reverse cholesterol transport pathway" is highly dependent upon apo A-I's ester conversion in the plasma. Blockage or reduction in apo A-I's ability to carry out this function can lead to reduced reverse cholesterol transport and inefficient removal of peripheral tissue cholesterol. Data from the applicants' laboratory show that structural alterations in the conformation of plasma apo A-I can have a more profound effect on HDL apo A-I formation and maturation than merely the absence of native apo A-I alone. Their studies show that LCAT activation and thus, plasma cholesterol esterification is inhibited by the presence of a mutant form of apo A-I in plasma. The mutant apo A-I does this by inhibiting plasma cholesterol esterification even in plasma containing native or wild type apo A-I. Thus, they propose to investigate the molecular and cellular basis for the severe disruption in HDL metabolism resulting from the hepatic expression of the mutant human apo A-I, termed 6 apo A-I. This mutant of apo A-I lacks repeat 6, a single proline punctuated 22-mer and has been shown to have a similar plasma lipoprotein phenotype to a known human apo A-I mutation, called apo A-I. In a newly created transgenic mouse model, designated Tg6 apo A-I the applicants propose to conduct dietary-cholesterol feeding studies to determine if mutant apo A-I protects against atherosclerosis in mice with hypercholesterolemia. They also plan to elucidate the molecular and cellular basis for 6 apo A-I's disruption of HDL apo A-I metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: APO B TRANSLOCATION AND DEGRADATION Principal Investigator & Institution: Davis, Roger A.; Professor; Biology; San Diego State University 5250 Campanile Dr San Diego, Ca 92182 Timing: Fiscal Year 2004; Project Start 01-SEP-1994; Project End 31-MAY-2008 Summary: (provided by applicant): Hepatic production of apo B-containing lipoproteins plays an integral role in lipid metabolism. Imbalances of the production of apo Bcontaining lipoproteins or their removal by the liver are associated with several diseases including atherosclerosis, obesity and diabetes. Data obtained using cultured hepatocytes and genetically altered mice have led us to hypothesize that hepatic secretion of apo B containing lipoproteins is regulated post-transcriptionally. During its translation, apo B has two metabolic fates: translocation into the lumen of the endoplasmic reticulum (ER) during the addition of lipid to form a lipoprotein particle or degradation by an ubiquitin-dependent proteasome pathway. Microsomal triglyceride transfer protein (MTP) and the supply of glycerolipids (phospholipids and triglycerides)
Studies
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play an essential role in mediating apo B translocation and assembly into a lipoprotein particle. Based on new and intriguing insights gained during the previous funding period, we will direct our efforts to the following Specific Aims: Specific Aim 1: To define how COUP-TFII interacts with a conserved DR1 site in the MTP promoter and alters gene transcription in rat hepatoma cells and in vivo in the livers of mice. Specific Aim 2: To examine the role of ubiquitin-dependent proteasome degradation in regulating the metabolic fate of apo B in vivo in the livers of mice. Specific Aim 3: To examine the mechanism through which genetic deletion of Txnip alters the flow of carbon units into lipids and secretion of apo B-containing lipoproteins. Clearly, MTPmediated translocation and lipid transfer is an effective target for ameliorating one of the most severe forms of hypercholesterolemia (for which most other drugs [e.g. statins] are ineffective; i.e., homozygous familial hypercholesterolemia). We are confident that our proposed studies will provide new insights that will add further proof to the feasibility and advance the therapeutic potential of controlling the apo B processing pathway. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: APOJ/CLUSTERIN:A PROTECTIVE PROTEIN IN VASCULAR BIOLOGY Principal Investigator & Institution: Granholm, Norman A.; Pathology and Lab Medicine; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Vascular reocclusion remains a significant complication of stent placement: vascular reocclusion occurs in 30-50% of subjects within 1 year of vascular surgery. In-stent restenosis is due primarily to neointima hyperplasia of smooth muscle cells. Thus, understanding the mechanism(s) and biochemical participants in neointima hyperplasia will optimize the design of intervention protocols that reduce the risk of restenosis after vascular surgery. Our Preliminary Results suggest that apolipoprotein (apo) J / clusterin may be an important regulator in determining the vascular response to injury and the development of the neointima lesion. With genetically defined mice as the model, our results show that apoJ expression is induced in response to mechanical injury of the carotid artery. Importantly, apoJ(-/-) mice developed a more severe neointima lesion 2 wk after arterial injury in comparison to wild type mice. Moreover, additional Preliminary Results demonstrate that apoJ(-/-) mice develop increased hypercholesterolemia compared to apoJ wild type mice fed the same cholesterol enriched atherogenic diet. This hypercholesterolemia is associated with an altered distribution of apoE among lipoprotein particles. Therefore, the current study uses the in vivo mouse model to test the hypothesis that apoJ has a direct vascular protective function in vivo by modulating one or more of the cardinal events that contribute to vascular occlusive disease. Specific Aim 1 contains three parts. First, the sequence of events from the time of vascular injury to the time of neointima formation in wild type and apoJ(-/-) mice is compared. The time when differences in vascular pathology are observed is correlated with the temporal expression of apoJ in wild type mice. With these data as a guide, the second part performs gene expression profiling studies to determine the biologic and functional pathways that are modulated by apoJ in the vascular response to injury. The third part uses apoJ-tg mice and adenovirus mediated apoJ gene transfer directly to the vessel wall to test the corollary hypothesis that increased apoJ expression is a viable tactic to limit neointirna hyperplasia. Specific Aim 2 tests the hypothesis that apoJ deficiency exacerbates diet induced hypercholesterolemia by decreasing lipoprotein catabolism
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Hypercholesterolemia
via alteration of apoE distribution among lipoproteins. We will characterize the metabolism of VLDL particles in apoJ wild type and apoJ(-/-) mice: quantify catabolism, quantify lipoprotein synthesis and secretion, and quantify transter of apoE from HDL to VLDL. In Specific Aim 3 wild type, apoJ(-/-), and apoJ-tg mice are fed a cholesterol enriched atherogenic diet to test the hypothesis that apoJ is protective, also, against progressive atherosclerosis. Taken together, these studies will identify novel functions of apoJ as well as contribute to our better understanding of the pathogenic events in the vascular response to injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ARTHEROSCLEROSIS IN INSULIN-RESISTANT, HYPERLIPIDEMIC P* Principal Investigator & Institution: Clemmons, David R.; Professor of Medicine; Medicine; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): It is unknown why patients with type II insulin resistant (IR) diabetes mellitus have an increased incidence of atherosclerosis when compared to non-diabetics. Our goal is to develop porcine models of IR and a mixed model of IR plus familial hypercholesterolemia that will be useful in studies to define the role of IR in atherosclerosis. The pigs will be used to determine if the presence of IR causes an increased burden of atherosclerosis compared to control animals without IR and to determine if markers of atherosclerosis that are present in these animals will correlate with disease progression in IR animals. Two unique strains of pigs will be used, one from Chapel Hill (CH) with increased total body fat and a second with familial hypercholesterolemia (FH) that are lean. Both the CH and FH strains have subpopulations with and without increased insulin resistance (IR). In Aim I, CH-IR and FH-IR pigs will be bred for increased severity of IR. In Aim II, the effect of IR on the extent of coronary, aortic, and carotid artery atherosclerosis and the changes in serum and tissue markers of atherosclerosis will be determined in CH-IR pigs and compared to CH pigs without IR, both groups being fed a high fat atherogenic diet. A second study will compare these same variables in FH-IR and FH-nonIR pigs fed normal (low fat) pig chow. Intravascular ultrasound (IVUS) will be used during the study to monitor disease progression in vivo. Both IVUS and morphometry of fixed vessels will be used to measure atherosclerosis at termination. In Aim III, insulin like growth factor-I (IGF-1) will be given to the CH-IR pigs to reduce IR, and the pigs will be fed a high fat atherogenic diet. The extent of atherosclerosis and the changes in markers in these IGF-I treated pigs will be compared to controls. In Aim IV, the FH-IR pigs will be fed normal (low fat) pig chow and an aVb3 inhibitor that we have shown reduces atherosclerosis in non-IR pigs and its effect on lesion development determined. Our overall objective is to develop a useful, relevant, available model of IR and atherosclerosis that can be used to identify mechanisms that lead to accelerated atherosclerosis in insulin resistant humans and to develop and test potential new treatment strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ATHEROSCLEROSIS AND CEREBRAL ISCHEMIA Principal Investigator & Institution: Huang, Paul L.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009
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Summary: (provided by applicant): Although cerebral ischemia and stroke commonly occur in patients with atherosclerosis, the specific effects of atherosclerotic vascular abnormalities are not reflected in most animal models of stroke. This proposal addresses the effects of atherosclerosis and endothelial dysfunction on cerebrovascular function, reactivity, and response to ischemia, using Western diet-fed apoE knockout mice as an animal model. We have found that apoE knockout mice show decreased resting cerebral blood flow, impaired response to whisker stimulation, and impaired autoregulation, while the response to hypercapnia is relatively preserved. In addition, apoE knockout mice have substantially larger infarcts after middle cerebral artery occlusion than do wild-type mice. We propose four specific aims: Aim 1 tests the hypothesis that hypercholesterolemia and endothelial dysfunction alter cerebrovascular anatomy, physiology (hypercapnia, whisker stimulation, and autoregulation), and pharmacology (pial arteriolar response in cranial window studies) of apoE knockout mice. Aim 2 examines the effects of atherosclerosis and endothelial dysfunction on the response to focal ischemia. We will use high-resolution laser speckle imaging to generate real-time maps of temporal and spatial pattern of cerebral blood flow, and quantitate effects on leukocyte-endothelial cell interactions. Aim 3 tests the hypothesis that superoxide generation is an important mediator of endothelial dysfunction. We will use chemiluminescence detection in endothelial cells, and dihydroethidium staining in sections and in vivo. We will also test the effects of superoxide scavengers on cerebral vascular reactivity (Aim 1) and effects on ischemia (Aim 2). Aim 4 tests whether genetic or pharmacologic interventions directed at augmenting endothelial NO production will restore cerebrovascular reactivity (Aim 1), and ameliorate the response to ischemia (Aim 2). Together, these experiments outline how atherosclerosis and endothelial dysfunction affect the cerebrovasculature, and whether pathophysiologic mechanisms operative in the peripheral circulation also apply to the cerebrovasculature. They also provide proof of principle for approaches that directly target cerebral vascular dysfunction for the treatment and prevention of stroke. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: B VITAMIN ATHEROSCLEROSIS INTERVENTION TRAIL Principal Investigator & Institution: Hodis, Howard N.; Associate Professor; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 20-SEP-2000; Project End 31-AUG-2005 Summary: (adapted from the application): Although primary prevention strategies have focused on key modifiable risk factors for development and progression of atherosclerosis, such as hypercholesterolemia, coronary heart disease (CHD) remains the leading cause of death in the United States. Many individuals who present with clinical sequelae of atherosclerosis do not have identifiable conventional risk factors for CHD. Epidemiological studies indicate a strong association of plasma tHcy levels with atherosclerosis from childhood to the elderly. A large number of studies have shown plasma tHcy levels to be an independent risk factor for CHD that is easily modifiable with the B-vitamins, folic acid, vitamin B12, and vitamin B6. Plasma tHcy levels rise 25 % after 50 years of age and may partially account for the age-related risk for CHD. The rise in plasma tHcy levels parallel the age-related decrease in serum levels of folate, vitamin B12, and vitamin B6. Elevated they levels result even with these vitamin levels in the normal to low-normal range. Elderly individuals seem to be most susceptible to development of subclinical vitamin deficiencies since dietary intake of these B-vitamins is approximately 50% the Daily Value after 50 years of age. Low serum folate and vitamin B6 levels are significantly associated with CHD risk. Therefore, low B-vitamin
12
Hypercholesterolemia
status and elevated plasma tHcy levels are important risk factors for atherosclerosis. Evidence, including data from the investigator's laboratory suggests that B-vitamin supplementation can reduce the progression of subclinical atherosclerosis in healthy individuals. Therefore, the investigators propose a multisite, randomized, double-blind, placebo-controlled, 2.5-year, arterial imaging clinical trial with folic acid 5 mg, vitamin B12 2 0.4 mg, and vitamin B6 50 mg versus placebo in healthy men and women >40 years old with LDL-C >130 mg/dL and plasma tHcy >8.5/micromol/L. They will target a cohort of 50% elderly (2-60 years old), 50 % women and 50 % minority subjects. The impact of B-vitamins on the progression of subclinical atherosclerosis will be noninvasively quantitated across several vascular beds with computer image processed B-mode ultrasonograms of carotid artery intima-media thickness and EBCT of the coronary arteries and abdominal aorta. B-vitamin supplementation may provide a promising approach for reducing the progression of atherosclerosis since it is natural, inexpensive, highly tolerable, and safe. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BLOCKING INTIMAL HYPERPLASIA FOLLOWING VASCULAR TRAUMA Principal Investigator & Institution: Tzeng, Edith; Assistant Professor of Surgery; Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 31-MAR-2005 Summary: Atherosclerotic vascular disease is the leading cause of morbidity and mortality in the United States. Conventional treatments such as angioplasty and bypass procedures are limited in success by the development of intimal hyperplasia (IH). Over the last decade, gene therapy approaches to treating IH have been developed. We propose that one of the best candidate genes for the prevention of IH is the inducible nitric oxide synthase (iNOS) gene. iNOS produces NO which can inhibit smooth muscle cell (SMC) proliferation, promote endothelial cell (EC) regrowth, inhibit platelet and leukocyte adhesion, and promote vasodilation. These properties would be advantageous in treating IH. We used adenoviral mediated iNOS gene transfer in animal models of IH and showed dramatic reductions in IH using very low viral titers. The predominant actions of NO appear to be directed at SMC antiproliferation and EC growth. The efficacy of iNOS gene transfer has fueled an effort to develop this therapy for clinical applications. In this proposal, we will pursue three interrelated aims to further evaluate iNOS gene transfer. AIM 1: To determine the optimal conditions for therapeutic NOS gene transfer for the prevention of vascular injury induced IH. We will evaluate the impact of arginine and cofactor limitations on the efficacy of iNOS gene transfer. In addition, we will perform direct comparisons between the different NOS isoforms to see if any is NOS more efficacious. We will evaluate modified adenoviral vectors that target vascular cells for improving NOS gene delivery. AIM II: To evaluate the consequences of NOS gene therapy in a pi, model of atherosclerosis. Human vascular disease occurs in the setting of atherosclerosis. Therefore, this AIM will focus on studying the impact of hypercholesterolemia and atherosclerosis on iNOS gene transfer efficiency and efficacy. We will also determine if a longer duration of NO production will be required in the setting of atherosclerosis to inhibit IH by a recombinant adeno-associated virus. AIM III: To further characterize the molecular mechanisms of NO- mediated vasoprotection. In this AIM, we will characterize the mechanisms by which NO inhibits SMC proliferation and promotes EC growth, focusing on the role of G-proteins, mitogen-activated protein kinase pathways, and cyclooxygenase-2. At the completion of our studies, we will have the necessary
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information to develop NOS gene therapy as a safe and effective treatment for vascular IH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CATABOLISM AND EXCRETION OF CHOLESTEROL AND BILE ACIDS Principal Investigator & Institution: Loose-Mitchell, David S.; Integrative Biology and Pharmacology; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 31-AUG-2003 Summary: The goal of this proposal is to determine how two key pathways of bile acid biosynthesis are regulated by dietary cholesterol and to determine the mechanisms regulating the apical Na+ -dependent bile-acid transport protein (ASBP) in the ileum. This proposal combines approaches and animal models that have not been combined before to test some basic hypotheses regarding the metabolism and excretion of cholesterol. The proposal has the following goals: 1). To test the hypothesis that the two pathways of bile acid synthesis, the cholesterol 7alpha-hydroxylase pathway and the sterol 27-hydroxylase pathway, are regulated independently, and patterns of regulation depend on cholesterol responsiveness. This will be tested by three different approaches and will take advantage of a unique hypercholesterolemia-resistant rabbit developed at the University of Texas. The applicant proposes a longitudinal study using deuterated 7alpha hydroxycholesterol and 27-hydroxylated cholesterol as bile acid precursors. These studies will precisely measure rates of bile acid synthesis in vivo as animals are fed a hypercholesterolemic and then a hypocholesterolemic diet. The second component of this specific aim will assess rates of bile acid synthesis by the two pathways in an animal with a total bile acid diversion. The third component of this specific aim is directed a elucidating the mechanism through which these two pathways are regulated. The applicant will examine both steady-state rates of mRNA and use a novel transcription assay to assess how altered rates of enzyme biosynthesis is achieved in vivo. 2). To test the hypothesis that expression of ASBP is regulated by both transcriptional and posttranscriptional mechanisms. This will be tested both in normal and in the hypercholesterolemia-resistant rabbits and the applicant will examine levels in the activity, mRNA, and transcription of the transporter and determine if changes in mRNA are reflected in levels of ASBP protein and localization. In addition, the applicant will determine the functional consequences of ASBP allele found in the hypercholesterolemic rabbit. These studies will make a significant contribution to the understanding of the only routes by which significant cholesterol is removed from the body. In this respect the applicant anticipates that the results will impact upon the treatment of cardiovascular diseases well as having significance for fundamental biological questions of the control of cholesterol homeostasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CEREBRAL ATHEROSCLEROSIS
VASCULAR
EFFECTS
OF
DIABETES
AND
Principal Investigator & Institution: Heistad, Donald D.; Director; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: Diabetes is a major risk factor for stroke. Clinical evidence indicates that diabetes accelerates development of atherosclerosis, but mechanisms that account for this interaction are not clear. The investigators speculate that hypercholesterolemia may
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Hypercholesterolemia
exaggerate endothelial dysfunction through increased superoxide in vessels during hyperglycemia. The goal of this project is to examine pathophysiological interactions between hyperglycemia and hypercholesterolemia in carotid and intracranial cerebral arteries. It is likely that hyperglycemia will accelerate development of atherosclerosis in the carotid artery, but because diabetes is also a disease of small vessels, it will be particularly important to examine effects in the cerebral microcirculation. There are 3 major aims. First, studies are proposed to test the hypothesis that hypercholesterolemia augments generation of superoxide and endothelial dysfunction in carotid and cerebral arteries during hyperglycemia. Second, studies are planned to identify the contribution of endothelium, vascular muscle, and adventitia to superoxide in carotid and cerebral arteries during hyperglycemia and hypercholesterolemia. Third, studies are proposed to elucidate enzymatic mechanisms that account for cerebral vascular dysfunction. The investigators propose to test the hypothesis that vascular NADPH oxidase contributes to increased levels of superoxide and, therefore, vascular dysfunction during diabetes and hypercholesterolemia. Studies are planned in carotid and basilar artery of rabbits and mice in vitro, and in carotid artery and cerebral vessels in vivo. Endothelial vasomotor function will be examined, and superoxide in vessels will be studied with lucigenin chemiluminescence, and with laser confocal microscopy. Levels of superoxide dismutase (SOD) and superoxide in the vessel wall will be altered by pharmacological approaches, adenoviral mediated gene transfer of CuZnSOD to different layers of the vessel wall, with a newly made CuZnSOD transgenic mouse targeted to vascular smooth muscle, and with mice lacking functional NADPH oxidase. These studies may provide important insight about mechanisms which produce accelerated cerebral vascular dysfunction during diabetes and hypercholesterolemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: APOPTOSIS
CHARACTERIZATION
OF
OST-BASED
ACTIVATION
OF
Principal Investigator & Institution: Brewster, Jay L.; Natural Sciences; Pepperdine University 24255 Pacific Coast Hwy Malibu, Ca 90265 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant) The proper synthesis and processing of proteins is critical to normal cellular function. The endoplasmic reticulum (ER) is an organelle found in all higher organisms, whose central role in cell function is to mediate protein synthesis. Humans afflicted with abnormal protein processing in the ER and a related organelle, the Golgi body, suffer from devastating developmental abnormalities and comprise a broad category of disease known as Congenital Disorders of Glycosylation (CDGs). The key aspect of protein processing in the ER and Golgi is the addition of sugars to newly synthesized proteins, called glycosylation. This proposal seeks to characterize fundamental aspects of protein glycosylation, specifically how abnormal glycosylation influences the generation of signals within a cell. These signals are generated as a result of abnormal protein synthesis, which results in ER stress. The activation of ER stress can result in cell suicide (apoptosis), adaptation to the stress, growth arrest, or stimulation of localized inflammation. Our long-term goals focus upon how cells activate apoptosis following ER stress. This proposed project will allow characterization of the molecules that carry this stress signal, and examine how this cell suicide is executed. The improper processing of proteins in the ER and Golgi causes mutations in a variety of genes, and the type of disease that results from such mutations depends upon the identity of the mutated protein. Cystic fibrosis patients suffer lung degeneration that is the result of ER stress-activated signals as a membrane protein is
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improperly glycosylated, and one type of inherited hypercholesterolemia (high cholesterol) is the result of ER-associated processing deficiencies of a signal receptor. The characterization of ER stress and its signaling mechanisms will offer vital insight into the cell biology of stressed cells, and will be valuable to our understanding of diseases that result from abnormal ER function/processing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHOLESTEROL AND AMYLOIDOGENESIS Principal Investigator & Institution: Pappolla, Miguel A.; Professor; Pathology; University of South Alabama Mobile, Al 366880002 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-JAN-2004 Summary: (provided by applicant): Recent studies have shown that increased levels of Ab peptides are among the earliest detectable abnormalities in Alzheimer's disease and may mediate a chain of downstream events leading to neuronal degeneration and cognitive decline. There is increasing evidence from clinical, epidemiological and laboratory studies that cholesterol plays a role in the pathogenesis of Alzheimer's disease. This body of evidence includes in vitro studies indicating that cellular cholesterol levels modulate Ab production and the enzymatic processing of APP, animal studies demonstrating that cholesterol levels modulate Ab accumulation in the brain (preliminary data) and several observational, clinical studies suggesting that the prevalence and incidence of probable Alzheimer's disease was significantly lower in patients taking cholesterol-lowering drugs. Taken together the studies support the hypothesis that Alzheimer's disease may be a disease in which cholesterol homeostasis is altered and that cholesterol may participate in a chain of events that modulate the disease neuropathology. The application proposes to test the following hypotheses: 1that in the human brain increased cholesterol content contributes to amyloid accumulation by changing APP processing in a more amyloidogenic manner. 2-that there are correlative interactions between levels of apoE expression, cholesterolemia and amyloid pathology. 3-that certain apoE promoter polymorphisms act in concert with cholesterol levels influencing the extent of apoE expression and amyloid accumulation. Preliminary and recently published data from our laboratory suggest that cholesterol content in plasma and brain of Alzheimer's transgenic mice is strongly correlated with rate of development of amyloid pathology and with apoE expression. These hypotheses are amenable to testing as outlined in the corresponding sections of the proposal and their study will advance our understanding of the pathogenesis of Alzheimer's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORE--TRANSGENIC MOUSE Principal Investigator & Institution: Sigmund, Curt D.; Professor; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: The overall goal of this program is to define mechanisms that regulate cerebral blood vessels under normal and pathophysiological conditions. The program has successfully integrated emer4ging molecular techniques with more traditional physiological approaches to examine mechanisms that regulate structure and function of the cerebral circulation under normal and pathophysiological conditions. This evolution within the program continues with this renewal as new approaches and investigators continue to be incorporated. The program has several well-defined themes: First, protective mechanisms [nitric oxide, superoxide dismutase (SOD)], and
16
Hypercholesterolemia
peroxisome proliferator activated receptor (PPAR) in cerebral blood vessels. Second, sources of superoxide within the vessel wall [NAD(P)H oxidase and cyclooxygenase (COX)] and the role of the major cell types-endothelium, smooth muscle, and adventita. Third, pathophysiology and risk factors for cerebral vascular disease and stroke. Modern molecular and mechanistic approaches are used to examine effects of chronic hypertension, diabetes, hypercholesterolemia, hyperhomocysteinemia, and inflammation on cerebral vascular structure and function. The Program has several strengths. First, the investigators have a long, productive history of studies of cerebral circulation under physiological and pathophysiological conditions. Second, strong new investigators with key expertise have been integrated into the program. Third, the investigators use diverse, cutting edge approaches altered mice and viral mediated gene transfer, were successfully incorporated during the last funding period and continue to be used heavily. Fourth, the investigators are leaders in several areas of study of the cerebral circulation (endothelial cell biology, nitric oxide, potassium channels, vascular structure) as well as leaders in studies of the impact of cardiovascular risk factors on cerebral vascular biology. The program consists of four projects supported by two core facilities: Administration and Transgenic Animal Core. This integrated, multidisciplinary approach is intended to facilitate, rapid progress, and more penetrating insight, in understanding mechanisms that regulate cerebral vascular structure and function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORONARY VASA VASORUM - ROLE OF 3D BRANCHING GEOMETRY Principal Investigator & Institution: Ritman, Erik L.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (Verbatim from the Applicant's Abstract): This resubmission consists of a chronological sequence of three overlapping aims which test the overall hypothesis that the vasa vasorum play an important role in the initiation of coronary atherogenesis (i.e., prior to cellular invasion and/or proliferation) by virtue of disturbed solute transport via the vasa vasorum This, in turn, is due to the perfusion pressure in their distal vasa vasorum lumens being less than the compression in the arterial wall. Our approach is to quantitatively describe detailed branching geometry and solute transport of the vasa vasorum of coronary arteries, primarily by use of micro-CT-based imaging methods. This will involve analysis of coronary arteries of normal pigs, a porcine (diet-induced) model of hypercholesterolemia and a porcine (renal artery stent) model of arterial hypertension (both being risk factors for atherogenesis). AIM I is for the initial development and integration of the various techniques we propose to use throughout the proposal and to establish the normal state. AIM II applies the developments in Aim I to hypercholesterlemic and to hypertensive pigs' coronary artery walls so as to relate the response of the vasa vasorum to these pathological conditions. AIM III builds on Aim II in that we will combine the hypercholesterolemia and hypertension to see if they are linearly additive in effect, as would be predicted by our hypothesis. The primary objective is to relate the transport capacity of vasa vasorum to the spatial density of coronary artery vasa vasorum and the fluid dynamic implications of both the 3D branching geometry of the vasa vasorum and the spatial distribution of compressive stresses within the coronary artenal wall. The significance of this proposal is that if the hypothesis of this study is supported, it should give insight into several puzzling observations. One is that atherosclerosis does not generally form in veins (which have
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vasa vasorum) or in small arteries (which have no vasa vasorum). Equally intriguing is the observation that early atherosclerosis does not form in the outer media or adventitia even though vasa vasorum provide a sizable endothelial surface (which presumably also becomes dysfunctional) in the outer media and adventitia. Another observation is that artenes whose adventitia are manipulated and veins, which are subjected to arterial pressure or surgically manipulated, do develop atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CUTANEOUS GENE TRANSFER FOR SYSTEMIC DELIVERY Principal Investigator & Institution: Taichman, Lorne B.; Professor; Oral Biology and Pathology; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2002; Project Start 01-MAY-1979; Project End 31-JAN-2005 Summary: ( Investigator's abstract): The goal of this research is to develop a gene-based therapy for metabolic deficiency disorders using cutaneous cells as a vehicle for systemic delivery. New genetic material would be introduced into epidermal keratinocytes and dermal fibroblasts to create a cutaneous source of secreted protein. For example, the hypercholesterolemia and atherosclerosis of type III hyperlipoproteinemia may be ameliorated by creation of a cutaneous source of apolipoprotein E3 (apoE). The question posed here is, can sufficient protein be produced and delivered to the circulation to ameliorate such a disorder? To date, the Principal Investigator has made substantial progress in development of methods for ex vivo and in vivo gene transfer, using retrovirus vectors in analysis of the secretory capacity of fibroblasts and keratinocytes, and in creating culture and animal models for quantitative analysis and efficacy testing. The Principal Investigator has succeeded in transducing keratinocyte stem cells through ex vivo and in vivo approaches and has demonstrated long term (10 month) reporter gene expression in animal models. In this revised application three specific aims are proposed. In Aim 1, studies are proposed to optimize systemic replacement therapy through ex vivo gene transfer. First a system that allows repeated monitoring of secreted protein in the same animal will be developed and then that system will be used to develop predictive in vitro tests, to examine dermal versus epidermal delivery, and to gauge if lymphatic uptake is rate limiting. As proof of principal, two animal models will be used, one involving apoE-deficient mice and the other involving diabetic rats. In Aim 2, the methods for in vivo transduction of mouse skin will be optimized. Specifically the use of lentivirus vectors to transduce slowly cycling stem cells in skin and application of a topical selective agent to augment the number of transduced cells in the tissue will be used. To control transgene expression in vivo, Aim 3 will involve construction of two retroviral vectors, one to permit transgene induction with topically applied inducers and the other to evade potential modulating effects of host cytokines. These studies probe the interface between cutaneous biology and corrective gene transfer and will provide a foundation for future clinical cutaneous gene therapy trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DETERMINANTS OF CLATHRIN STRUCTURE AND FUNCTION Principal Investigator & Institution: Ybe, Joel A.; Biology; Indiana University Bloomington P.O. Box 1847 Bloomington, in 47402 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Clathrin coated vesicles (CCVs) carry out receptormediated endocytosis (RME) at the plasma membrane, where they drive the uptake of
18
Hypercholesterolemia
receptor bound nutrients, hormones and proteins targeted for degradation. Clathrin is shaped like a "three-legged" pinwheel to fit its function of forming honeycomb lattices around transport vesicles. The long-term goal of this proposal is to define and validate productive atomic contacts between lattice-bound clathrin molecules to elucidate the fundamental principles of how clathrin function is regulated in cells. The first specific aim is to determine the crystal structure of the clathrin trimerization domain, where the three filamentous legs meet, to complete the atomic level reconstruction of the entire clathrin molecule. Trimerization domain crystals are highly ordered, diffracting between 1.7-2.3 A at Argonne and at the Advanced Light Source. Selenomethionine crystals have been prepared to solve the phasing problem by MAD analysis, while heavy metal replacement and "cryo-halide" soaking methods are being performed as alternative phasing strategies. The X-ray model of trimerization domain will then be docked into the 21 A cryo-EM image of the clathrin barrel (with Barbara Pearse, Corrine Smith and Alan Roseman) to identify productive molecular contacts between the trimerization domain and segments of other clathrin molecules in the lattice. Revealed interactions will be tested biochemically and validated in living cells. The second aim is to explore how cysteines in the trimerization domain stabilize this structure by using structural information from Aim 1 to design mutants to test specific linkages. The third aim explores whether there is a relationship between the cysteines in the trimerization domain and those in light chain subunit to understand why these two groups of cysteines impact regulation of clathrin assembly. The experimental approach is to determine whether light chains can confer structural stability to trimerization domain constructs weakened by mutations made in Aim 2. The final aim of this proposal is to test the possibility that light chain control of lattice formation might involve the transfer of the light chain EED Ph switch between an "active" and "inactive" position on the proximal domain of clathrin. The approach is to use light chain fragments and molecule mimics to ferret out these putative sites and to use X-ray crystallography to try to capture the orientation of light chain fragments bound to the proximal region. Understanding the structural basis for clathrin function is central to defining the role of RME malfunction in hypercholesterolemia and heart disease, as well as understanding the mechanism of virus infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIET, HYPERLIPIDEMIA
ENDOTHELIAL
FUNCTION
AND
PEDIATRIC
Principal Investigator & Institution: Engler, Marguerite M.; Physiological Nursing; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-DEC-2004 Summary: Coronary heart disease (CHD) remains the leading cause of death in the United States. The pathogenesis of atherosclerosis and CHD is thought to be initiated by endothelial dysfunction or injury. Factors that contribute to oxidative stress such as elevated cholesterol-rich low density and very low-density lipoproteins (LDL and VLDL) result in endothelial dysfunction. The long term goal of this proposal is to develop dietary interventions for the prevention and treatment of endothelial dysfunction in children and adolescents who are at high risk for premature CHD due to the genetic lipid disorders of familial hypercholesterolemia (FH) or familial combined hyperlipidemia (FCH). This experimental, randomized, double blind crossover, placebocontrolled clinical trial will include 96 hyperlipidemic children and adolescents aged 10 to 18 years who will receive dietary supplements and an intensive dietary educational program. The following hypothesis will be evaluated: Specific nutrients in the diet will
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have direct beneficial vascular effects and/or indirect effects on lipoprotein composition which will in turn decrease the oxidation of LDL and the level of vascular oxidative stress, thereby improving endothelial function. The primary specific aims are: 1) to determine whether a National Cholesterol Education Program (NCEP) Step II diet alone or together with one of four putative vasculoprotective supplements (Vitamins C & E, w-3 fatty acids, L-arginine, folic acid) will improve endothelial function in children and adolescents with FH and FCH, and 2) to evaluate the effects of these supplements on plasma lipoprotein profiles, LDL composition, lipoprotein-associated antioxidant enzymes (paraoxonase and platelet activating factor acetyl hydrolase), indices of oxidative stress (oxidized LDL, 8-hydroxy-2'-deoxyguanosine), immune function (inflammatory cytokines, plasma adhesion molecules), and blood pressure. Vascular reactivity, a sensitive indicator of endothelial function, will be measured noninvasively using high-resolution external vascular ultrasound of the brachial artery. The secondary aims are: 1) to examine children and adolescents psychological well being, beliefs and feelings about their cardiovascular status and its relation to health outcomes, and 2) To explore their practices and health risk behaviors specifically in the area of dietary adherence. These studies will provide important insight into the mechanism of endothelial dysfunction and should serve to identify potential treatments for pediatric hyperlipidemia. Preventive nursing strategies aimed at early detection of endothelial dysfunction and dietary modification may restore endothelial function in children and adolescents at high risk for CHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DYNAMICS OF FLOW-DEPENDENT ARTERIAL PERMEABILITY Principal Investigator & Institution: Friedman, Morton H.; Professor; Biomedical Engineering; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-APR-1994; Project End 31-MAR-2004 Summary: The overall objective of this research is to understand the factors affecting the transendothelial entry of macromolecules into the arterial wall, and particularly the mediation of this process by local hemodynamics. The interest in macromolecular transport is prompted by its importance in the genesis and development of artherosclerosis. The mediation of arterial uptake by hemodynamic factors is of particular interest because the distribution of atherosclerotic lesions suggests that hemodynamic factors may be involved in the localization of the disease; furthermore, there is evidence that hemodynamic stress can influence endothelial permeability. A primary hypothesis of this research is that an important fraction of the transendothelial flux occurs during increases in permeability prompted by changes in flow; accordingly, particular emphasis is placed on the dynamic response of the barrier function of the endothelial lining to changes in the hemodynamic environment. The research objectives are addressed through a unique combination of animal experiments, computer simulation and cell and molecular biology. The spatial variation of the albumin permeability in the eternal iliac arteries of swine, either at baseline or subsequent to interventions that alter flow, will be obtained using photographic densitometry of Evans Blue dye to measure albumin uptake. The alterations in flow will be produced by reversible, adjustable femoral arteriovenous shunts. The distribution of wall shear stress, and of the changes in stress caused by manipulating the shunt, in the iliac vessels will be obtained from validated fluid dynamic computations in regions derived from injection casts of the arteries and the proximal vasculature; the dependence of albumin uptake on hemodynamic stress, and alterations in stress, will be assessed and modeled. In a separate set of animals, casting material will not be injected, and tissue from the region
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Hypercholesterolemia
of interested will be fixed or explanted and cultured, and a variety of techniques will be used to relate the variations in permeability to cellular properties. Of particular interest are properties that mediate the redox state of the cell, the integrity of the cytoskeleton, and its junctions with neighboring cells and adhesion to the substratum. The effects of hypercholesterolemia on vascular permeability and its dynamic response to changes in flow will be examined as well, to determine whether high lipid levels potential the effects of flow changes on vascular uptake. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFECT OF LIPIDS ON VASCULAR GRAFT HEALING Principal Investigator & Institution: Graham, Linda M.; Professor; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: (Adapted from Applicant's Abstract): Prosthetic grafts are used widely in vascular reconstructive surgery, but their long-term patency is limited, perhaps due to altered cell function caused by oxidized low density lipoprotein (oxLDL). In preliminary studies they have shown that: 1) graft material stimulates monocytic cells to oxidize LDL in vitro, 2) this oxLDL inhibits endothelial cell (EC) migration in vivo. This contributes to the prolonged thrombogenicity and eventual failure of these grafts. The goal of this project is to determine the effect of lipids, especially oxidized lipids, on EC migration on prosthetic grafts. To test their hypothesis, the effect of oxidized lipids on EC migration and the mechanism by which oxLDL inhibits EC migration will be studied. The investigators will first investigate the role of reactive oxygen species (ROS) in oxLDL's inhibition of EC migration. They will characterize the effect of oxLDL on superoxide production by EC, assessing the effect of ROS on EC migration, and determining the ability of antioxidants to restore EC migration in the presence of oxLDL. Since ROS alter membrane fluidity and changes in fluidity affect migration, they will investigate the effect of oxLDL on EC membrane fluidity. They will also evaluate the ability of vitamin E and other antioxidants to prevent changes in membrane fluidity and preserve EC migration. The effect of oxLDL on EC migration on ePTFE graft material in vitro will be studied, and the ability of vitamin E or superoxide dismutase to restore migration determined. Finally, they will study the effect of hypercholesterolemia on EC ingrowth onto prosthetic grafts implanted in rabbits, and assess the ability of vitamin E to preserve endothelial migration. The proposed studies will investigate the role of lipids and lipoproteins, and their oxidatively modified derivatives, in the failure of synthetic vascular grafts to endothelialize. Studies will also address the efficacy of treatment with dietary antioxidants to control lipid oxidation and promote graft healing. This will lead to a better understanding of the role of lipids in the pathophysiology of graft failure. Ultimately, this may lead to methods to promote endothelialization of prosthetic grafts and prolong patency of small-diameter vascular grafts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENDOTHELIAL PROGENITOR CELL GENE TRANSFER Principal Investigator & Institution: Asahara, Takayuki; Assistant Professor; St. Elizabeth's Medical Center of Boston 736 Cambridge St Boston, Ma 02135 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: Previous studies from our laboratory and others' have established that bone marrow-derived endothelial progenitor cells (EPCs) are present in the systemic
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circulation, are augmented in response to certain cytokines and/or tissue ischemia, and home to sites of neovascularization. More recently, EPCs have been investigated as therapeutic agents to successfully enhance neovascularization. Just as classical angiogenesis may be impaired in certain pathologic phenotypes, however, ageing, diabetes, hypercholesterolemia, and hyperhomocysteinemia may likewise impair EPC function, including mobilization from the bone marrow and/or incorporation into neovascular foci. Gene transfer of EPCs during ex vivo expansion constitutes a potential means of addressing such putative liabilities in EPC function. Moreover, phenotypic modulation of EPCs during ex vivo expansion constitutes a potential means of addressing such putative liabilities in EPC function. Moreover, phenotypic modulation of EPCs ex vivo may also reduce the number of EPCs required for optimal transplantation post- ex vivo expansion, and thus serve to address a practical limitation of EPC transplantation post-ex vivo expansion, and thus serve to address a practical limitation of EPC transplantation, namely the volume of blood required to extract an optimal number of EPCs for autologous transplantation. The experiments outlined in this Proposal will investigate the thesis that gene transfer can be employed to achieve phenotypic modulation of EPCs. The Proposal has three specific aims. First, we will perform in vitro assays, as well as in vivo experiments in animal models of tissue ischemia, to optimize the methodology and effectiveness for EPC gene transfer of angiogenic growth factors. Second, we will investigate the role of the serine-threonine protein kinase, Akt (also known as protein kinase beta), in the biological activation of EPCs, using gene transfer strategies involved constitutively active and dominant negative forms of Akt. Third, we will investigate the impact of telomerase reverse transcriptase (TERT) gene transfer on EPC function and survival, in vitro and in vivo. We anticipate that the results of these experiments will yield new insights regarding both the fundamental biology as well as therapeutic applications of EPCs for postnatal neovascularization. If we are successful, these results will resolve certain issues sufficiently to permit translation to clinical studies, and provide new questions that will stimulate additional inquiries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENHANCED LINKAGE MAPS FROM FAMILY-BASED GENETICS STUDIES Principal Investigator & Institution: Matise, Tara C.; Associate Research Professor; Biology; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Meiotic linkage maps are the foundation of both linkage and linkage disequilibrium studies for mapping disease genes. Despite the importance of precise maps, existing genome-wide linkage maps were built using only a small collection of pedigrees, and so have wide confidence intervals surrounding estimates of map distance. Incorrect marker order and map distances can have a profound effect on linkage analyses. Using a sex-averaged map instead of a sex-specific map biases the lod scores upward, markedly increasing the false positive rate. Since it is very costly to follow-up many false-positive results, there is a clear need for more precise and accurate sex-specific genetic maps. Accurate estimates of meiotic map distance cannot be obtained by any means other than by linkage analysis using genotype data. We propose to build improved highly-precise sex-specific linkage maps utilizing thousands of individuals who have previously been genotyped. After filtering out obvious relationship and genotype errors, we will incorporate methods that properly model for genotyping errors. In addition to creating precise maps for the
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scientific community, we also propose to use these genotype data to study how recombination may vary between ethnic groups. The genotypes generated by the NHLBI Mammalian Genotyping Service are precisely the type of data required to produce more accurate maps. These data collections contain over 3,400 pedigrees with more than a 1 00-fold increase in information compared to that contained in the 8 CEPH families that have been used to construct current genome-wide linkage maps. Our new maps will be made publicly available and the genotype data from our study will be accessible by the MAP-0-MAT linkage mapping server. In the future, we anticipate broadening our study to incorporate genotype data from additional genotyping centers such as the Center for Inherited Disease Research (CIDR). The inaccuracies present in current maps can contribute to misleading results, and may be one of the reasons that disappointingly few genes have been definitively identified that contribute to such complex diseases as asthma, cardiovascular disease, hypertension, hypercholesterolemia, diabetes, obesity, and cancer. The more precise maps that we propose to construct will improve the power and value of many ongoing and new disease studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FETAL DETERMINANTS OF ATHEROSCLEROSIS Principal Investigator & Institution: Palinski, Wulf; Professor of Medicine; Medicine; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): We previously showed that atherogenesis already begins during fetal development and that maternal hypercholesterolemia during pregnancy is associated with enhanced fatty streak formation in fetuses and a much faster progression of atherosclerosis in normocholesterolemic children that could not be explained by conventional risk factors. Although in humans inherited genetic differences are likely to contribute, we hypothesize that maternal hypercholesterolemia per se induces pathogenic events in fetal arteries that determine their later susceptibility to atherosclerosis. We also hypothesize that oxidative stress caused by maternal hypercholesterolemia leads to persistent changes in the expression of genes modulating atherogenesis. An important corollary is that cholesterol lowering and antioxidant interventions in mothers during pregnancy may provide long-lasting benefits to their offspring. Using genetically homogeneous animal models, we recently provided direct evidence for the causal role of maternal hypercholesterolemia and oxidative stress in both enhanced fetal lesion formation and accelerated post-natal atherogenesis. We also provided proof in principle for persistent regulation of gene expression in the arterial wall. We now propose to better define the in utero programming associated with maternal hypercholesterolemia, to identify genes influencing post-natal susceptibility to atherosclerosis, and to investigate whether interventions during pregnancy also decrease the susceptibility in offspring of "normocholesterolemic" mothers. Different levels of maternal hypercholesterolemia and antioxidant protection will be achieved by transferring embryos of LDL receptor deficient (LDLR-/-) mice into treated or untreated C57BL/6, LDLR -/- or apoE -/- mice. Offspring will be subjected to post-natal atherogenic conditions and lesion formation followed over time. Laser-capture microdissection, gene microarray and PCR techniques will be used to determine persistence of gene regulation and its correlation with atherosclerosis, immunocytochemical presence of gene products and measurements of oxidative stress. These studies should yield fundamentally new insights into in utero programming and atherogenic mechanisms, and may establish a novel preventive approach.
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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 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
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Project Title: GENES CAUSING SPONTANEOUS OBESITY Principal Investigator & Institution: Warden, Craig H.; Associate Professor; Pediatrics; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAY-2003 Summary: The long-term goal of this research is to investigate the mechanisms of spontaneous obesity in mice. Previous work has identified 4 chromosomal regions
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(mouse chr. 6,7,12,and 15) or loci (QTLs) that contribute to obesity in spontaneously obese BSB mice. BSB mice were produced by a backcross of (Mus spretus x C57BL/6J) F1 x B6. Preliminary data on an available congenic mouse strains confirm that the locus on chr. 7 affects adiposity. The objective of this present proposal is to identify the genes underlying these obesity loci. Congenic mouse strains carrying the spretus chromosomal regions as donor DNA on the B6 background will be created. As co-incident QTLs for obesity, plasma cholesterol and hepatic lipase (HL) activity on mouse chr. 7 were found, the already constructed B6 HL knockout will used to test the hypothesis that alterations of HL activity determine these cholesterol and/obesity loci. BSB backcrosses with the HL KO B6 mouse will yield animals both homozygous and heterozygous for the HL knock-out. QTLs at chromosome 7; will be compared and contrasted in these two groups. The mouse chr. 6,7, and 1 loci include within their 90 percent confidence intervals, respectively, the obese, tubby, and uncoupling protein 2-genes. Molecular and biochemical studies of these candidate genes will be performed to test whether differences are likely to explain the observed effect on the trait. If there are differences in the coding portion of the spretus and B6 leptin, then the biological consequence of the differences will be tested. The chromosome 6 locus was linked to just one of the four fat pads measured in BSB mice. Leptin mRNA levels in the four fat pads will be determined to examine their correlations with plasma leptin and fat pad sizes. They have already found that spretus and B6 UCP2 differ for 2 amino acids, so uncoupling activity of UCP2 from these strains will be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC AND BIOMEDICAL STUDIES OF SITOSTEROLEMIA Principal Investigator & Institution: Patel, Shailendra B.; Professor; Medicine; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: Heart disease remains the major cause of death and morbidity in the US. Reduction in the risk factors for heart disease remains a priority for Healthy People 2000. One of these risk factors is cholesterol. Understanding the factors that normally regulate net dietary cholesterol intake may allow us to reduce the impact of this risk factor. One such factor may the gene that is responsible for causing the autosomal recessive disease, sitosterolemia (OMIM 210250). The purpose of this study is to identify, map, and clone and characterize the biology of this gene. This gene is hypothesized to play a key role in regulating the absorption of cholesterol from the diet and its excretion from the body via the bile. Sitosterolemia is characterized by a marked elevation of plant sterols in the blood, resulting in tendon xanthomas, premature coronary artery disease and death. Knowledge of the genetic mechanisms underlying these biological processes may allow us to explore ways to manipulate cholesterol absorption and excretion through the activities of this gene product and thus control plasma cholesterol levels. 27 well-characterized family pedigrees have been assembled, providing considerable power to map and localize of the gene defect. Following the exclusion of a number of candidate genes, a genome-wide scan has been performed. The gene has been mapped to chromosome 2p21, with a maximum lodscore of 4.6. Fine mapping and haplotype analyses has narrowed the sitosterolemia locus to within a region approximately 2 cM in size. Additional families will be recruited and analyzed for evidence of recombination within this region to help further narrow this critical region. Once a suitably narrow region has been defined, cDNAs mapping to this region will be identified and used as candidate genes to allow us to identify the defective gene. The identification of this gene defect will not only allow characterization of the
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mutations that cause sitosterolemia, but will also provide the basis for in vitro expression studies to define some of this gene's normal functions in sterol absorption and excretion. This knowledge will allow us to test the hypothesis that the normal function of this gene product is to tightly regulate net dietary cholesterol absorption. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENOMIC RESOURCE DEVELOPMENT IN THE LABORATORY OPOSSUM Principal Investigator & Institution: Samollow, Paul B.; Southwest Foundation for Biomedical Res San Antonio, Tx 782450549 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: (Adapted from the applicant's abstract): The gray-short-tailed opossum, M. domestica, has been established as a model organism for comparative biomedical research on a broad range of topics that are relevant to human development, physiology, and disease susceptibility. However, a lack of basic information on fundamental genetic characteristics limits its potential for inquiries involving the genetic regulation of normal developmental and physiologic processes, and the influences of genetic variation on health-related physiologic characteristics. To mitigate this situation, a map of the M. domestica genome will be constructed that can be used to detect, map, and ultimately isolate and clone genes that influence normal and abnormal phenotypic variation. The overall objectives are to construct a linkage map of 200 or more polymorphic marker loci, to use physical mapping studies to anchor the linkage map on the physical genome, and to use the map to determine the locations of one or more genes that influence variable responsiveness of dietary cholesterol and fat. The Specific Aims are to: 1) expand the number of anonymous and functional gene markers on the existing, sparsely-filled linkage map through continuing linkage studies utilizing an existing backcross mapping panel; 2) complete a 5 cM linkage map by creating, and utilizing for mapping, a new backcross mapping panel designed to maximize opportunities for the detection and mapping of polymorphisms at functional gene loci; 3) develop a physical map showing the locations and orientations of known linkage groups on M. domestica chromosomes; and 4) detect and map one or more of the genes responsible for highly heritable variation in diet-induced hypercholesterolemic responsiveness that occurs in this species. The linkage map, comprised of polymorphic genetic marker loci including anonymous micosatellite loci and functional genes, will be developed by analysis of intergenic recombination rates determined from genotype analyses of offspring from two large backcross family panels. Fluorescence in situ hybridization (FISH) will be used to locate the physical positions of the known linkage groups on individual chromosomes. Parametric LOD-score linkage analyses and pedigree based variance components methods will be used to seek linkage between marker genes on the linkage map and genes that influence plasma lipoprotein phenotypes in a family panel that has been subjected to a dietary challenge regimen. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GUTLESS VECTOR MEDIATED HYPERLIPIDEMIA AND ATHEROSCLEROSIS
GENE
THERAPY
OF
Principal Investigator & Institution: Chan, Lawrence; Professor of Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2003
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Summary: The overall objective of this project is to develop gutless adenovirus vectors for use in experimental animals, to determine the best protocol for prolonged expression following delivery in vivo, and to use these vectors to express low density lipoprotein receptor (LDLR) and very low density lipoprotein receptor (VLDLR) in animal models of familial hypercholesterolemia (FH). The specific aims are (i) We will examine the effect of long-term expression of VLDLR and LDLR in transgenic mice with an LDLR -/background using an inducible binary transactivation system. This system was developed by investigators in Project 3. Different levels of expression of the transgene can be accomplished by graded subphysiological doses of an exogenous compound RU486. (ii) We will develop gutless adenovirus vectors expressing reporter genes (e.g. alpha1- antitrypsin), VLDLR and LDLR which will be tested in mice and rhesus monkeys. (iii) We will develop a protocol for the repeated administration of gutless vectors to mice and rhesus monkeys. Transient immunosuppression protocols and vectors of different serotypes will be tested. (iv) We will test and compare the gutless vectors expressing mouse LDLR and VLDLR in LDLR -/- mice for their efficacy in reversing the hypercholesterolemia and their general health effects, and the extent of aortic atherosclerosis. (v) We will examine the effect of hepatic transfer of the rhesus LDLR and VLDLR genes in heterozygous and possibly homozygous LDLR-deficient rhesus monkeys. This project interacts closely with Project 2 for the gutless vector development, and Project 3 for the regulated expression system. It will be supported by the scientific Cores A (Primate Core), B (Vector Production Core) and C (Pathology Core). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNOBIOLOGY OF APOLIPOPROTEIN E Principal Investigator & Institution: Curtiss, Linda K.; Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 01-DEC-1988; Project End 31-MAR-2003 Summary: Coronary artery disease, the major manifestation of atherosclerosis, is the leading cause of death in the Western world. In spite of this striking impact, the pathogenesis of atherosclerosis is till poorly understood. Controversy exists regarding the participation of innate immunity involving macrophages. (Mphi) and natural killer (NK) cells versus antigen-specific acquired immunity involving lymphocytes. Mphi predominate in atherosclerotic lesions. NK cells, although smaller in number a present as well. Furthermore the T lymphocytes that participate in acquired immunity are frequently observed in lesions and have been demonstrated to modulate lesion progression. This proposal will address directly the participation of the innate inflammatory and acquired immune responses in vivo. To demonstrate the participation of NK cells in atherosclerosis resulting from moderate as well as profound hypercholesterolemia, we will combine the use of well characterized mouse models of atherosclerosis with inbred strains of mice that are deficient in T and B cell and / or NK cell function. Our first aim is to detail the frequency and the kinetics of NK cell and T cell localization within lesions of apolipoprotein E-deficient (apo E -/-) and low density lipoprotein receptor-deficient (LDL-R-/-) mice with both moderate and severe hypercholesterolemia. This aim will determine the degree to which NK cells and T lymphocytes influence the progression of ahteroma and reveal whether T and NK cell cytokine expression are responsible for the characteristic pathology of the disease. Because the participation of NK cells will be examined in both immune-competent as well as severely immune-deficient animals, these studies will provide valuable information on the participation of NK cells will be examined in both immune-
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competent as well as severely immune-deficient animals, these studies will provide valuable information on the participation of both innate and acquired immune responses in atherosclerosis. Our second aim will identify if NK cell and T lymphocyte function within atherosclerotic lesions are influenced by locally produced Mphi apo E. WE have determined that macrophage-derived apo E plays a protective role within the lesions o LDL-r-/- mice and this aim will reveal if regulation of NK cell and/or T cell function is a mechanism by which apo E bestows this protection. The successful completion of these studies will provide critical data about the role of T cells and/or NK cells in arherosclerosis that will aid in the development of new treatment strategies to alter the course of atherosclerosis in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INFLAMMATION IN VEIN GRAFT DISEASE: A GENETIC APPROACH Principal Investigator & Institution: Peppel, Karsten C.; Medicine; Duke University Durham, Nc 27710 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 31-MAY-2008 Summary: (provided by applicant): Aortocoronary vein graft atherosclerosis afflicts over two million Americans. While it shares many features with atherosclerosis of native arteries, vein graft atherosclerosis progresses considerably more rapidly. Inasmuch as atherosclerosis is a chronic inflammatory disorder, inflammatory cytokines such as Tumor Necrosis Factor alpha (TNFalpha) might contribute to vascular lesion development. Preliminary studies demonstrate a strong proatherogenic activity of TNF on vascular smooth muscle cells (SMCs) in vitro. Our Central Hypothesis is that TNF contributes substantially to vein graft failure in vivo. While both activated macrophages and SMCs can produce TNF, the contribution of this cytokine to vein graft disease, and the cellular and molecular mechanisms by which TNF may accentuate vein graft atherosclerosis, are incompletely understood. To study these issues, we recently developed a new murine vein graft model that uses congenic inferior vena cavae to carotid artery interposition grafts. As a result, we can manipulate the genetic background of the vein graft wall independently from that of the recipient's circulating cells. Our preliminary studies show a significant reduction (40%) of vein graft neointima formation in grafts that are deficient in TNF receptor 1 signaling (TNFR1-/-), when placed into normolipidemic TNFR1-/- recipients. Our first aim is to determine the role of TNFalpha in vein graft atherosclerosis under normal and hyperlipidemic conditions in vivo. To achieve this aim, we will use wild type (C57Bl/6) or congenic apolipoprotein E deficient (ApoE-/-) mice as pro-atherogenic recipients of congenic vein grafts. The vein grafts will be derived from either wild type or TNF receptor-1-deficient (TNFR1-/-) mice. All of the recipient mice will also express the beta-galactosidase marker gene (from the Rosa 26 mouse strain) to allow for evaluation of vein graft infiltration by recipient-derived cells. Our second aim is to assess the potential for a recombinant TNF Inhibitor to attenuate vein graft neointima formation in mice with normal or elevated lipid levels. This will be achieved by examining vein graft remodeling in wild-type or ApoE-/- mice, that have been infected with a recombinant adenovirus expressing a p55TNFR1-IgG fusion protein that we have created. Defining cellular mechanisms by which TNF promotes vein graft atherosclerosis may have therapeutic implications for the many patients with vein graft disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INFLUENCE OF DIETARY FLAVONOIDS ON THE EXPRESSION OF AT* Principal Investigator & Institution: Keen, Carl L.; Professor and Chairman; Nutrition; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200 Timing: Fiscal Year 2002; Project Start 15-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant) Oxidative stress is characterized by excessive concentrations of reactive oxygen and reactive nitrogen species (ROS and RNS). Excessive oxidative damage has been implicated in the pathogenesis of numerous degenerative diseases including coronary vascular diseases (CVD). A current hypothesis suggests that ROS, RNS and oxidized LDL (ox-LDL) induce the expression of atherogenic genes via redox-sensitive signaling pathways. The oxidative stress-induced gene expression has been shown to be mediated via the activation of redox sensitive transcription factors such as nuclear factor- kappaBeta (NFkB), and redox-sensitive transduction pathways such as those involving members of the mitogen activated protein kinase (MAPK) family as well as members of the Src family. Genes regulated by NFkB activation encode for proteins implicated in acute phase and inflammatory responses including certain cytokines and chemokines, cell adhesion molecules and inflammatory enzymes; several of these molecules are involved in the pathogenesis of atherosclerosis. Similarly, studies have shown that JNK, BMK-1 and cSrc are involved in signaling events stimulated by ROS that contribute to atherosclerosis such as smooth muscle cell proliferation. It is well known that diet plays a important role in a large number of chronic diseases. The investigators suggest that this is due in part to an effect of diet on a individual's antioxidant status. Vitamins and minerals contribute to the oxidative defense system because: (1) they are antioxidants (vitamins E, C and Bcarotene); (2) they are essential for the function of enzyme antioxidants (Zn, Cu, Fe, Mn, Se and riboflavin); or (3) they act to maintain low levels of potentially pro-oxidant molecules (vitamins B12, B6 and folate). On the other hand, the cardio-protective effects of flavonoids result in part from their antioxidant properties, and their ability to modulate the activity of a wide spectrum of enzymes. The researchers propose to investigate the hypothesis that diet may influence vascular redox-mediated signaling and transcriptional activities. Using the mouse model, they will test the hypothesis that a diet marginal in select micronutrients will induce a pro-oxidative state that will worsen the pathophysiological state of atherosclerosis. Finally, they will test the hypothesis that addition of flavonoids to diets marginal in antioxidants will attenuate the atherogenic effect of the pro-oxidative effect of micronutrient deficiency and hypercholesterolemia. These issues will be addressed using mutant mice in which the LDL receptor (LDLr) has been inactivated. The researchers will measure the progression of atherosclerosis in LDLr +/+ and -/- mice fed a high fat-micronutrient adequate diet, or a high fat-micronutrient marginal diet, supplemented or not with the flavonoids, quercetin and catechin. They will use biochemical markers and immunohistochemistry to evaluate antioxidant capacity and redox status in the LDLr mice, and correlate these with the severity of atherosclerosis determined by lesion progression and atherogenic gene expression. Finally, they will examine the effects of the diets on the activation of NFkB and cell signaling pathways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IS THERE ATHEROSCLEROSIS
A
LINK
BETWEEN
ALZHEIMER'S
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AND
Principal Investigator & Institution: Grammas, Paula; Shideler Professor; Pathology; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2004; Project Start 15-JAN-2004; Project End 31-DEC-2007 Summary: (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease that affects over 4 million Americans. We are the first to demonstrate that brain blood vessels release neurotoxic proteins in Alzheimer's disease. However, the factors that cause this vessel dysfunction are not known. It is our hypothesis that risk factors involved in the pathogenesis of atherosclerosis are also causally linked to the development of vascular-mediated neuronal cell death in Alzheimer's disease. Our studies are timely and important as increasing evidence points to a link between atherosclerosis and Alzheimer's disease. Aim 1: To determine the effects of systemic oxidant stress or hyperlipidemia on vascular thrombin release, vascular-mediated neurotoxicity and on the cognitive performance of apoE transgenic mice. Brain blood vessels isolated from apoE knockout or transgenic mice expressing human E3 or E4 are used to assess the role of apoE isoforms on vascular expression of thrombin. Dietinduced hyperhomocystinemia and hyperlipidemia, are used to assess the role of oxidant stress and lipids, respectively, on vascular thrombin release and vascularmediated neurotoxicity. Also, these transgenic mice are utilized to evaluate possible apoE isoform-specific effects of oxidant and lipid stress on impairments in learning and memory. Aim 2: To determine if risk factors involved in the pathogenesis of atherosclerosis are also causally linked to the development of vascular-mediated neuronal cell death in Alzheimer's disease. Brain microvessels are isolated from AD patients and non-demented patients and analyzed for levels and/or activity of thrombin and other possible neurotoxic proteins, including, matrix metalloproteinases (MMPs), inflammatory cytokines and chemokines, and endothelin-l. Protein levels are determined by ELISA and Western blots and Mrna levels assessed by Northern blots and RT-PCR. The role that apoE isoforms play in regulating these proteins is determined by comparing microvessels isolated from patients with different APOE genotypes. In vitro addition of oxygen species or lipid molecules to isolated brain microvessels is used to assess the effects of oxidative stress and lipids, respectively, on release of thrombin, MMPs, inflammatory proteins, and endothelin-l. Apoptosis and necrosis are measured in cultured neuronal cells exposed to these proteins. These results would, for the first time, identify a mechanistic cascade linking cardiovascular risk factors to vascularmediated neuronal cell death in Alzheimer's disease and identify novel targets for therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ISOPRENOID METABOLISM IN THE RETINA Principal Investigator & Institution: Fliesler, Steven J.; Professor; Ophthalmology; St. Louis University St. Louis, Mo 63103 Timing: Fiscal Year 2002; Project Start 01-MAR-1988; Project End 31-MAR-2005 Summary: (provided by applicant): The long-range goal of this project is to determine the biological roles of cholesterol (CHOL) and related molecules in the retina in both normal and pathological states. Oxygenated derivatives of CHOL and other sterols occur naturally in cells and tissues, being formed both by autoxidation as well as enzymatically. Such "oxysterols" regulate normal cellular physiology, but also are potent
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cytotoxins that have been implicated in diseases such as atherosclerosis, diabetes, and cancer. The involvement of oxysterols in retinal diseases is unknown and has yet to be investigated. However, given the association between hypercholesterolemia and atherosclerosis as risk factors in prevalent retinal diseases such as age-related macular degeneration (AMD), research in this area seems warranted. Herein, we evaluate the formation and biological activity of oxysterols in the retina of normal rats in comparison with those that have been treated with a drug (AY9944) that causes accumulation of 7dehydrocholesterol (7DHC) in the retina and other tissues. AY9944-treated rats are an animal model for the Smith-Lemli-Opitz syndrome (SLOS), a common, autosomal recessive disease with associated ophthalmic defects, including retinal dysfunction. New results presented herein show that AY9944-treated rats develop retinal dysfunction prior to obvious histological damage, yet when exposed to intense green light for only 24 h, a massive, rapid retinal degeneration ensues that is much more severe and extensive than occurs in normal rats under the same conditions. We will examine the time course of retinal degeneration in AY9944-treated rats relative to controls, in both normal, dim cyclic lighting and with the "light damage" paradigm, correlating retinal structure and function with the formation, amounts, and types of oxysterols in the retina. We will compare the effects of intravitreally-injected oxysterols on the structure and function of the retina in normal rats, with and without pretreatment with dimethylthiourea (DMTU), a potent antioxidant. We also will evaluate the ability of DMTU pretreatment to reduce or prevent both oxysterol formation and the retinal damage observed in AY9944-treated and normal rats following exposure to intense green light. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LIPID TESTING /TREATMENT IN OLDER MI PATIENTS Principal Investigator & Institution: Foody, Joanne M.; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): While it is clearly established that elevated total and low density lipoprotein cholesterol predict future cardiac events in younger patients, there is lack of consistent data regarding the prognostic value of these lipoproteins in elderly (age >75) patients with CAD. Further, while lipid lowering therapy is associated with significant clinical benefits in patients less than 75 years with MI, no randomized clinical trial has assessed their efficacy in the older (>75) patient with MI. Finally, older patients? knowledge, beliefs and preferences regarding prevention have not been elucidated. The proposed project seeks specifically to broaden our understanding of the prognostic role of cholesterol n the elderly, provide insight into the effectiveness of lipid lowering, and determine domains of 0 der patients? preferences regarding lipid lowering and preventive care. This is a research plan with four specific aims. Aims 1,2, and 3 address critical gaps in knowledge surrounding lipids n the elderly utilizing an innovative collaboration between academia and the National AMI project, a quality improvement initiative sponsored by HCFA. This project, organized and implemented by the current investigators, contains medical record abstraction for over 250,000 Medicare beneficiaries hospitalized with MI in the U.S. in 1994-1995 and 1998-1999. The investigators seek to use data and enrich them to create research database capable of producing knowledge about lipid lowering therapy and future efforts to improve I the care and outcomes of older persons with MI. Aim 4 extends research into patient preferences in the elderly, l a generally unexamined area. This phase will use qualitative methodology to ascertain older patients? preferences regarding preventive treatment,
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treatment goals and quality of life, and to develop a taxonomy for elderly patients? primary prevention treatment preferences. Capitalizing on institutional strengths in outcomes research, geriatrics, and cardiology, the proposed research builds on prior work to form the basis for a sustained career in prevention in the elderly. The applicant will gain experience and insight to conduct independent health services research aimed at improving quality of care and clinical outcomes for older people with cardiovascular disease. This work will ultimately improve care for the elderly patient with cardiovascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LIPOPROTEIN PATHOPHYSIOLOGY Principal Investigator & Institution: Albers, John J.; Research Professor of Medicine; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-MAY-1983; Project End 31-MAR-2004 Summary: Premature vascular disease in young hyperlipidemic subjects remains a major unsolved health problem in terms of pathogenesis and treatment. Recent research advances have led to new markers for genetic analysis, new methods for studying lipoprotein metabolism and atherosclerotic disease progression and regression, and reference values for diagnosing hyperlipidemia. With these advances, the opportunity now exists for further in-depth focused studies of lipoprotein physiology and pathophysiology in genetically characterized patients with the objectives of understanding disease mechanisms, developing better treatments, and identifying and preventing early vascular disease. This will be accomplished by focusing our attention on the molecular, genetic and pathophysiological basis of the inherited dyslipoproteinemias associated with premature coronary artery disease with particular reference to familial combined hyperlipidemia, familial moderate hypercholesterolemia, familial elevation of Lp(a) and the carrier state for homocysteinemia. Coordinated studies of characterization of the pathophysiological state, the identification of possible molecular biological defects and the evaluation of these results in families by statistical genetic techniques will be performed in each disorder. The role of protein mediated intravascular modification of lipoproteins and the role of oxidation of lipoproteins in each disorder will lead to characterization of these genetic lipoprotein abnormalities. The Program Project, comprised of four coordinated projects, four supporting core facilities and a multidisciplinary team of investigators will combine the expertise in physiology, molecular biology, biochemistry, genetics, immunochemistry, nutrition, endocrinology, metabolism, epidemiology, and statistical genetics, to study lipoprotein physiology and pathophysiology at several levels of biological organization from basic molecular and cell biology through in vivo studies in humans to studies in populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISM OF ACTIVATION OF THE JNK PATHWAY BY BILE ACIDS Principal Investigator & Institution: Gupta, Seema; Microbiology and Immunology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2007 Summary: (provided by applicant): The studies in this proposal address the specific role that signaling pathways play in regulation of bile acid biosynthetic enzymes, specifically the enzyme cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the
32
Hypercholesterolemia
neutral pathway of bile acid biosynthesis. Recent findings from our laboratory provide strong evidence that activation of the c-Jun N-terminal Kinase (JNK) pathway by bile acids plays a pivotal role in regulation of CYP7A1 in primary rat hepatocytes. However, the molecular events by which bile acids activate this pathway have not yet been fully elucidated, but may have important implications in the pathogenesis of hypercholesterolemia and cholestatic liver diseases. It is proposed that interplay of ceramide and FAS within outer membrane lipid rafts is capable of regulating CYP7A1 through JNK activation. The objectives of this application are to (1) determine the mechanism(s) of activation of the JNK pathway by bile acids by defining the role of the FAS receptor in the activation of JNK in primary hepatocytes, (2) investigate the involvement of sphingomyelinases and ceramide in activation of the FAS receptor by bile acids, (3) determine whether the mechanism(s) of in vitro regulation of CYP7A1 by bile acids also apply in vivo, using FAS and acidic sphingomyelinase knock-out mice. An integrative approach combining kinase assays, ceramide measurements, fluorescence imaging, serum lipid analysis, and other molecular biology techniques will be applied to the proposed studies. Studies will be performed at Virginia Commonwealth University's-Medical College of Virginia Campus. The Department of Microbiology and Immunology and the Liver Centre at VCU are fully committed to support this research endeavor and to further develop the candidate's research career by providing the protected time, resources, and continuing research educational opportunities. This will enable the candidate to achieve her long term career goals of forming a fundamental understanding of bile acid-mediated signaling to serve as a basis for the development of effective therapies to reduce serum cholesterol levels and limit cholestasis-associated liver damage, and to develop an independent and successful research career. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM OF ENDOCYTIC TRAFFICKING OF CHOLESTEROL Principal Investigator & Institution: Ory, Daniel S.; Assistant Professor; Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (Provided by applicant): Hypercholesterolemia is a major risk factor for the development of coronary artery disease (CAD) and cerebral vascular disease (CVD). Increased plasma levels of low-density lipoprotein (LDL) leads to deposition of excess cholesterol in arteries, initiating atherosclerosis. While homeostatic mechanisms that regulate LDL uptake and de novo synthesis of cholesterol are well characterized, the cellular mechanisms that regulate trafficking of LDL cholesterol after internalization are not well understood. Evidence is emerging that the NPC1 and HE1 proteins participate in a common pathway for the efficient trafficking of internalized membrane cholesterol to the plasma membrane (PM) and to the ER. We hypothesize that NPC1 promotes formation of vesicles and/or tubules through the budding of the limiting endosomal membrane. NPC1-containing vesicles then traffic to the PM or ER to deliver their sterol cargo. The purpose of this project is to identify the molecular machinery in the sterol trafficking pathway and to test our hypothesis regarding this role of NPC1 in the sorting and distribution of internalized membrane cholesterol. This will be achieved by the following specific aims: (1) Use of a functional mammalian genetic screen to isolate Chinese hamster ovary (CHO) mutants with impaired intracellular trafficking of cholesterol, (2) Characterization and identification of the cholesterol trafficking defects in the mutant CHO cell lines, and (3) Compositional and functional analysis of proteins in the NPC1-containing late endosomal compartment, and examination of whether
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NPC1 membrane vesciulation is dependent on sterol concentrations and/or an intact sterol-sensing domain in NPC1. The studies outlined in this proposal will further our understanding of the critical role of NPC1 in cholesterol homeostasis. Furthermore, study of the function of gene products identified by our genetic screens and by compositional analysis of the NPC1-containing endosomal compartment may identify novel targets within the sterol transport pathway for pharmacologic therapy of CAD and CVD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS OF P42/44MAPK-INDUCED LDL RECEPTOR EXPRESSION Principal Investigator & Institution: Mehta, Kamal D.; Molecular/Cellula/Biochemistry; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-AUG-2005 Summary: Of all known risk factors promoting coronary artery disease, a high serum low density lipoprotein (LDL) level is the most important. The regulation of hepatic LDL receptor expression is a potential mechanism by which dietary and humoral factors alter plasma LDL levels, and upregulation of LDL receptor expression is the basis for current treatment of hypercholesterolemia. The negative regulation of LDL receptor transcription by sterols has been extensively delineated; however, the molecular mechanisms of induction and the signaling cascades controlling activity of critical nuclear factor(s) are not known. Recently, we provided the first evidence that specific activation of the p42/44mitogen-activated protein kinase (MAPK) is not only required but is sufficient to fully induce LDL receptor expression. Our recent observations supporting the requirement of CREB-binding protein (CBP) in p42/44MAPK-induced LDL receptor transcription are the basis of Specific Aim 1, and the studies proposed will link CBP acetyltransferase activity with modification of sterol responsive element binding proteins (SREBPs) and/or chromatin remodeling in the promoter region. Effects of CBP-SREBP protein-protein interactions on transactivation and on chromatin structures during the induction process will be examined by using a p42/44MAPKresponsive mammalian two-hybrid system and in vivo footprinting techniques. The Specific Aim 2 will study interleukin-1beta- and hepatocyte growth factor-induced LDL receptor expression to examine how p42/44MAPK participates during induction by sterol-sensitive and sterol-independent mechanisms. The Specific Aim 3 will establish a negative relationship between stress-activated p38MAPK alpha- isoform and LDL receptor expression and then examine the role of p38MAPK activation in stress-induced hypercholesterolemia through suppression of LDL receptor expression. This aim is based on our observation that specific inhibition of p38MAPK alpha-isoform induces LDL receptor expression via suppression of p42/44MAPK. Finally, in light of the crucial roles of MAPKs in hepatic cells, the Specific Aim 4 will examine the roles of p42/44MAPK and p38MAPK cascades in regulating expression of LDL and scavenger receptors that are a critical determinant of lipid accumulation in the macrophages and their conversion to foam cells. Defining the molecular mechanisms and the signaling pathways regulating the induction process will help in understanding the pathologic states under which the receptor pathways are perturbed, resulting in hypercholesterolemia. This knowledge could be exploited to develop improved hypercholesterolemia therapies and to reduce foam cell formation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Hypercholesterolemia
Project Title: MECHANISMS HOMOCYSTEINEMIA
OF
VASCULAR
DYSFUNCTION
IN
Principal Investigator & Institution: Lentz, Steven R.; Associate Professor; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2004; Project Start 01-AUG-2000; Project End 31-JUL-2008 Summary: (provided by applicant): Hyperhomocysteinemia, or elevation of plasma total homocysteine, is an emerging risk factor for cardiovascular disease and stroke. Numerous retrospective and prospective studies have suggested that hyperhomocysteinemia is an independent risk factor, and that the magnitude of risk is similar to that for conventional risk factors such as hypercholesterolemia or hypertension. The potential cardiovascular benefits of homocysteine-lowering therapy are currently being evaluated in several prospective clinical trials. Despite its clear association with clinical cardiovascular disease, however, the mechanisms responsible for the vascular pathology of hyperhomocysteinemia are still incompletely understood. Our group was among the first to demonstrate that moderate hyperhomocysteinemia produces impaired vascular function in vivo. To better examine the mechanisms of vascular dysfunction in hyperhomocysteinemia, we have developed genetic and dietary approaches to produce hyperhomocysteinemia in mice. Our data, and data from others, have provided strong evidence that endothelial dysfunction during hyperhomocysteinemia is related to impaired bioavailability of endothelium-derived nitric oxide (NO). Proposed mechanisms include oxidative inactivation of NO and decreased production of NO due to inhibition of endothelial nitric oxide synthase by asymmetric dimethylarginine (ADMA). The goals of this project are to define the role of ADMA in decreasing NO bioavailability and to determine the sources of reactive oxygen species (ROS) that mediate vascular dysfunction in hyperhomocysteinemia. A key feature of our experimental design is the use of genetically-altered mice to examine the contributions of ADMA, the inducible isoform of nitric oxide synthase, and vascular NAD(P)H oxidases in impairing endothelial function during hyperhomocysteinemia. This project has the potential to suggest novel therapeutic approaches to the prevention and treatment of vascular disease associated with hyperhomocysteinemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MENTORED DEVELOPMENT AW
PATIENT-ORIENTED
RESEARCH
CAREER
Principal Investigator & Institution: Reilly, Muredach P.; Assistant Professor of Medicine and Phar; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: PROPOSAL (Adapted from the applicant's abstract): Atherosclerosis remains the leading cause of death in the developed world. The signaling pathways involved in this chronic inflammatory disorder of the vasculature are poorly understood. PKC isozymes are potentially critical intracellular mediators of atherosclerotic regulatory signals in vivo. Recent data are consistent with a specific role for PKC in angiogenic signaling in vitro and in the development of vascular complications of diabetes in vivo. One of the challenges in the PKC field is to dissect the distinct roles of individual isozymes of PKC in atherosclerosis. It is the long-term goal of the applicant to determine the isozyme specific functions of PKC in atherosclerosis in vivo with a view to developing novel pharmacological therapies aimed at retarding this process in humans. Presently, it is unknown which PKC isozymes are activated in atherosclerotic tissue in
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vivo. Thus, despite the recent development of specific PKC inhibitors for use in humans, the isozymes that represent the best potential targets in atherosclerosis have not been identified. The investigator's specific aims, therefore, are: 1) to identify isozyme specific PKC activation in atherosclerotic mouse models and to modulate their activity in these models; 2) to confirm isozyme specific activation in human atherosclerosis and to investigate the effects on endothelial function of inhibition of specific isozymes inpatients with hypercholesterolemia; and 3) to examine the relevance of specific isozymes to angiogenesis in vitro and in vivo. By working closely with a multidisciplinary group with a strong background in both basic and translational research the applicant strives to obtain the practical experience necessary to develop an independent career in clinical investigation. Focussed coursework in patient-oriented research will compliment practical experience obtained during the development of this application. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: METABOLIC EFFECTS OF PROTEASE INHIBITORS IN HIV DISEASE Principal Investigator & Institution: Mulligan, Kathleen; Associate Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-AUG-2004 Summary: (Adapted from applicant's abstract). Reports of increased glucose triglyceride, and cholesterol levels in HIV-infected patients on protease inhibitors (PI) have prompter speculation that these agents have unique metabolic effects. Additionally, some HIV-infected patients have noted increased abdominal girth and buffalo humps that clinicians and patients attribute to the use of Pi's. In preliminary studies, we have observed significant increases in glucose, insulin, TG and total LDL cholesterol in a group of patients following initiation of therapy with a PI, whereas no such changes occurred in patients beginning therapy with lamivudine or maintaining constant regimen that did not include lamivudine or a PI. Because hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and central obesity are associated with increased risk of cardiovascular disease, these effects may impact on the long-term prognosis in patients whose life expectancies are extended due to effective viral suppression. As yet, these metabolic and body composition changes have not been systematically characterized, nor is it known if these changes represent one year syndrome or are unrelated findings. Therefore, to evaluate the scope of and mechanisms underling these changes in carbohydrate and lipid metabolism and their relationship, if any, to changes in body composition, e propose to perform intensive metabolic ward studies in which we prospectively evaluate changes in glucose and lipid metabolism and body composition in separate cohorts of HIV-infected men and women before and after beginning Pi therapy. These studies are designed to: (1) test the hypothesis that PI's induce insulin resistance (as assessed by oral glucose tolerance test, hyperinsulinemic, euglycemic clamp, stable isotope studies of hepatic glucose production, gluconeogenesis and glycogenesis); 2) test the hypothesis that PI's produce an atherogenic lipid profile (plasma lipids and lipoprotein composition, intravenous fat tolerance test, stable isotope studies of whole body lipolysis, de novo hepatic lipogenesis, and cholesterolgenesis); and (3) to determine whether patients uniformly develop changes in regional fat distribution while on PI therapy and the relationship, if any, or changes in glucose and lipid metabolism to changes in body composition (dual-energy X-ray absorptiometry, computed tomography)> The role of glucoregulatory, adrenal, and gonadal hormones in mediating these effects will also be evaluated.
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Hypercholesterolemia
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR PHYSIOLOGY OF BILIARY LIPID SECRETION Principal Investigator & Institution: Cohen, David E.; Associate Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2003; Project Start 01-FEB-1996; Project End 31-JUL-2008 Summary: (provided by applicant): Bile is the principal pathway for cholesterol elimination from the body, and high density lipoproteins (HDL) in plasma are the principal source of biliary cholesterol. However, hepatocellular mechanisms for uptake, transport and biliary secretion of HDL-derived cholesterol remain poorly understood. Scavenger receptor class B type I (SR-BI) is highly expressed in liver and promotes uptake of HDL lipids. Caveolae are cholesterol- and sphingolipid-rich membrane microdomains, which participate in cellular cholesterol transport. Both caveolin-1, the structural protein of caveolae, and SR-BI are expressed on the sinusoidal and canalicular domains of hepatocyte plasma membranes. Specific Aims 1 and 2 of this proposal will test the hypothesis that caveolae constitute a vesicular pathway that is responsible for sinusoidal HDL uptake and delivery to the canalicular membrane. Using mice with targeted disruption of genes encoding caveolin-1 and SR-BI, Specific Aim 1 will explore contributions of caveolin-1 and SR-BI to hepatic lipoprotein clearance and biliary lipid secretion. Primary cultures of hepatocytes from genetically engineered mice will be used to dissect contributions of caveolin-1 and SR-BI to binding and uptake of HDL. Specific Aim 2 will examine a role for caveolae in trafficking of HDL through the hepatocyte. Real time confocal fluorescence microscopy of HUH-7 hepatoma cells, which have been transfected with a green fluorescent protein-caveolin-1 fusion protein, will be employed to characterize uptake of luorescence-labeled HDL, processing within the endosomal compartment and trafficking to the canalicular membrane. An in vitro vesicle motility assay will be used to explore a role for microtubules in transport and sorting of vesicles containing HDL, SR-BI and caveolin-1. Hepatocellular secretion of phosphatidylcholines into blood and bile is critical for HDL metabolism and bile formation, respectively. Phosphatidylcholine transfer protein (PC-TP) is a cytosolic lipid transfer protein of unknown function that is highly expressed in liver. Specific Aim 3 will utilize PC-TP knockout mice to test the hypothesis that PCTP provides a nonvesicular pathway for phosphatidylcholine transport to the plasma membrane for incorporation into biliary vesicles and HDL particles. PC-TP knockout mice will be used to explore a role for this protein in biliary elimination of plasma cholesterol. These studies should elucidate the mechanisms of biliary lipid secretion at a fundamental cellular level and potentially lead to early interventions in cholestasis and cholelithiasis, as well as new strategies for management of hypercholesterolemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOLECULAR REGULATION OF ILEAL/RENAL BILE ACID TRANSPORT Principal Investigator & Institution: Shneider, Benjamin L.; Associate Professor of Pediatrics; Pediatrics; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2003; Project Start 30-SEP-1997; Project End 31-MAR-2007 Summary: (provided by applicant): The apical sodium-dependent bile acid transporter (ASBT) is the major carrier protein involved in intestinal reclamation of bile salts. Complete genetic disruption of its activity leads to pathologic bile acid induced diarrhea
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in humans, while partial inhibition can be used to treat hypercholesterolemia and cholestasis. ASBT is expressed on the apical surface of ileal enterocytes, renal tubules, and cholangiocytes. In the rat ileum, ASBT undergoes a biphasic pattern of developmental expression. Bile acid responsiveness of ASBT is species specific. ASBT is down regulated in the ileitis and up regulated by corticosteroids. Adaptation by ASBT after intestinal resection is dependent upon the length of residual ileum. These changes in ASBT expression are controlled at the level of transcription and mRNA stability. The rat, mouse, and human ASBT promoters have been cloned in my laboratory. HNF1alpha, AP-1 and LRH-1 are critical elements in the transcriptional regulation of ASBT. This proposal will define the molecular mechanisms involved in the regulation of the ASBT gene. Transcriptional regulation will be studied with chimeric luciferase promoter reporter constructs, DNA:protein gel shift analysis, and transgenic mice. Molecular mechanisms of transcriptional modulation of ASBT gene expression will be analyzed in normal physiology and pathologic states (altered bile acid homeostasis, ileal inflammation and intestinal resection). The role of mRNA stability will be assessed by identification of mRNA destabilizing elements in the ASBT transcript and by characterization of RNA:protein interactions. Cell-free systems and/or transgenic animals will be utilized to assess the role of these elements in developmental-stage and organ specific expression. The results of these studies will be highly significant in light of the crucial role that ASBT plays in human health and disease. The ASBT gene also represents a valuable model of important and poorly defined biological processes in the intestine, such as transcriptional regulation of ontogeny and tissue specificity and the role of mRNA stability in intestinal gene regulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NONALCOHOLIC FATTY LIVER DISEASE IN HISPANIC OBESE YOUTH Principal Investigator & Institution: Butte, Nancy F.; Associate Professor of Pediatrics; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 15-JAN-2004; Project End 31-DEC-2005 Summary: (provided by applicant): Childhood obesity and type II diabetes are reaching epidemic proportions in the U.S. particularly among Hispanic and African-American children, and the consequences of this epidemic in terms of nonalcoholic fatty liver disease (NAFLD) are understudied and under appreciated. Hispanic and AfricanAmerican children are at greater risk for the development of obesity and type II diabetes which are major risk factors for NAFLD. The full impact of this metabolic syndrome will not be realized until these children become adults and develop the long-term consequences of obesity, diabetes and liver disease. The primary objective of this grant is to characterize children at risk for NAFLD and explore possible mechanisms underlying the development of NAFLD in 1000 Hispanic children enrolled in an ongoing NIH genome-wide linkage study designed to identify genes that influence the expression of childhood obesity. The long-term objective is to develop an clinical intervention trial to treat the adverse effects of NAFLD in obese children. Hypothesis: Oxidative stress, endotoxemia and systemic inflammation superimposed on hepatic fat accumulation may lead to liver damage in obese children. Specific Aims: 1. To characterize Hispanic children at high risk of developing NAFLD in terms of age, gender, body composition, diet, physical activity, and severity and duration of obesity. 2. To determine the relationships between fasting hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperleptinemia, and elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). 3. To obtain
38
Hypercholesterolemia
evidence that oxidative stress, endotoxemia and measures of systemic inflammation are associated with elevations in serum ALT and AST. Design: Obese Hispanic children and their nonobese siblings will be screened for NAFLD using serum liver function tests; total sample size will be 1000. We will characterize children at risk for NAFLD and explore possible mechanisms of oxidative stress, endotoxemia and systemic inflammation underlying NAFLD. Methods: Liver function tests, ALT and AST will be analyzed in relation to in-depth phenotyping and genetic linkage analysis performed under the on-going NIH study. Newly proposed tests include chromogenic assays to measure lipid peroxidation end products and endotoxins, and ELISA and RIA to measure cytokine and markers of systemic inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL DRUG TARGET FOR BILE AND CHOLESTEROL METABOLISM Principal Investigator & Institution: Thacher, Scott M.; Orphagen Pharmaceuticals 5310 Eastgate Mall San Diego, Ca 921212804 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-MAY-2004 Summary: (provided by applicant): Regulation of bile acid metabolism is a therapeutic target for treatment of hypercholesterolemia as well as for cholestasis, the pathological buildup of bile in liver. Therapeutic options for direct modulation of hepatic bile formation and transport are limited. Orphagen proposes to develop and commercialize lead molecules that regulate gene transcription by the orphan nuclear receptor LRH-1 (liver receptor homolog-1). LRH-1 appears to stimulate reverse cholesterol transport, bile formation, and bile transport. The effort to identify the first pharmacologically active compounds to LRH-1 is part of a larger program to create drugs to structurallyrelated orphan nuclear receptors that regulate mammalian steroid and cholesterol metabolism. In Phase I, an indirect binding assay for compound screening at LRH-1 will be implemented based on findings from Drs. Holly Ingraham and Kip Guy at U. C. San Francisco. LRH-1 will be screened against a focused small molecule compound library developed at Orphagen. Cell-based reporter gene assays will be implemented in parallel to accelerate identification and confirmation of small molecules that regulate gene transcription by LRH-1. Drug candidates suitable for animal studies of hypercholesterolemia and cholestasis will be synthesized and tested in Phase II and a strategic partner recruited for further development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NUTRITION INTERVENTION: METABOLIC COMPLICATIONS OF HIV+ Principal Investigator & Institution: Woods, Margo N.; Associate Professor; Family Medicine & Cmty Health; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): As the HIV population survives and ages, a new syndrome is being observed that appears to be affected by PI medications but is also seen independent of PI use. This syndrome is characterized by hyperlipidemia, lipodystrophy and insulin resistance. Elevated triglycerides are a common observation with or without hypercholesterolemia. Since statin do not reduce serum triglycerides and may be counter-indicated to lower serum cholesterol because of potential liver damage in the HIV+ population that are on PI, dietary interventions have been getting more attention. Literature suggests that a diet lower in fat with reduced levels of
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39
saturated fat relative to polyunsaturated fat, increased omega 3-fatty acids intake, high fiber, and use of carbohydrates lower in glycemic index may be beneficial when they were studied individually. We propose to use a nutrition intervention in a HIV+ population that has elevated triglycerides (>220 mg/dl) to test whether a diet that combines all of these factors can have a significant effect on reducing serum triglycerides. The nutrition intervention will be a low fat diet (25% of calories from fat) with a 1:1:1 ratio of Saturated:Monounsat: Polyunsaturated fat, high in fiber (40 g/day) with carbohydrates of lower glycemic index (< 70 whenever possible). This diet will contain 3 g/day of omega 3-fatty acids which will be supplemented with 3.0 g of omega 3-fatty acids from capsules to give a total of 6 g/day of omega 3-fatty acids and a ratio of n-6/n-3 of 4:1. In addition to measuring triglycerides, serum cholesterol and its subfractions will be determined as well as insulin area under the curve (AUC) and body composition using CT scan. HIV+ participants eligible for the study (N=100) would be randomized into a control or nutrition intervention group and be tested for changes after 3 weeks, 13 weeks and 6 months of intervention. During the first 3 weeks the intervention group will be given all their meals at the hospital General Clinical Research Center, followed by an additional 10 weeks in which some food products are supplied to them along with the continued use of omega 3-fatty acids supplements at 3 gms/day (in 10 capsules). After 13 weeks the participants will be asked to continue to take the omega 3-fatty acid capsules but food products high in n-3 fatty acids will not be supplied. A 6-month follow-up will then remeasure all the study parameters to determine if the nutrition intervention group had experienced an improvement of the listed risk factors compared to the control group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OSTEOBLASTOGENESIS IN AORTIC VALVE CALCIFICATION Principal Investigator & Institution: Rajamannan, Nalini M.; Feinberg Cardiovascular Inst; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): This proposal is for a new K08 application which proposes a detailed plan for the candidate's research and a 4-year goal driven plan for further career development. The candidate's career goal is to become a successful independent scientific investigator. A career development plan is described that delineates the specific goals over the award period and the mechanisms that will be used to achieve them. Through didactic training and ongoing supervision through mentors and advisory committee, the candidate expects to 1) further develop as a basic science investigator, 2) conduct the proposed study with the highest degree of quality 3) present and publish studies in valvular heart disease at National conferences and leading journals 5) compete for advanced sources of funding and 6) develop insights in to the pathogenesis of valvular heart disease. The underlying mechanism for the pathogenesis of calcific aortic stenosis is unknown. This trend is becoming more pronounced with the aging population. Clinical studies indicate parallel risk factors for vascular atherosclerosis and aortic valve disease, the principle causative factor is elevated cholesterol levels. Due to these clinical observations, the PI has developed a translational approach to studying aortic valve disease. It is our hypothesis that calcification of the aortic valve is a direct result of valvular cellular transformation to an osteoblast phenotype that is initiated by hypercholesterolemia. The PI plans to test the hypothesis by the following specific Aims: Aim 1: Using the in vivo rabbit model, analyze the effects of hypercholesterotemia with and without statins in the atherosclerotic and proliferative aortic valve. Aim 2: Using the in vivo rabbit model,
40
Hypercholesterolemia
analyze the effects of hypercholesterolemia with and without statins in the calcification and mineralization of aortic valve. Aim 3: Using the in vivo rabbit model, determine the specific signaling pathways in the aortic valve which mediate the development of aortic valve atherosclerosis and osteoblastogenesis. Aim 4: Imaging the in vivo rabbit model of aortic valve disease. These studies provide the first in vivo model of aortic valve calcification which correlate the epidemiologic studies of atherosclerotic risk factors to the development of calcific aortic valve disease. If hypercholesterolemia stimulates the development of calcification in the aortic valve then the use of medical therapy such as HMG CoA reductase medications may have a role in the medical therapy of calcific aortic stenosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OSTEOGENIC CALCIFICATION
REGULATION
OF
MACROVASCULAR
Principal Investigator & Institution: Towler, Dwight A.; Chief, Division of Bone and Mineral Dise; Barnes-Jewish Hospital Ms 90-94-212 St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2003 Summary: (provided by applicant): Epidemiology suggests that diabetes and hypercholesterolemia increase risks for atherosclerotic & osteoporotic diseases. The regulation of vascular calcification is poorly characterized; the LDLR -/- mouse model & human valve specimens implicate heterotopic osteogenic mechanisms. It is important to understand aortic calcification and metabolism in our aging population since pharmacotherapies implemented to promote bone formation & preserve bone mass may alter progression of calcific vasculopathy. The 3 specific aims of this proposal are: Aim 1: "To characterize the activities of prolonged dysmetabolic exposure and osteoanabolic pharmacotherapy on orthotopic (skeletal) vs. heterotopic aortic osteogenic gene expression programs, using the diabetic LDLR -/- mouse as a model." In vivo data suggest overlapping yet distinct transcription mechanisms are rate limiting in the initiation of orthotopic vs. aortic calcium deposition. We will directly assess the aortic vs. osseous responses to osteoanabolic pharmacotherapy in the presence or absence of the dysmetabolic state. PTH will be used as a relevant, prototypic osteoanabolic stimulus in the dysmetabolic LDLR -/- mouse model. Gene expression of key osteogenic transcription factors, morphogens, & matrix molecules will be quantified by fluorescence RT-PCR, & spatially resolved by in situ hybridization. Temporo-spatial deposition of aortic calcium will be quantified by image analysis of von Kossa stained sections. Aim 2: "To identify the transcriptional mechanisms that regulate aortic mesenchymal cell osteogenic gene expression, using the osteopontin (OPN) & Msx2 promoters as models for study." The goal is to identify specific DNA-protein interactions that mediate responses to dysmetabolic signals (e.g., diabetes, hyperlipidemia) that control expression of these key osteogenic genes in vascular smooth muscle cells, peri-aortic adventitial cells, and osteoblasts using (a) transfection and gel shift analyses in primary cell cultures and cell lines; and (b) cDNA cloning techniques. Aim 3: "To identify if the gene expression programs elaborated during aortic calcification in the diabetic, hyperlipidemic LDLR -/- mouse provide a molecular phenocopy of human aortic calcification via molecular analysis of calcified human valves." We will determine if human aortic valve calcification quantified by spiral CT is associated with up-regulation of specific osteoblast transcriptional regulatory programs controlled by Msx2, Dlx5, & Runx2/Cbfa1/Osf2 (osteoblast transcription factors). Gene expression will be quantified by fluorescence RT-PCR and spatially resolved by in situ
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hybridization. A sub-aim will validate methods for quantifying aortic valve calcium content by spiral CT for future studies of patients treated with osteoprotective agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OVEREXPRESSION OF ENOS IN CRITICAL LIMB ISCHEMIA Principal Investigator & Institution: Messina, Louis M.; Associate Professor; Surgery; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2009 Summary: (provided by applicant): Despite advances in the surgical and catheter-based treatments for critical limb ischemia (CLI), 150,000 patients require lower limb amputation in the United States annually. Believing that an effective molecular therapy would have a significant clinical impact on the disability and limb loss rates in these patients, this study looks specifically at the role of endothelial nitric oxide synthase (eNOS) in collateral artery development (arteriogenesis). Because such development can reverse CLI, our central hypothesis maintains that the overexpression of eNOS will induce the ordered and sustainable development of collateral arteries in a way that will reverse CLI. Specifically, this research proposal aims 1) to identify the optimal gene transfer condition in a rat hind limb mode of ischemia; 2) to examine whether these eNOS gene transfer techniques can also reverse CLI clinically relevant animal models of diabetes, advanced age and hypercholesterolemia, and cigarette smoking; and 3) to characterize the molecular mechanisms by which eNOS overexpression increases arteriogenesis. To accomplish these aims, our research plan employs novel gene delivery techniques and sites of delivery. In particular, a unique method of intra-arterial gene transfer under vascular isolation that results in highly efficient and localized transgene expression will be used for gene transfer and laser Doppler perfusion imaging to measure dermal blood flow will facilitate the accomplishment of the above aims. Understanding the mechanisms by which eNOS exerts its powerful effects on arteriogenesis should provide additional insight into the fundamental mechanisms regulating arteriogenesis, and therefore open new therapeutic approaches for the treatment of CLI and other vascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OXIDATION RISK FACTORS AND IMT PROGESSION IN FH Principal Investigator & Institution: Hopkins, Paul N.; Research Associate Professor; Internal Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: (Verbatim from the application): In 346 patients with heterozygous FH we found 20-fold higher incidence rates of early coronary artery disease (CAD) compared to a general population. Yet, clinical disease onset varied greatly in these FH patients. We examined a comprehensive battery of suggested risk factors in these FH patients, and found only factors implicated in the LDL oxidation hypothesis appeared to be associated with CAD risk. We therefore hypothesize that factors related to LDL oxidation (rather that factors unrelated to the inherently high LDL in FH) are the major determinants of CAD risk among FH patients. Our experience from this study and from others suggests that change in repeated carotid intima-medial thickness (IMT) measurements, as opposed to a single measurement, will provide a good index of ongoing atherosclerosis progression and risk related to oxidant stress. Though evidence supports a major role for oxidized lipids in atherogenesis, this has not been critically examined in patients with FH. We propose a 5-year study, now including a vitamin
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Hypercholesterolemia
intervention component, to determine IMT progression rate among 200 patients with familial hypercholesterolemia. In addition to state-of-the-art IMT determination we will measure coronary calcification by spiral CT, brachial artery flow-mediated dilation, and perform high resolution MR angiography of the carotid tree. Using a random effects model, rate of change of these non-invasive measures of disease burden will be related to previously identified risk factors (including ultracentrifuged lipids and LDL apoB, plasma Lp(a), and total homocysteine) and oxidation-related risk factors (plasma concentration of F2-isoprostanes; susceptibility of LDL to copper-induced oxidation; dietary intake and plasma levels of vitamin E, vitamin C, and carotenoids; as well as plasma platelet-activating factor acetylhydrolase and paraoxonase). Our major hypothesis is that IMT progression will be strongly related to the balance of pro-oxidant and antioxidant factors. The newly added imaging techniques will allow us to compare and contrast results using these endpoints as well. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OXIDATIVE AND ATHEROGENIC ACTION OF IN VIVO MODIFIED LDL Principal Investigator & Institution: Sevanian, Alex; Professor; Molecular Pharm & Toxicology; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-AUG-1995; Project End 31-MAY-2005 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PERSONALITY AND HEALTH-- A LONGITUDINAL STUDY Principal Investigator & Institution: Goldberg, Lewis R.; Professor; Oregon Research Institute Eugene, or 97403 Timing: Fiscal Year 2002; Project Start 20-SEP-1997; Project End 31-AUG-2007 Summary: (provided by applicant): The broad objectives of this project are to test the models and mechanisms by which childhood personality traits predict adult healthrelated behaviors, health status and, eventually, mortality. The specific aims are to test three increasingly complex versions of a health-behavior model in which personality traits influence health status through health behaviors, and to evaluate any cultural influences on these models. The participants comprise a cohort of middle-aged adults for whom unique and irreplaceable teacher personality assessments were obtained about 40 years ago. Specifically, 1,770 members of the original population of Hawaiian schoolchildren have been located and 1,055 have been recruited to participate in this longitudinal study of personality and health. The recruited sample is representative of the original population in terms of personality attributes and gender. Over the next five years, information about the participants' personality traits, health behaviors, and health outcomes will be obtained. The personality measures will be based on several different theoretical perspectives including the five-factor framework. Health behaviors will include dietary practices, physical activity levels, and tobacco and alcohol usage. Health outcomes will include objectively assessed physical fitness and flexibility, obesity, and cholesterol level. Assessment methods will include self-reports, reports from knowledgeable others, observer ratings, physical/medical examinations, and laboratory tests. Frequency and appraisals of stressful life events, coping strategies, and constructs from the Theory of Planned Behavior will also be assessed to evaluate the more complex versions of the proposed health-behavior model. The effects on these models of cultural
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variables, socioeconomic status, and gender will be examined. The cross-sectional and longitudinal influences of personality traits will be evaluated by bivariate and multivariate linear models and structural equation modeling. This project will create a longitudinal data archive that will be a treasure chest for the scientific community for years to come. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHARMACOGENETICS NETWORK FOR CARDIOVASCULAR RISK THERAPY Principal Investigator & Institution: Krauss, Ronald M.; Senior Medical Scientist; Children's Hospital & Res Ctr at Oakland Research Center at Oakland Oakland, Ca 946091809 Timing: Fiscal Year 2002; Project Start 27-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): The goal of this Pharmacogenetics Research Group is to identify common gene variants that contribute to interindividual differences in response to drugs used to reduce risk for cardiovascular disease (CVD). The Group comprises a multidisciplinary team of investigators with expertise in lipoprotein metabolism and blood pressure regulation; genomics and related computational methodology; clinical trials; human genetics and genetic epidemiology; transgenic mouse models, and database management and biostatistics. For the present study, the drugs chosen are atorvastatin, an HMG CoA reductase inhibitor that lowers plasma lipid levels, and ramipril, an ACE inhibitor that lowers blood pressure. Candidate genes are those with products in metabolic pathways that are potential targets of these drugs. DNA sequence variations in 50 genes will be determined in 24 Caucasians and 24 African-Americans, two ethnic groups with differing degrees of sequence diversity. Based on patterns of single nucleotide polymorphisms (SNPs), haplotypes will be constructed for each gene in both ethnic groups, and groups of SNP genotypes will be identified that are characteristic for the 2-4 most common haplotypes in each gene, present in at least 10 percent of the population. Haplotypes for genes related to atorvastatin effects (27 genes) will be determined in 600 individuals (300 from each ethnic group) who will receive 10 mg/day of this drug for 8 weeks. Haplotypes for genes related to ramipril effects (23 genes) will be determined in 600 individuals (300 from each ethnic group) who will receive 10 mg/day of this drug for 12 weeks. Detailed measurements of phenotypes related to lipoprotein and blood pressure regulation will be performed in the two respective cohorts, and associations will be sought with each of the respective candidate haplotypes. Functional effects of specific sequence variants will be tested in appropriate transgenic mouse models. Future studies will corroborate positive findings using samples from large ongoing clinical endpoint trials of atorvastatin and ACE inhibitor therapy. Data will be transmitted to the Pharmacogenetics Knowledge Base and other genomic databases. The findings will advance our fundamental understanding of the roles of specific genes and their variants in modulating biologic pathways of importance in the pathogenesis and management of CVD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PON2 AND PON3 PROTEINS IN ATHEROSCLEROSIS Principal Investigator & Institution: Reddy, Srinivasa T.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006
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Summary: (provided by applicant): A number of pathophysiological observations in humans and animal models led to the hypothesis that atherosclerosis, a disease of the large arteries that is the primary cause of coronary heart disease (CHD) and stroke, is a multifactorial chronic inflammatory disease in which low plasma levels of HDL and high plasma levels of LDL, are a strong predictor of the condition. LDL oxidation is considered to be an essential process in the development of atherosclerotic lesions. The pro-inflammatory constituents of oxidized LDL are various oxidized phospholipids resulting from the scission and rearrangement of oxidized, unsaturated fatty acids. HDL and HDL-associated enzymes possess anti-atherogenic properties that are due, in part, to their inactivation of oxidized LDL. Although genetic and biochemical studies demonstrated anti-atherogenic role for paraoxanase-1 (PON1), a HDL associated protein, to date, the physiological functions of PON family of proteins; PON1, PON2 and PON3, remain unknown. Based on our preliminary findings, we hypothesize that PON2 and PON3 proteins inhibit the accumulation of oxidized phospholipids in LDL, protect artery wall cells against oxidative stress from reactive oxygen species (ROS) and oxidized phospholipids, and prevent the development of atherosclerotic lesions. In this application, we propose to i) characterize the biochemical and enzymatic properties of PON2 and PON3 proteins, ii) determine cellular localization, products of enzyme activity and the expression levels of PON2 and PON3 proteins in HDL and hyperchloesterolemic animal models, iii) develop transgenic mice and knockout mice to determine the physiological function of PON2 and PON3 proteins as well as the role of PON2 and PON3 in atherosclerosis, and iv) identify and characterize proteins that interact with PON2 and PON3 to delineate the biological substrates of PON2 and PON3 proteins. Understanding the biology and function of the PON proteins will pave way for the discovery of novel therapeutic agents in the fight against atherosclerosis and other inflammatory diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PRECONDITIONING IN OPEN HEART SURGERY Principal Investigator & Institution: Maulik, Nilanjana; Associate Professor and Director; Surgery; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2003; Project Start 01-FEB-1998; Project End 31-JAN-2007 Summary: (provided by applicant): The application proposes to continue examining the molecular and cellular mechanisms of ischemic preconditioning (PC). During the current years' funding we demonstrated the role of multiple kinases including receptor tyrosine Idnases and stress-regulated mitogen-activated protein kinases in PC and established an essential role of nuclear transcriptional factor NFkappaB. Our studies also demonstrated that PC potentiates a survival signal by activating several antiapoptotic genes and transcription factors simultaneously blocking the proapoptotic factors leading to the inhibition of apoptosis, which is now showed to independently contribute to myocardial infarction. While, PC has been proven to be the most powerful and state-of-the-art technique for cardioprotection, its clinical applicability is limited. Not only very limited studies exist in the literature to determine if PC could protect diseased hearts, the results are also confusing. We, therefore, propose to study if the cardioprotective abilities of PC are equally applicable to diseased hearts. We selected three most problematic diseased states: cardiomyopathy, hypertension and atherosclerosis which were found relatively less responsive to PC stimulus. We have already established our models to study these diseased hearts. Since adenosine, protein kinase C, protein tyrosine kinase, MAP kinases and KATP channels are the principle
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regulators for PC; we plan to determine the status of these factors in the diseased hearts. We anticipate inherent problems in one or more of these factors; and we will attempt to correct the deficiency by exogenous supplementation or by devising means to augment the deficient factors. We also anticipate reduced cardiac defense system in the diseased hearts, which consist of several intraceliular antioxidants and heat shock proteins. Again, we will attempt to precondition these hearts by devising methods to augment these defense elements. Our ultimate objective is to apply the preconditioning modality to protect diseased hearts which are resistant to preconditioning stimulus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REAL-TIME ANALYSIS OF CLATHRIN MEDIATED ENDOCYTOSIS Principal Investigator & Institution: Rappoport, Joshua Z.; Lab/Cellular Biophysics; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): This project involves the development and application of a system for the real-time analysis of clathrin-mediated endocytosis in living cells utilizing total internal reflection fluorescence microscopy (TIR-FM) TIR-FM represents a microscopy technique capable of selectively imaging events occurring adjacent to the plasma membrane with very high sensitivity. Clathrin mediated endocytosis is responsible for the internalization of activated receptors and ligands, nutrients, and cell adhesion molecules. Several genetic diseases are caused by defects in endocytosis (e.g. familial hypercholesterolemia) and numerous pathogens (e.g. influenza virus) gain entry into cells by exploiting the endocytosis machinery. Although many proteins involved in clathrin mediated endocytosis have been identified, the current techniques for studying endocytosis lack a real-time kinetic analysis of the formation and internalization of individual coated pits and of the interactions among the proteins involved. TIR-FM has the potential to permit analysis of clathrin mediated endocytosis in living cells and allows simultaneous imaging of the proteins involved the formation and fission of clathrin-coated pits under various physiological conditions (e.g. migrating cells, polarized cells and specialized cells). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REDOX-ACTIVATION OF VASCULAR STORES OF NO BY VITAMIN C Principal Investigator & Institution: Feelisch, Martin; Molecular and Cellular Physio; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, La 71103 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2006 Summary: (provided by applicant): Early in atherosclerosis endothelium-dependent relaxation is impaired. The underlying endothelial dysfunction is thought to involve inadequate bioavailability of nitric oxide (NO). Mechanisms that underlie this effect remain uncertain but may include reaction of NO with free radicals and depletion of substrate. Since NO plays a crucial role in atherogenesis, it is important to determine if NO bioavailability can be enhanced. Recent clinical studies suggest that vitamin C (ascorbate) can reverse endothelial dysfunction by enhancing endogenous NO-mediated vasorelaxation. However, the molecular mechanisms underlying this effect are not clearly understood. The current concepts are that ascorbate acts as an antioxidant by either sparing intracellular thiols or by scavenging superoxide radicals produced during an enhanced oxidative stress. Preliminary data presented in this application suggest an alternative hypothesis that encompasses both aforementioned concepts. We propose a
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Hypercholesterolemia
unique role for ascorbate in the vasculature based on the finding that, in addition to eliciting vasorelaxation, part of the NO produced from endothelial NO-synthase (eNOS) is stored in the tissue in the form of stable NO adducts. While the existence of such tissue stores of NO has been recognized earlier, its potential physiological and clinical implications have not yet been examined. We have observed that ascorbate relaxes vascular aortic rings in vitro by redox-activating tissue stores to release NO. Our preliminary data suggest that NO is bound in endothelial and smooth muscle cells in the form of S-nitrosothiols, which are cleaved by an increase in intracellular reduced glutathione. The intriguing and novel hypothesis built on these observations is that vitamin C reverses endothelial dysfunction by allowing the release of NO from a preformed vascular pooi. Using a combined biochemical/functional approach, the following three specific aims are proposed to address the above hypothesis: 1. To investigate the mechanism of ascorbate induced vasorelaxation and its relationship to the cellular redox status; 2. To identify the chemical nature and localization of NO stores in the vasculature and determine the factors that govern their stability and bioactivation to yield NO; and 3. To investigate the role of ascorbate in the maintenance of vascular homeostasis using different animal models of endothelial dysfunction. Results from these investigations are expected to significantly enhance our understanding of the role of NOS dependent and -independent NO production in endothelial dysfunction. Moreover, they should provide new insight into the actions of ascorbate beyond those of mere antioxidant nature and a rationale for vitamin C supplementation in disease states associated with an enhanced oxidative stress such as hypertension, hypercholesterolemia, and diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATABLE GENE TRANSFER SYSTEM Principal Investigator & Institution: Tsai, Sophia Y.; Professor; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2003 Summary: Human LDL receptor is expressed primarily in the liver and functions to clear the LDL and cholesterol from the circulation. Mutations of the LDL receptor have been shown to cause hypercholesterolemia which often results in cardiovascular diseases and myocardial infarction at an early age. The goal of this project is to use an inducible system to specifically target the human LDL receptor to the liver in transgenic mice as well as to study the efficacy of using adenoviral vector to deliver this inducible system into cell culture. The inducible system consists of a chimeric transcriptional regulator GLVP and a target gene containing the binding sites recognized by the regulator. In the presence of an inducer, RU486, the regulator binds and activates target gene expression. This inducible system has previously been demonstrated to effectively induce the expression of various target genes in cell culture and transgenic mice up to 5000-fold. To investigate controlled expression of human LDL receptor, we propose to: 1). Generate transgenic mouse target lines containing the human LDL receptor- cDNA; 2). Generate bitransgenic mouse lines capable of expressing the human LDL receptor in response to exogenous ligand; 3). Modify the regulator by substituting the viral activation domain with an activation domain from a human transcription factor to facilitate the future application of this inducible system for gene therapy; 4). Inducible expression of the LDL receptor in cultured cells using adenoviral delivery system. These studies are crucial in providing us with important kinetic data on LDL receptor expression and clearance of serum LDL and cholesterol. We expect that the results from
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this investigation shall enable us to formulate better protocols for future human gene therapy study in hypercholesterolemia and other cardiovascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF INTESTINAL CHOLESTEROL ABSORPTION Principal Investigator & Institution: Ostlund, Richard E.; Professor of Medicine; Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-MAY-1994; Project End 31-DEC-2003 Summary: The long-term objective of this project is to reduce coronary heart disease risk through a better understanding of the mechanisms of intestinal cholesterol absorption and the importance of cholesterol absorption in lipid removal of endogenous biliary cholesterol, but surprisingly few studies have actually measured cholesterol absorption in human subjects. Over the last several years this laboratory has developed cholesterol tracers and mass spectrometric methods that allow stable isotopic analysis of cholesterol absorption and metabolism in human subjects at high sensitivity. In this application we exploit these methods to address three important clinical questions. Specific Aim #1 tests the hypothesis that phytosterols (plant sterols) are much more active in reducing cholesterol absorption and LDL cholesterol levels than previously thought. This follows up our interim results which show that sitostanol, without effect in powdered form, has a nearly maximum effect at a dose of less than 300 mg when properly solubilized. Neomycin, an unrelated intra-intestinal cholesterol absorption inhibitor, will be compared to phytosterols and cooking oils with and without natural phytosterols will be examined. Specific Aim #2 tests the hypothesis that oxysterols, including those derived from phytosterols, are absorbed and biologically active. Interim work in rats demonstrated that dietary oxysterols are nearly quantitatively absorbed and also rapidly metabolized. Specific Aim #3 tests the hypothesis that cholesterol absorption is related to chronic dietary cholesterol, dietary fat, and plasma insulin level. Subjects will be fed from the GCRC kitchen and cholesterol absorption measured by isotopic methods. Successful completion of this project will provide new information in areas that have not received sufficient research attention. Knowledge of the importance of phytosterols, oxysterols and dietary determinants of cholesterol absorption will be used in supporting future dietary recommendations and research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REPRODUCTIVE HORMONES AND PRE-CLINICAL CVD IN WOMEN Principal Investigator & Institution: Bairey Merz, C. Noel.; Associate Professor and Medical Director; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 900481804 Timing: Fiscal Year 2003; Project Start 19-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Cardiovascular disease is the leading killer of women, yet prior research has failed to provide any clear understanding of the gender gap wherein women appear to be relatively protected from CVD while premenopausal, compared to men. Recent randomized trials of hormone replacement therapy (HRT), described below, have failed to demonstrate CVD benefit, and call into question the "estrogen protection" hypothesis. Alternative explanations for the gender gap, e.g., androgen exposure, have not been explored. This application, developed in response to the NHLBI's Innovative Research Grant Program Request for Application HL-01-016 and using existing data sets and biological specimens, is designed to support
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collaborative feasibility research in an innovative and high impact area relevant to CVD in women. The overall aim of this application is to use the existing data and stored blood samples from the NHLBI-sponsored Los Angeles Atherosclerosis Study (LAAS, HL-490-10) to explore new and innovative hypotheses with regard to reproductive hormones and progression of pre-clinical cardiovascular disease (CVD), measured by carotid intima-media thickness (IMT), in the 269 women (45% minority) in the Los Angeles Atherosclerosis Study (LAAS), an ongoing NHLBI-sponsored study of employed utility workers in Southern California without CVD at study entry. Hormonal assays will be performed on stored samples by a NHLBI Reproductive Hormone Core Laboratory, and subsequent analyses will characterize relationships to carotid IMT measured by the LAAS Ultrasound Core Laboratory. The following hypotheses will be test ed: 1) Reproductive hormonal profiles characterized by a relative estrogen deficiency and/or relative androgen excess will be directly correlated with increased baseline carotid IMT and predict greater carotid IMT progression over time in women; 2) Reproductive hormone effects on carotid IMT progression will be observed dominantly in situations of intimal injury, e.g. cigarette smoking, hypercholesterolemia, hypertension or diabetes in women. Innovative aspects of this application include evaluation of reproductive hormones repeatedly and prospectively in women across the spectrum of menopause (pre-, peri- and post-) using innovative methodologies including the sensitive reproductive hormonal assays used in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) core laboratory, and a newer quantitative carotid intimal media thickness (carotid IMT) protocol from the NHLBIsponsored LAAS. The current application represents an opportunity to gain feasibility pilot data in the area of the role of reproductive hormones and CVD in women using novel measures and a collaborative approach in order to plan further investigation, if warranted. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF NO AND ESTRADIOL IN AGING AND ATHEROGENESIS Principal Investigator & Institution: Chaudhuri, Gautam; Professor; Obstetrics and Gynecology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: During aging in women, two important changes occur which affect the vascular system. The first is menopause which is associated with estrogen withdrawal and the other is endothelial dysfunction manifested by a decrease in endothelium dependent vasodilation, possibly a reflection of a decrease in NO production by endothelial cells. These two changes may be independent of each other or may be interlinked. We and others have demonstrated that estradiol (E2) increases NO production. Therefore, endothelial dysfunction seen during aging and menopause as manifested by a decrease in endothelium dependent vasodilation and decrease in NO production may be explained just on the basis of E2 withdrawal alone. Estrogen replacement to postmenopausal women has been utilized for potential benefits related to the cardiovascular system. However, the precise mechanism(s) by which estrogens exert a beneficial effect on the cardiovascular system is not known. On the other hand, a recent study indicates that administration of a combination of estrogen and a progestin to women with well-documented coronary artery disease was associated with an increase in the incidence of a second coronary event in the first year of the study compared to the placebo group. In this study, there was no group in which women received E2 alone. Therefore, the role of E2 in modulating atherogenesis, once the
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disease is established is not known. Similarly, post-menopausal women are occasionally administered testosterone (t) to increase their sexual function but the effect of T on atherogenesis is not known. The overall hypothesis to be tested is that "the mere withdrawal of E2 or T leads to a decrease in NO synthesis, and thereby, to a proinflammatory response of the vascular wall leading to changes seen early in atherogenesis. A corollary could be that the atherogenic process on the extreme might increase the production of OONO and under such conditions NO inhibition might actually be beneficial." We propose to mimic the postmenopausal state in experimental animals by ovariectomy (OVX). We propose to mimic endothelial dysfunction by pharmacological means by administering animals an inhibitor of NO synthesis. The hypothesis will be tested under three specific aims. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF SCAVENGER RECEPTORS IN RENAL FIBROSIS Principal Investigator & Institution: Eddy, Allison A.; Professor; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-APR-1992; Project End 31-MAR-2007 Summary: Description (provided by applicant) Progressive renal disease is caused by a process of fibrosis that relentlessly destroys normal renal architecture and function. The number of patients with end-stage renal disease continues to rise exponentially, at an annual cost to Medicare that now exceeds $12 billion. The goal of the proposed studies is to determine how abnormalities of lipoprotein metabolism, which are frequently present in patients with renal disease, contribute to the pathogenesis of renal fibrosis. The overall hypothesis to be tested is that macrophage scavenger receptors process low density lipoproteins that have been oxidatively modified within the kidney to initiate fibrosis-promoting events. It is further hypothesized that this pathway worsens fibrosis in the face of hypercholesterolemia. Three Specific Aims are proposed. (1) To determine the effects of hypercholesterolemia on the severity of renal fibrosis and to delineate the pattern of renal scavenger receptor expression in murine models of renal fibrosis. (2) To investigate the role of the macrophage scavenger receptor class A type I/II (SR-AI/II) and scavenger receptor CD36 in renal fibrosis. (3) To elucidate intrarenal changes in prooxidant and anti-oxidant enzymes that could promote lipoprotein oxidation in murine models of renal disease associated with hyperlipidemia. These in vivo studies will be based on four murine models of renal disease. The functional significance of the two best characterized macrophage scavenger receptors, which are also known to participate in atherogenesis, (SR-AI/II and CD36), will be determined by comparing renal disease severity between wild-type animals and scavenger receptor-deficient animals. Bone marrow transplantation studies will be done to distinguish between the role of renal and macrophage scavenger receptors. Our long-term objective is to provide a scientific basis for the development and use of new therapies for patients with progressive renal disease. It is anticipated that the results of the proposed studies will prove that hypercholesterolemia, intra-renal oxidation of low density lipoproteins and scavenger receptor-dependent interactions with oxLDL represent an important pathogenetic pathway of progressive renal damage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ROLE OF STEROLS & INSULIN IN CARDIAC AUTONOMIC RESPONSE Principal Investigator & Institution: Galper, Jonas B.; Associate Professor; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533
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Hypercholesterolemia
Timing: Fiscal Year 2004; Project Start 01-AUG-2004; Project End 31-JUL-2008 Summary: Considerable evidence supports a role for parasympathetic stimulation in protection of the heart from the genesis of iarrhythmias. A major complication of diabetes mellitus is the development of an autonomic neuropathy which is associated with an impaired response of the heart to autonomic stimulation. The increased incidence of sudden death in diabetic patients, which is exacerbated by hypercholesterolemia and other cardiac risk factors, may be due at least in part to the increased likelihood of arrhythmia in the presence of an impaired parasympathetic response. The long-term goal of this application is to determine a new relationship between sterols, lipid lowering, insulin signaling and the response of the heart to parasympathetic stimulation. In a cell culture model for lipid lowering, in which embryonic chick atrial cells are cultured in medium supplement with lipoprotein depleted serum (LPDS), we have previously demonstrated that lipoprotein depletion results in a marked enhancement of the negative chronotropic response to parasympathetic stimulation and an increased expression of the M2 muscarinic receptor, the alpha-subunit of the heterotrimeric G-protein, Galpha(i2); and the inward rectifying K channel protein, GIRK1, which mediate the response of the heart to parasympathetic stimulation. Based on preliminary data which suggest that the expression of all 3 of these genes might be regulated by the binding of a sterol regulatory element binding protein, SREBP, a transcription factor which regulates cholesterol, fatty acid and glucose metabolism, to a putative sterol regulatory element in their upstream promoters, we will test 4 major hypotheses: 1.) that the expression of M2, Galpha(i2) and GIRK1/GIRK4 in embryonic chick atrial cells is coordinately regulated by SREBP at the level of transcription; 2.) that lipoprotein depletion stimulates M2, Galpha(i2) and GIRK1/GIRK4 expression and the parasympathetic response of the heart by a dual effect on SREBP: an increase in the level of SREBP and a Ras dependent phosphorylation of SREBP and; 3.) that insulin stimulates M2, Galpha(i2) and GIRK1/GIRK4 expression and the parasympathetic response of chick atrial cells via a similar dual effect on the level and phosphorylation of SREBP and; 4.) that SREBP expression regulates parasympathetic responsiveness of the mouse heart and muscarinic stimulation of IKAch in atrial myocytes from these hearts. These studies would support the existence of a new relationship between lipid lowering, insulin function and the parasympathetic response of the heart which could have important implications for the genesis and treatment of cardiac arrhythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SMOOTH MUSCLE CELL MEMBRANE DURING ATHEROGENESIS Principal Investigator & Institution: Tulenko, Thomas N.; Professor of Bioc. and Mole. Phar.; Lankenau Institute for Medical Research Wynnewood, Pa 19096 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-JUL-2002 Summary: Atherosclerosis continues to be the single leading cause of mortality in Western cultures. The development of atherosclerotic lesions is thought to follow the phenotypic modulation of medial smooth muscle cells (SMC) from the contractile to the synthetic state. A variety of signals have been identified that appear to participate in this modulation including oxidative stress, cytokines and interleukins of macrophage origin and endothelial factors (endothelins and NO.). The primacy of serum hypercholesterolemia as a risk factor suggests that the molecule cholesterol may also play a role in atherogenesis. Work performed by our lab has shown that enrichment of the SMC plasma membrane with cholesterol induces alterations in SMC very similar to those seen in atherosclerosis. Moreover, these alterations are reversed by estrogen. We
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hypothesize that enrichment of the SMC plasma membrane with cholesterol is an important factor contributing to SMC modulation during atherogenesis, and that estrogen's ability to reverse this effect contributes to its atheroprotective actions. We will test this hypothesis in 2 aims. Aim l will determine whether cholesterol's ability to alter the SMC membrane bilayer structure, as a single, isolated and independent variable contributes to the phenotypic and gene expression alterations in SMC during atherogenesis. Aim 2 will determine whether the atheroprotective effects of estrogen are mediated A), directly at the level of the arterial SMC and B), whether the mechanism of estrogen's actions are mediated, in part, by countering cholesterol's effects on the arterial SMC membrane. For these studies,we will employ two preparations of vascular cells: 1. early passage (equal to or <3) rabbit aortic SMC, and 2, early passage (equal to or <3) human aortic and coronary artery SMC. Phenotypic alterations will be followed including cell proliferation and collagen synthesis. NFkappaB activation and the generation of reactive oxygen intermediates will be measured as potential signaling intermediates using appropriate techniques. Alterations in gene expression will be assessed by measuring message and protein levels for 2 genes we have identified to be upregulated in SMC during atherogenesis (hn-RNP-K and prolyl-4-hydroxylase) as well as genes identified by others reflecting the synthetic phenotype in SMC, collagens I and III. Combining these approaches will provide essential insights into the cellular basis for the early defects in human SMC during atherogenesis and how estrogen provides cellular protection in this disease Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SOLID CHOLESTEROL
SITOSTANOL
FORMULATIONS
LOWER
LDL-
Principal Investigator & Institution: Spilburg, Curtis A.; Lifeline Technologies, Inc. 16052 Clarkson Woods Dr Chesterfield, Mo 63017 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-JAN-2004 Summary: (Scanned from the Applicant's Abstract): Incorporation of a new water-based sterol/stanol formulation system in foods and capsules lowers intestinal cholesterol absorption. This methodology is fat-free and provides a distinct improvement over existing inflexible oil-based strategies that increase the consumer's caloric load. A series of 14-week, double blind placebo controlled trials will examine the effect of formulated sterols on LDL-cholesterol reduction in mildly hypercholesterolemic adults maintained on the American Heart Association Step I diet. Two dosing strategies will be examined. In the first, formulated soy sterols will be dry blended with Instant Breakfast to provide a convenient, once a day dosing regimen. In the second strategy, soy stanols will be delivered in capsules to determine the optimum dose and dosing regimen. Each of these methods will then be tested in subjects who have problems with lipid management. Children who are not candidates for statin therapy because of long-term safety concerns will be enrolled and their LDL-cholesterol reduction monitored while consuming soy sterols in Instant Breakfast. Similarly, adults on statin drugs who have not reached their target LDL-cholesterol level will receive soy stanols in capsules to determine the extent of LDL-cholesterol reduction using this adjunct therapy. Positive results from these studies will provide a safe non-pharmaceutical approach to cholesterol reduction. PROPOSED COMMERCIAL APPLICATION: A new formulation system allows plant sterols and stanols to be effective cholesterol absorption inhibitors in aqueous media. This will be used to determine the reduction in LDL cholesterol when these compounds are incorporated in capsules or a food product. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SOY PROTEIN +/- ISOFLAVONOIDS AND PLASMA LIPIDS Principal Investigator & Institution: Lichtenstein, Alice H.; Professor; Medicine; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2005 Summary: The objective of the proposed studies is to assess, in older (40-70 years), hypercholesterolemic [low density lipoprotein (LDL) cholesterol 130-160 mg/dl] male subjects, the impact of consuming different sources of protein (mixed-animal versus soy) and/or different levels of isoflavonoids (primarily genestein and diadzein) on the concentration of plasma lipids [total cholesterol, very low density lipoprotein cholesterol, LDL cholesterol, high density lipoprotein cholesterol, triglyceride] and apolipoproteins (apo) [apo A-1, apo B, Lp (a)]; as well as isoflavonoids in plasma and urine; and hormonal status. The experimental design consists of two multi- phased studies devised to determine the independent effects of type of protein and/or level of isoflavonoids; in Study 1, within the context of a diet approximating that currently consumed in the U.S. [15 energy (E) % protein, 47 E% carbohydrate, 38 E% fat (15 E% SFA, 14 E% UFA, 6 E% PUFA), 170 mg cholesterol/1000 kcal] and Study 2, within the context of a diet consistent with recommendations for individuals with moderate hypercholesterolemia (Step 2 diet) [15 E% protein, 49 #% carbohydrate, 24 E% fat (7 E% SFA, 7 E% MUFA, 8 E% PUFA), 61 mg cholesterol/1,000 kcal]. The variable components of the diets, type of protein and isoflavoniods, will respectively comprise two-thirds (67%) of the protein of 10% of energy, and range from 3 to 49 mg/1000 kcal. The aims of the study are to determine the effect of 1) a one to one (E/E) substitution of soy for mixed-animal protein on plasma lipoprotein, on plasma lipoprotein patterns associated with CHD risk; 3) increasing the isoflavonoid content of the diet in a dose-related manner on plasma lipoprotein patterns associated with CHD risk; 4) dietary protein source on hormonal status (androgens, estrogens, thyroid); and 5) dietary isoflavonoids on hormonal status (androgens, estrogens, thyroid). The area of soy protein and isoflavonoids is highly controversial and in the public domain. The results of these studies, whether positive or negative, should contribute to the data base on which to formulate more specific public health recommendations with respect to decreasing risk of developing CHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SOY SUPPLEMENTS INTERACT WITH CHOLESTEROL-LOWERING DRUGS Principal Investigator & Institution: Shay, Neil F.; Biological Sciences; University of Notre Dame 511 Main Bldg Notre Dame, in 46556 Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 31-DEC-2004 Summary: (provided by applicant): This project will investigate potential interactions between phytochemical-containing soy extracts and the prescription phamaceuticals, the statins. Statins are a pharmaceutical approach to reducing blood cholesterol levels, and soy supplements are an alternative, botanical approach to to reduce blood cholesterol levels. The long term goal of this research project is to enable individuals and physicians to include soy supplement products as a complementary treatment in addition to prescibing statin intake to reduce blood cholesterol levels. Currently, physicians typically advocate that individuals first use diet to try to reduce cholesterol levels. When a low-fat diet does not reduce cholesterol levels, then physicians will prescribe a cholesterol-lowering drug. Soy has been of interest since it is know that intake of soy reduces cholesterol levels. Nutrition researchers suspect a number of properties of soy
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may contribute to its cholesterol-lowering effect. Soy also has a second property, it can enhace the 'cytochrome P450' detoxification system of the liver. The P450 proteins enhance metabolism of organic compounds that enables them to be more easily excreted from the body. P450 proteins metabolize the category of cholesterol-lowering drugs called statins. This project will help determine how soy lowers cholesterol and which liver P450s are activated by soy. It appears that these two actions may simultaneously help and hinder the ability of an individual to lower their cholesterol levels while taking statins. This project will help provide critical information that could enhance the effectiveness of statins, help further lower an individual's cholesterol levels, and perhaps reduce the cost of routine drug therapy often required for those with elevated cholesterol levels. In the future, it may be possible to determine and chemically separate the different components of soy that reduce cholesterol and activate the P450 proteins. If this could be done, it is possible that a specific soy extract product could be produced that has a singular effect that helps lower blood cholesterol levels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEROL DEVELOPMENT
METABOLISM
DURING
PREGNANCY
AND
Principal Investigator & Institution: Woollett, Laura A.; Associate Professor; Pathology and Lab Medicine; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 31-MAY-2006 Summary: The acquisition of sterol by the fetus is essential for development and growth. The fetus has two potential sources of cholesterol, de novo synthesis and exogenous sterol. Without the required amount of cholesterol from these sources, the fetus will not survive or will develop abnormally. Data obtained during our previous funding period suggests that the fetus acquires cholesterol from the maternal circulation in addition to that derived from de novo synthesis. The accretion of maternal- derived sterol seems to be dependent upon the sterol balance in the extra-embryonic fetal tissues that protect the fetus from direct contact with circulating maternal constituents, the placenta and yolk sac. Thus, the hypotheses for the present proposal are 1) that the fetus acquires cholesterol from the maternal circulation and 2) that the maternal cholesterol within the fetus is metabolically active. There are 4 specific aims which will test these hypotheses. First, the amount of cholesterol acquired from the maternal circulation will be quantitated. To delineate the processes involved, transport will be examined using different lipoproteins at different stages of development and with varied maternal plasma cholesterol concentrations. The role of specific proteins that have been implicated in fetal development will also be examined in genetically altered animals lacking the proteins in question, such as megalin. Second, the processes involved in the uptake, transport and secretion of cholesterol from the placenta will be evaluated. These studies will be completed in a human derived carcinoma trophoblastic cell line and in human placental perfusions. To examine the processes, we will study the effects of increasing concentrations of lipoproteins (LDL and HDL), cellular cholesterol and lipid acceptors (lipid-poor apoAI and phospholipid vesicles). Third, the effectors of lipoprotein secretion from the yolk sac will be determined in a yolk sac organ culture. Cholesterol and triglyceride concentrations and triglyceride composition will be manipulated in the yolk sacs and the resultant effect this has on lipoprotein secretion will be examined. The role of specific proteins in this process will also be examined. Finally, the processing of proteins involved in sterol balance, the sterol regulatory element binding proteins, and the activation of Sonic hedgehog, a protein involved in patterning of the forebrain, will be studied in fetal tissues that have accrued different
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amounts of maternal cholesterol. Based on the results of this proposal, we expect to define new approaches to enhance the presentation of exogenous cholesterol to the developing fetus or embryo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STRUCTURE AND FUNCTION OF THE LDL RECEPTOR Principal Investigator & Institution: Blacklow, Stephen C.; Associate Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-FEB-1998; Project End 31-MAR-2007 Summary: (provided by applicant) The long-term goal of this research is to elucidate the detailed mechanistic basis for ligand binding and release by the low-density lipoprotein receptor (LDLR), and to understand signal transduction by structurally related proteins of the LDLR family. The LDLR is the primary mechanism for uptake of cholesterol carrying particles into cells; the genetic disease familial hypercholesterolemia (FH), which affects about 1 in 500 persons worldwide, results from loss-of-function mutations in the LDLR gene. The LDLR also serves as a prototype for a versatile family of cellsurface receptors that participate in a diverse range of biological processes, including lipoprotein uptake, brain development, and Wnt signal transduction. These proteins combine several types of structural units in similar arrangements, such that groups of cysteine rich LDL-A modules precede regions with clusters of epidermal growth factorlike (EGF) modules and B-propeller domains containing conserved YWTD motifs. Each receptor then terminates with a transmembrane segment and a cytoplasmic tail of variable length. Although these receptors carry out a variety of crucial biological functions, the basis for ligand recognition by the ligand binding, LDL-A modules of the LDLR and related receptors remains poorly understood. In addition, the mechanism by which the LDLR releases ligands in the acidic milieu of the endosome, a process intrinsic to the purified receptor and mediated by the EGF-like modules and the YWTD domain, is also unknown. During the next period of grant support we will address these unanswered questions in lipoprotein receptor biochemistry by pursuing the following specific aims: 1. Determine how the ligand-binding modules of the LDL receptor recognize apolipoprotein E (apoE)-containing ligands. 2. Elucidate the mechanism of ligand release by the LDLR at low pH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SURGICAL INTRAMYOCARDIAL ANGIOGENESIS IN A SWINE MODEL Principal Investigator & Institution: Sellke, Frank W.; Professor and Chief; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: Angiogenesis is a promising new therapeutic modality for the treatment of coronary artery disease (CAD). However, despite impressive results of animal studies from our laboratory as well as others, preliminary clinical use of angiogenic therapy in humans has only resulted in modest if any objective benefit. Patients with end-stage CAD, who represent the population currently targeted by angiogenic therapy, virtually all have advanced endothelial dysfunction that results in abnormal production and response to endothelial substances. Since angiogenic growth factors operate in large part through the release of endothelial-derived nitric oxide via the activation of tyrosine kinase receptors, the observed failure of effect in patients with end-stage CAD may relate to a deficiency in the stimulated release of these endothelial-derived substances.
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This research proposes to define the role of endothelial function on the effects of exogenous growth factor therapy and on the endogenous angiogenic response to myocardial ischemia. To this end, a hypercholesterolemic porcine model will be used that recreates myocardial microcirculatory changes similar to those encountered in humans with CAD. Several study groups that include animals with normal, dysfunctional, or pharmacologically- treated endothelium will be created, in which surgical induction of chronic myocardial ischemia and implantation of sustainedrelease growth factor devices (FGF-2, VEGF, or placebo) will be performed. In each study group, endothelial responses will be assessed in vitro on microvascular reactivity studies, and the angiogenic response will be quantitatively determined at the functional, microvascular, histological, and molecular levels, using tools such as isotope-labeled microsphere assays of myocardial perfusion, sonomicrometry, immunocytochemistry and real time PCR analysis. By clarifying the role of the endothelium and endothelialmodulating agents in the functional angiogenic response, the findings from this research will lead to a more complete understanding of therapeutic angiogenesis, and may allow for the development of this modality towards a safe, effective, and attractive option for the treatment of CAD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TETRAHYDROBIOPTERIN: REGULATOR OF ENDOTHELIAL FUNCTION Principal Investigator & Institution: Katusic, Zvonimir S.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-DEC-1994; Project End 31-MAR-2005 Summary: (Verbatim from the application): Cardiovascular diseases, including atherosclerosis, remain a leading cause of death and disability in the United States. Nitric oxide is a key regulator of vascular tone, platelet aggregation, white blood cell adhesion, and smooth muscle cell proliferation. Nitric oxide has also been recognized as a critical mediator of angiogenesis. Endothelial dysfunction due to decreased production of nitric oxide is an early event believed to play a major role in initiation and progression of atherosclerosis. Tetrahydrobiopterin (BH4) is an essential cofactor needed for enzymatic activity of nitric oxide synthase. BH4 plays a key role in the control of endothelial nitric oxide production. The general hypothesis of this proposal is that during development of atherosclerosis, up-regulation of BH4 biosynthesis is an adaptive response designed to preserve biosynthesis of nitric oxide and protect the vascular wall from oxidative stress. To test this hypothesis we propose studies with the following specific aims: (1) determine the effects of oxidative stress on vascular BH4 metabolism, (2) characterize the relationship between BH4 metabolism and endothelial dysfunction in arteries exposed to hypercholesterolemia in vivo, and (3) analyze the role of superoxide anion in BH4 metabolism and endothelial dysfunction in murine models of atherosclerosis. Apolipoprotein E (ApoE)-deficient mice and low-density lipoprotein (LDL) receptor-deficient mice develop spontaneous hypercholesterolemia and atherosclerosis with many features that are characteristic of lesions in humans. Preliminary findings indicate that endothelial dysfunction, as reflected in impaired endothelium-dependent relaxations, is present in murine models of atherosclerosis. The exact mechanism responsible for endothelial dysfunction induced by hypercholesterolemia is not understood. Initial analysis performed on isolated aorta of ApoE-deficient mice indicated that increased production of superoxide anions in the vascular wall plays a major role in inactivation of endothelial nitric oxide. However, the effects of superoxide anions and oxidative stress on BH4 metabolism have not been
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studied. To characterize the role of superoxide anion in BH4 metabolism and endothelial dysfunction, arteries from superoxide dismutase (SOD) transgenic mice and SODdeficient mice will be studied. Overexpression of SOD in ApoE-deficient mice will be used to protect BH4 from superoxide anion-induced oxidative stress and rescue endothelial dysfunction. Double knockout ApoE-SOD-deficient mice will be created to determine whether increased production of superoxide anion accelerates oxidation of BH4 and impairment of endothelium-dependent relaxation. It is anticipated that the results of the proposed experiments will provide novel and important information concerning the effect of oxidative stress on vascular BH4 metabolism and the pathogenesis of atherosclerosis. This information may help to develop new therapeutic interventions designed to prevent endothelial dysfunction and progression of atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE CENTER OF URBAN RESEARCH AND EDUCATION IN DIABETES Principal Investigator & Institution: Norris, Keith C.; Professor and Chair; Internal Medicine; Charles R. Drew University of Med & Sci 1731 East 120Th Street Los Angeles, Ca 900593025 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Support is requested to establish a Clinical Center of Research Excellence through the Research Center for Minority Institutions (RCMI) at the Charles R. Drew University of Medicine and Science (Drew). This center, entitled "The Center of Urban Research and Education in Diabetes and Metabolism" (CUREDM), is designed to attract an established research investigator with independent research support and provide research resources for investigators who will study diabetes, insulin resistance states, hypercholesterolemia, obesity, hormonal dysregulation and other metabolic related diseases. These resources will include the development of two core facilities complemented by a developmental project. CUREDM will augment and strengthen Drew's clinical research capabilities through its independent research and its ability to mentor junior investigators. Consistent with the request for this application CUREDM will address health care issues that disproportionately affect the indigenous populations served by the RCMI institutions and are recognized as national health care priorities. The unique patient population at Drew University is comprised of approximately 55 percent Hispanic, 35 percent African Americans, and 10 percent Asian/Pacific Islander who suffer disproportionately from diabetes and metabolic related disorders. Over the last 4 years Drew has experienced a progressive enhancement in the clinical research infrastructure and an increasing number of investigators with research interest and activity in diabetes and metabolic related diseases. This creates an appropriate environment of professional interaction and growth that will facilitate the recruitment of a highly qualified investigator to direct CUREDM. Thus, Drew is an ideal location for the establishment of CUREDM. Although there is a particularly high prevalence of diabetes and metabolic disorders in underserved populations, these disorders are pervasive in our society and information gained from CUREDM is likely to yield important contributions toward improving health care for the nation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE CHEMOKINE RECEPTOR CXCR-2 IN ATHEROSCLEROSIS Principal Investigator & Institution: Boisvert, William A.; Assistant Member; Scripps Research Institute Tpc7 La Jolla, Ca 92037
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Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-AUG-2003 Summary: (Adapted from Investigator's Abstract): Multiple mechanisms operate to promote macrophage accumulation within the atherosclerotic intima. This proposed work stems in part from observations by others, including the finding that in apoE knockout mice which are deficient in the MCP-1 receptor CCR2, atherosclerosis is diminished, but lesion size and complexity still progress from 5-13 weeks. Also monocyte CCR2 expression in vitro is attenuated by several inflammatory mediators which can be in the plaque, or by differentiation to macrophages. They therefore propose that other mechanisms are at play in promoting macrophage retention and expansion within the atherosclerotic lesions. Base on their previous work, they have found that intimal macrophages express the chemokine receptor CXCR2, and the CXCR2 ligands, GROalpha, and IL-8. Initial data also indicate that leukocyte deficiency of the mouse CXCR2 homologue, mIL-8RH, arrested progression of early macrophagerich lesions and decreased retention of lesion macrophages. They therefore hypothesize that specific CXCR2 effects mediate the intra-lesional growth, inflammatory differentiation and activation of recruited macrophages. Their specific aims are as follows: Define the sequence of atherogenic events mediated by CXCR2, using two animal model systems. They will first transplant irradiated LDLR-/- mice with bone marrow from mIL-8/ CXCR2-/- or control mice under gnotobiotic conditions. Mice will be fed a chow or high cholesterol diet to define the role of mIL-8RH in mild vs. severe hypercholesterolemia-induced atherosclerosis. Second, to assess the role of mIL-8RH in cells other than leukocytes, they will study LDLR-/-, mIL-8RH-/- mice derived by crossbreeding. Early monocyte ingress, fatty streak formation, and lesion progression will be studied in both groups at 3 to 30 weeks. They will concurrently detect lesion mIL-8RH and macrophage markers including MOMA2 in each group of mice. They will also compare temporal and spatial macrophage accumulation, expression of mIL-8RH, KC/GROalpha, JE/MCP-1 and CCR2, the appearance of oxLDL epitopes and lipid deposition. Test the hypothesis that CXCR2 expression acts by promoting macrophage retention in early atherosclerotic lesions, and does so in part by increasing macrophage beta1 integrin-mediated adhesion. First they will determine if retention of lesion monocytes is greater in LDLR-/-, mIL-8RH+/+ than LDLR-/-, mIL-8RH-/- mice. To do so they will isolate, label (using [3H]-glycerol) and infuse bone marrow monocytes into LDLR-/- mice on a high fat diet. Migration and retention of labeled monocytes in vivo will be measured in aortic lesions at 2,4,7, and 14 days post infusion. They will then test the hypothesis that the generalized cell culture adhesion defect of macrophages from mIL-8RH-/- mice is associated with decreased activation of beta1 integrins, which bind fibronectin (VLA-4, VLA-5). They will also study CXCR2-mediated effects on adhesion of human peripheral blood monocytes using specific neutralizing antibodies for integrins and integrin ligands. They will also test the hypothesis that macrophage CXCR2 expression is necessary for macrophage matrix invasion. Test the hypothesis that CXCR2 expression, via effects on macrophage adhesion, mediates macrophage differentiation to a distinct, pro-atherogenic inflammatory phenotype. Here they will further study human peripheral monocyte-derived macrophages and mouse wild type and mIL-8RH-/- bone marrow derived macrophages under conditions where CXCR2 is normally expressed in vitro. They will specifically look at the effects of the CXCR2 ligands, GROalpha, and IL-8 on macrophage proliferation and expression of JE/MCP-1. They will also determine if CXCCR2-mediated adhesion modulates the production of apoE, oxidation of LDL, and accumulation of cholesteryl ester. Finally based on the results of Specific Aim 2, they will test the hypothesis that VLA-5, and VLA-4 activation, via stimulation by CXCR2 ligands, regulate one or more of these activities. They will also correlate these results with the features of the mouse atherosclerotic lesions of
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Specific Aim 1 (i.e. in vivo correlation studies between CXCR2 expression and PCNA, oxidized LDL antigens, and scavenger receptor expression). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF NITRIC OXIDE IN CHOLESTEROL HOMEOSTASIS Principal Investigator & Institution: Ihrig, Melanie M.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant) Cholesterol homeostasis is maintained by balancing intestinal absorption, endogenous biosynthesis, hepatic uptake and biliary secretion of cholesterol and bile acids. Recently, there has been a renewed interest in the role of intestinal cholesterol absorption in cholesterol homeostasis. A number of studies have assessed the effect of reduced small bowel transit time on cholesterol absorption, and each found a significant correlation between transit time, cholesterol absorption and serum cholesterol concentration. We have demonstrated that mice with a targeted mutation in the inducible nitric oxide synthase (iNOS) gene have elevated serum cholesterol levels. Each of three unique isoforms of NOS is expressed in different cell types and under different conditions throughout the gastrointestinal tract. There is considerable evidence that nitric oxide (NO) produced in the gastrointestinal tract influences enteric myoelectrical activity, coordinates peristalsis and ultimately affects intestinal transit time. Nitric oxide acts as an inhibitory neurotransmitter, and as a vasodilator in the intestinal tract. Additionally, enteric pathogens, and the experimental administration of lipopolysaccharide (LPS), elicit excessive production of NO through transcriptional upregulation of iNOS. Thus, NO concentrations in the intestinal tract wax and wane depending on the immediate circumstances. A plausible explanation for the increased serum cholesterol levels observed in the iNOS-deficient mice, then, is delayed small bowel transit time, brought on by perturbation of the regulation and coordination of intestinal motility. Aberrant cholesterol homeostasis is a risk factor for both atherosclerosis and cholesterol gallstone formation. In addition to hypercholesterolemia, we observed aortic atheromas in the iNOS-deficient mice. Prolonged intestinal transit time augments formation of cholesterol gallstones, and if prolonged intestinal transit time is the underlying cause of hypercholesterolemia in iNOS-deficient mice, the manifestation of atherosclerosis and cholelithiasis may well be linked. The proposed studies will explore these possibilities in iNOS-deficient mice under various experimental conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THYROID HORMONE RECEPTOR Principal Investigator & Institution: Baxter, John D.; Professor and Director of Medicine; Metabolic Research Unit; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-AUG-1989; Project End 31-MAR-2007 Summary: Nuclear receptor genes comprise a large family and encode receptors for thyroid and steroid hormones, vitamin D, retinoids, prostaglandins, and other ligands. These receptors regulate most human processes and are important pharmaceutical targets. The receptors contain amino-terminal, DNA-binding and ligand-binding (LBD) domains. Ligand-induced receptor conformational changes induce receptor activities that regulate transcription. Receptors mediate effects through interactions with other proteins, including coactivators and heterodimerizing partners. Central to
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understanding receptor actions is knowing their atomic structures. The Principal Investigator and colleagues first solved the X-ray structure of a liganded nuclear receptor LBD, that of the thyroid hormone receptor- alpha (TRalpha) that revealed insights into receptor function, and subsequently solved other structures, including TRalpha LBD bound to several ligands, human (h) TRbeta bound to agonists, including one that is TRbeta-selective, hTRbeta bound to a coactivator peptide and mutated hTRbeta forms that cause thyroid hormone resistance. These structures have revealed more information about receptor function, have been useful for designing a ligand that selectively modulates hTRbeta bound to a coactivator peptide and mutated hTRbeta forms that cause thyroid hormone resistance. These structures have revealed more information about receptor function, have been useful for designing a ligand that selectively modulates hTRbeta thyroid hormone response sand may be a prototype drug for treating obesity and hypercholesterolemia, and for designing thyroid hormone antagonists that may be prototypes for treating hyperthyroidism. In the proposed studies it is planned to determine the X-ray crystal structure of the hTRbeta PBD bound to several different ligands that perturb the structure in different ways, hTRbeta complexed with a retinoid X-receptor (RXR) heterodimerizing partner, and liganded hTRbeta LBD complexed with a novel coactivator peptide and a cyclized high affinity binding coactivator peptide. It is also planned to determine X-ray structures of RXR and TR DBD-LBD proteins and the full-length TR. The new structures should provide information about hormone-induced conformational changes, mechanisms of receptor interaction with other protein, the multiple receptor domains, and relations between domains. The results should yield insights into TR function and how ligands act as agonists or antagonist, are applicable to nuclear receptors in general, and may facilitate pharmaceutical design. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSCAPILLARY FLUID EXCHANGE Principal Investigator & Institution: Granger, D. Neil.; Boyd Professor and Head; Molecular and Cellular Physio; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, La 71103 Timing: Fiscal Year 2002; Project Start 01-DEC-1986; Project End 31-MAY-2004 Summary: Hypercholesterolemia, an established risk factor for ischemic diseases of the heart, brain, liver and other tissues, appears to alter the function of both circulating blood cells and microvascular endothelial cells. Recent evidence in the literature and from our laboratory indicates that hypercholesterolemia profoundly exaggerates the microvascular dysfunction, inflammatory cell infiltration, and cellular necrosis associated with reperfusion of ischemic tissues. The work proposed in this application will extend our effort to define the mechanisms that underlie these exaggerated responses to ischemia/reperfusion (I/R) in hypercholesterolemic animals. We propose to assess the contributions of lymphocytes, platelets, and enhanced oxidant production to the leukocyte-endothelial cell adhesion, capillary malperfusion, tissue hypoxia, cytokine production, and cellular necrosis observed in an established model of I/R induced liver injury. Wild-type and LDL-receptor knockout mice with normal and elevated serum cholesterol levels will be studied. Intravital fluorescence microscopy will be used to monitor the number of perfused sinusoids and the accumulation of total leukocytes, lymphocytes, and platelets in liver sinusoids and hepatic venules after I/R. NADH autofluorescence will be monitored as an index of oxidative stress (tissue hypoxia) while the oxidation of dihyrorhodamine 123 will be used to monitor oxidant production. Plasma levels of liver enzymes will be used to assess hepatocellular injury,
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while a radiolabelled monoclonal antibody technique will be used to quantify the expression of P-selectin in the liver vasculature. One specific aim will focus on the influence of varying durations of ischemia, followed by reperfusion on the microvascular accumulation of total leukocytes, lymphocytes (T- and B-cells), and platelets in the postischemic liver of normal and hypercholesterolemic mice. A second specific aim will focus on the contributions of lymphocytes and platelets to the exaggerated responses of the liver microvasculature to I/R. SCID mice, reconstituted with specific lymphocyte populations from wild-type and mutant mice, will be used to address the role of lymphocytes in I/R-induced liver injury. Platelet-directed interventions (including neutralizing antibodies and mutant mice) will be used to assess the contribution of platelet accumulation. A third specific aim will determine whether the accumulation of these inflammatory cells and subsequent tissue injury is linked to an enhanced production of oxidants in hypercholesterolemic mice. Different mutant mice and oxidant-directed reagents will be used to assess the contribution and source of oxidants in normal and hypercholesterolemic mice. The results obtained from the proposed studies should lead to an improved understanding of the mechanisms by which hypercholesterolemia exacerbates ischemic tissue injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSCRIPTIONAL ANALYSIS OF POLLUTANT EXPOSURE Principal Investigator & Institution: Shohet, Ralph Victor.; Professor; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2004; Project Start 01-AUG-2004; Project End 31-JUL-2007 Summary: (provided by applicant): The overall objective of this application is to better understand the molecular mechanism of cardiovascular disease that are modified by environmental pollutants. The investigator's models of environmental toxicity will be diesel and gasoline emissions. The underlying hypothesis of this work is that transcriptional regulation in response to these emissions will identify genes that are important in the development of pollution-related cardiovascular disease. Their primary goal is to determine the transcriptional response to complex emissions and the secondary goal is to evaluate any synergistic effect of hypercholesterolemia on this process. Thus, this project will have two specific aims: Specific Aim 1: To define the transcriptional response to whole-exhaust emissions in monocytes and endothelial cells in vivo. The investigators hypothesis is that the different chemical make-up of diesel exhaust and coal emissions will elicit varied transcriptional responses in endothelial cells and monocytes. They will conduct exposures at two concentrations and with both acute (3 day) and chronic (6 week) duration. Specific Aim 2: To determine the interaction of hypercholesterolemia with inhaled pollutants on gene regulation in these cells. The hypothesis is that whole exhaust will elicit transcriptional pathways relevant to the formation of atherosclerotic vascular disease, and that these effects will be more substantial in a susceptible model. The investigators will therefore expose control and ApoE -/- mice, on a atherosclerotic diet, to low levels of whole exhaust for 6 weeks. The investigators will use thorough transcriptional analysis to identify genes that are regulated in response to emission, in a novel mouse model that permits assessment of in vivo endothelial responses. They expect that these studies will generate an understanding of the mechanism of exhaust-related cardiovascular morbidity and identify the most important components of whole exhaust that cause such morbidity. They further anticipate that these insights will enhance our understanding of vascular pathology and potentially direct efforts at reducing the toxicity of combustion exhaust. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSCRIPTIONAL ATHEROGENESIS
CONTROL
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Principal Investigator & Institution: Chawla, Ajay; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: Our long-term goal is to understand how lipids regulate gene expression in vascular cells, and how these pathways contribute to the pathogenesis of coronary artery disease. Epidemiologic studies have clearly established the pathogenic link between dyslipidemias, such as hypercholesterolemia and hypertriglyceridemia, and the development of atherosclerotic heart disease. Intensive research in understanding the biochemical modifications that confer pathogenicity to the LDL particles has elucidated the molecular route through which oxLDL regulates gene expression in lesional macrophages and contributes to the development of vascular disease. However, the molecular and cellular responses to triglyceride-rich lipoproteins, such as VLDL, remain poorly understood. Our previous studies have identified a transcriptional pathway in macrophages that is driven by VLDL through the activation of PPAR delta. Interestingly, these studies revealed that the fatty acids that are present in VLDL particle can potently transactivate the PPAR delta receptor. Consistent with this, treatment of wild type, but not PPAR delta null, macrophages with the VLDL particle resulted in transcriptional induction of target genes. The studies proposed in the present grant application will take molecular, cellular, and genetic approaches to further investigate how PPAR gamma and delta orchestrate the macrophage response to incoming fatty acids. Data from these studies will greatly enhance our understanding of the how these receptors regulate macrophage homeostatic responses in both physiologic and pathophysiologic conditions, and potentially lead to the identification of new therapeutic targets to treat this chronic disease. The specific aims of this proposal are to: 1) Determine the pathways by which PPAR gamma controls macrophage fatty acid metabolism, 2) Assess the regulatory role of PPAR delta in the utilization of fatty acids by macrophages, and 3) Determine the molecular mechanisms by which PPAR delta regulates macrophage inflammatory response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSGENIC RAT MODELS OF ALZHEIMER'S DISEASE Principal Investigator & Institution: Herrera, Victoria Lm.; Associate Professor; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 15-FEB-2000; Project End 31-JAN-2004 Summary: Animal models are proven investigative tools for study of complex human diseases such as Alzheimer s Disease (AD) and atherosclerosis. Trangenic and bigenic mouse models for presenilin-1 (PS1) and amyloid precursor protein (APP) human gene variants have been instrumental in delineating their roles in AD pathogenesis. However, to date these mouse models have not exhibited key AD pathology such as neurofibrillary tangles, neuronal loss and AD-associated cognitive/neurobehavioral deficits. We hypothesize that a more phenotypically robust and experimentally accessible model of Alzheimer s disease will be obtained in the rat based on key observations: a) rat ApoE is more homologous to human ApoE4 compared with mouse; b) rat complement, like the human has greater levels compared with the mouse and might be a key determinant to the development of neurofibrillary tangles; c) neurobehavioral studies assessing aging and hippocampal-specific learning and memory deficits have been validated in the rat; d) the size of the rat allows lesioning and
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imaging studies; f) the more robust atherosclerotic phenotype in transgenic rats compared with mice given the same human cholesteryl ester transfer (hCETP) transgene indicates valid modeling for complex diseases. This proposal focuses on the following specific aims. (1) Develop three key inbred Fischer 344 rat AD models with the highest probability for a robust AD phenotype: a) homozygous high-expresser of mutant human APPSWE AD gene, TgAPP, b) homozygous bigenic with both mutant human PSIM146L and hAPPSWE, 2TG[PS1xAPP], and a trigenic rat model, 3Tg]PS1 x APAP x hCETP], which imposes, if not test, hypercholesterolemia-induced exacerbaytion of amyloidogenic APP processing in vivo. (2) Investigate the degree of cognitive deficits in the combinational transgenic rat AD models by measuring hippocampal-dependent working memory and spatial learning and memory at 12, 18, 24 months. 3) Correlate observed hippocampal-dependent neurobehavioral alterations with AD- associated neuropathological alterations at 12, 18, and 24 months. (4) Correlate key neurobehavioral and neuropathological alterations with molecular and cellular markers of AD pathogenesis at 12, 18, and 24 months. Comparative analysis of the proposed rat models will not only address an accessible AD model for mechanistic dissection and therapy development, but also provide insight into the role of complement- and hypercholesterolemia-mediated disease paradigms in AD pathogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VALIDATION OF ADHERENCE DATA--USE IN CLINICAL PRACTICE Principal Investigator & Institution: Pladevall, Manel; None; Case Western Reserve Univ-Henry Ford Hsc Research Administraion Cfp-046 Detroit, Mi 48202 Timing: Fiscal Year 2003; Project Start 05-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): Non-Adherence to medications is a common problem in clinical practice especially among patients with asymptomatic chronic conditions like type II diabetes and hypercholesterolemia in whom some 50% of patients are non-adherent. The costs of poor adherence to medications have been estimated to approach $100 billion dollars a year and are the result of adverse outcomes such as hospitalization, the development of complications, disease progression, premature disability or death. Non-Adherence is the result of a complex interaction among the social environment, the patient and the health providers. Adherence to medications is not routinely measured in clinical practice and a gold standard that can be easily implemented even for research purposes does not exist. Yet, the use of claims data to measure adherence has been shown useful and, given the relatively small costs associated with its use, its implementation in routine clinical practice appears both feasible and sustainable. However, more information is needed on the validity of the method and on the consequences of making adherence information available to both patients and physicians. Using The Chronic Care model as a theoretical framework, we propose a two-phase study. In Phase I, claims data will be used to identify diabetic patients receiving pharmacological treatment for both diabetes and hypercholesterolemia and to measure their A to medications prescribed for the two conditions. The association between adherence indices and intermediate outcomes (glycosylated hemoglobin and cholesterol levels) will be estimated. In Phase II, qualitative (focus groups) and quantitative methods (telephone and mail surveys) will be used to examine patients' attitudes, beliefs, barriers, relationship with providers, and stages of change towards adherence and towards the introduction of adherence information in clinical practice in conjunction with the Health Belief and Stages of Change Models as explanatory theories. The study will help clarify the association
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between adherence and clinical outcomes as well as to estimate the predictive and convergent validity of prescription claims data as a method of measuring adherence to medications. Finally, we will explore intrinsic factors at the patient level related to adherence, and patient and provider preferences and attitudes towards the use of adherence information in routine clinical practice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VASCULAR RISK FACTORS IN ALZHEIMER'S DISEASE Principal Investigator & Institution: Li, Gail; Psychiatry and Behavioral Scis; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Candidate's Plan/Training: The Candidate plans a career as a patient-oriented clinical research investigator and academic geriatric psychiatrist bridging dementia, vascular risk factors and clinical epidemiology. Training will include formal didactics in lipid metabolism and augmentation of the Candidate's previous epidemiology training with additional advanced biostatistics and epidemiology courses and closely supervised completion of the research plan. Environment: The University of Washington Alzheimer's Disease Patient Registry (ADPR)/Adult Changes in Thought (ACT) and Alzheimer's Disease Research Center (ADRC) provide expertise in epidemiology, clinical dementia evaluation, and biostatistics to form an ideal research environment for epidemiological investigation of Alzheimer's disease (AD) and related dementias. Research: Recent studies suggest midlife hypercholesterolemia and hypertension increase risk of dementia and specifically AD in late life. Cholesterol-lowering medications, the 3-hydroxy-3-methylglutarylcoenzyme-A reductase inhibitors, i.e., statins, may reduce the risk of AD. We hypothesize that vascular risk factors increase the risk of AD and/or vascular dementia (VaD) and use of statins reduces this risk. To address these hypotheses, Specific Aim 1 will determine whether the use of statins decreases the risk of AD and/or VaD, and whether these effects are modified by the presence of the Apolipoprotein Ee4 allele. We also investigate whether high serum low-density lipoprotein (LDL) and low serum highdensity lipoprotein (HDL) are associated with increased risk for AD and/or VaD. Specific Aim 2 will determine if hypertension in older age (> 65 years) increases the risk of AD and/or VaD; we will also investigate blood pressure changes prior to the diagnosis of AD and/or VaD. A prospectively enrolled community-based cohort of 2581 initially cognitively normal elderly will provide the framework for this study. Results from the research project will provide insights into vascular risk factors for AD, thus providing additional information toward development of new prevention and treatment strategies. This research plan, together with the didactic and mentored instruction proposed, will provide the career development necessary for the candidate to conduct scientifically rigorous, independently funded, patient-oriented research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: XANTHINE OXIDASE AND VASCULAR DYSFUNCTION Principal Investigator & Institution: White, C Roger.; Associate Professor; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAY-2003 Summary: (Adapted from applicants' abstract) Reactive oxygen species induce changes in vascular function in conditions such as stroke, hypertension and atherosclerosis. The nature and complexity of lesion development in atherosclerosis suggest that the disease
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may have several etiologies. The generation of free radicals is associated with alterations in both vascular reactivity and lipoprotein metabolism. The studies proposed in this application are designed to provide new information concerning oxidant-induced damage in the vessel wall. It is hypothesized that impaired blood vessel function in hypercholesterolemic rabbits is due to the modification of nitric oxide (NO) by superoxide anion (O2-), leading to the production of the potent oxidant peroxynitrite (ONOO-). Reactive oxygen species are generated under normal physiological conditions, with native antioxidant scavengers minimizing oxidant-mediated injury. An imbalance in antioxidant defense mechanisms and changes in cellular metabolic processes then contributes to the development and progression of atherosclerotic disease. The studies outlined in this application are designed to provide new information describing the cellular mechanisms involved in these free radical reactions, namely that free radical injury in blood vessels of hypercholesterolemic rabbits is linked to the binding and concentration of xanthine oxidase (XO) at glycosaminoglycan (GAG) sites on the surface of endothelial cells and in the interstitial space. The hypothesis to be tested in this application is that GAG-bound XO is an important source of O2-, thus ONOOformation, and contributes to the oxidative component of hypercholesterolemia. GAG function or expression may be altered by hyperlipidemia, thereby facilitating incorporation of lipoproteins in the vessel wall as well as serving as a site for XO binding and incorporation, influencing changes in the vasculature and playing an important role in the pathological events associated with hypercholesterolemia. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: XANTHINE OXIDASE MODULATION OF CELL OXIDANT PRODUCTION Principal Investigator & Institution: Tarpey, Margaret M.; Associate Professor; Anesthesiology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: (Adapted from the Applicant's Abstract): The endothelium serves as a critical component in the maintenance of vascular homeostasis. Alterations in endothelial cell production of oxidants contribute to defective vascular function and are implicated in the pathogenesis of diverse vascular diseases. However, the tissue sources of enhanced vascular cell oxidant production and the sites of oxidant action have not been determined with certainty. Recently, recognition of a) elevated plasma levels of circulating xanthine oxidase activity in diverse disease processes (sepsis, hypercholesterolemia, post- liver transplantation) and b) the ability of xanthine oxidase to specifically bind to endothelium with resultant increases in intracellular xanthine oxidase activity provide potential mechanism(s) by which non-endothelial cell-derived xanthine oxidase could contribute to endothelial oxidant production. While enhanced production of superoxide can diminish nitric oxide bioavailability by virtue of its reaction with nitric oxide and thus, concomitantly yield secondary oxidants, the potential for superoxide and other cellular oxidants to directly modify the activity of endothelial nitric oxide synthase has not been fully explored. From this foundation of understanding, it is hypothesized that increases in cell-associated xanthine oxidase modulate endothelial-dependent vascular function. To address this hypothesis, the following Specific Aims will be pursued: 1) Characterize vascular cell interactions with circulating xanthine oxidase. The kinetics of cell binding and uptake of circulating xanthine oxidase/dehydrogenase will be determined. In addition, xanthine oxidase
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circulating and ultimate tissue distribution will be defined in vivo. 2) Explore the impact of elevated xanthine oxidase-derived products (reactive species, uric acid) on expression and activity of endothelial nitric oxide synthase. The effects of xanthine oxidase on transcription and translation of endothelial nitric oxide synthase will be ascertained as well. The vascular functional consequences of increased xanthine oxidase activity will also be determined. Upon successful completion of the proposed aims, a) the contribution of xanthine oxidase to endothelial cell oxidant production will be better defined, b) detailed mechanistic information will be available regarding the presence, reactions and regulation of specific oxidative pathways that modulate endothelial nitric oxide synthase expression and activity and c) new insight will be gained for prospectively devising mechanism-directed pharmacologic strategies. 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.; Director of Research; 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
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
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.
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unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “hypercholesterolemia” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for hypercholesterolemia in the PubMed Central database: •
Cardiovascular effects of acute hypercholesterolemia in rabbits. Reversal with lovastatin treatment. by Osborne JA, Lento PH, Siegfried MR, Stahl GL, Fusman B, Lefer AM.; 1989 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303702
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Defects of receptor-mediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo. by Thompson GR, Soutar AK, Spengel FA, Jadhav A, Gavigan SJ, Myant NB.; 1981 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=319395
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Degradation of cationized low density lipoprotein and regulation of cholesterol metabolism in homozygous familial hypercholesterolemia fibroblasts. by Basu SK, Goldstein JL, Anderson GW, Brown MS.; 1976 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=430973
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Evidence for a dominant gene that suppresses hypercholesterolemia in a family with defective low density lipoprotein receptors. by Hobbs HH, Leitersdorf E, Leffert CC, Cryer DR, Brown MS, Goldstein JL.; 1989 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=329701
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Familial Hypercholesterolemia (One Form of Familial Type II Hyperlipoproteinemia) A STUDY OF ITS BIOCHEMICAL, GENETIC, AND CLINICAL PRESENTATION IN CHILDHOOD. by Kwiterovich PO Jr, Fredrickson DS, Levy RI.; 1974 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302610
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Familial Hypercholesterolemia EVIDENCE FOR A NEWLY RECOGNIZED MUTATION DETERMINING INCREASED FIBROBLAST RECEPTOR AFFINITY BUT DECREASED CAPACITY FOR LOW DENSITY LIPOPROTEIN IN TWO SIBLINGS. by Ostlund RE Jr, Levy RA, Witztum JL, Schonfeld G.; 1982 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=370290
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Familial hypercholesterolemia in a rhesus monkey pedigree: molecular basis of low density lipoprotein receptor deficiency. by Hummel M, Li ZG, Pfaffinger D, Neven L, Scanu AM.; 1990 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=53846
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Homozygous familial hypercholesterolemia mutant with a defect in internalization of low density lipoprotein. by Miyake Y, Tajima S, Yamamura T, Yamamoto A.; 1981 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=320351
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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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•
Identification of a point mutation in growth factor repeat C of the low density lipoprotein-receptor gene in a patient with homozygous familial hypercholesterolemia that affects ligand binding and intracellular movement of receptors. by Soutar AK, Knight BL, Patel DD.; 1989 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=287410
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Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level. by Sorensen KE, Celermajer DS, Georgakopoulos D, Hatcher G, Betteridge DJ, Deanfield JE.; 1994 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=293724
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Inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase by mevinolin in familial hypercholesterolemia heterozygotes: effects on cholesterol balance. by Grundy SM, Bilheimer DW.; 1984 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=345098
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Knockout of the Mouse Apolipoprotein B Gene Results in Embryonic Lethality in Homozygotes and Protection Against Diet-Induced Hypercholesterolemia in Heterozygotes. by Farese RV Jr, Ruland SL, Flynn LM, Stokowski RP, Young SG.; 1995 Feb 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42602
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Localization of low density lipoprotein receptors on plasma membrane of normal human fibroblasts and their absence in cells from a familial hypercholesterolemia homozygote. by Anderson RG, Goldstein JL, Brown MS.; 1976 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=430596
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Metabolic Studies in Familial Hypercholesterolemia EVIDENCE FOR A GENEDOSAGE EFFECT IN VIVO. by Bilheimer DW.; 1979 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=372147
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Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. by Bilheimer DW, Grundy SM, Brown MS, Goldstein JL.; 1983 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=394213
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Relationship between apolipoprotein(a) phenotype, lipoprotein(a) concentration in plasma, and low density lipoprotein receptor function in a large kindred with familial hypercholesterolemia due to the pro664----leu mutation in the LDL receptor gene. by Soutar AK, McCarthy SN, Seed M, Knight BL.; 1991 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=295368
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Resistance to dietary-induced hypercholesterolemia exhibited by a unique strain of New Zealand white rabbits. by Overturf ML, Buck RA, Loose-Mitchell DS.; 1994; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325132
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Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1. by Eden ER, Patel DD, Sun XM, Burden JJ, Themis M, Edwards M, Lee P, Neuwirth C, Naoumova RP, Soutar AK.; 2002 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151635
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Saturation and suppression of hepatic lipoprotein receptors: a mechanism for the hypercholesterolemia of cholesterol-fed rabbits. by Kovanen PT, Brown MS, Basu SK, Bilheimer DW, Goldstein JL.; 1981 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=319137
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The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery. by Mishra SK, Watkins SC, Traub LM.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138571
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The familial hypercholesterolemia (FH)-North Karelia mutation of the low density lipoprotein receptor gene deletes seven nucleotides of exon 6 and is a common cause of FH in Finland. by Koivisto UM, Turtola H, Aalto-Setala K, Top B, Frants RR, Kovanen PT, Syvanen AC, Kontula K.; 1992 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=443084
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Treatment of familial hypercholesterolemia by portacaval anastomosis: effect on cholesterol metabolism and pool sizes. by McNamara DJ, Ahrens EH Jr, Kolb R, Brown CD, Parker TS, Davidson NO, Samuel P, McVie RM.; 1983 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=393420
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Treatment of severe hypercholesterolemia in apolipoprotein E-deficient mice by bone marrow transplantation. by Boisvert WA, Spangenberg J, Curtiss LK.; 1995 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185301
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Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners. by Leitersdorf E, Van der Westhuyzen DR, Coetzee GA, Hobbs HH.; 1989 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=329741
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. 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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To generate your own bibliography of studies dealing with hypercholesterolemia, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “hypercholesterolemia” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for hypercholesterolemia (hyperlinks lead to article summaries): •
A G-1-to-A acceptor splice site LDLR mutant allele leads to reduced relative transcript levels in patients with heterozygous familial hypercholesterolemia. Author(s): Jensen HK, Jensen LG, Hansen PS, Bolund L, Faergeman O, Gregersen N. Source: Clinical Genetics. 1996 April; 49(4): 175-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8828981
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A multinational study of the effects of low-dose pravastatin in patients with noninsulin-dependent diabetes mellitus and hypercholesterolemia. Pravastatin Multinational Study Group for Diabetes. Author(s): Behounek BD, McGovern ME, Kassler-Taub KB, Markowitz JS, Bergman M. Source: Clin Cardiol. 1994 October; 17(10): 558-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8001304
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A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Author(s): Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, Skolnick MH, Hopkins PN, Hunt SC, Shattuck DM. Source: Human Genetics. 2004 March; 114(4): 349-53. Epub 2004 January 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14727179
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A novel splice-site mutation in intron 7 causes more severe hypercholesterolemia than a combined FH-FDB defect. Author(s): deCampo A, Schallmoser K, Schmidt H, Toplak H, Kostner GM. Source: Atherosclerosis. 2001 August; 157(2): 524-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11472756
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A pedigree analysis of familial hypercholesterolemia in monozygote twin brothers. Author(s): Li JJ, Chen MZ, Chen X. Source: Angiology. 2003 November-December; 54(6): 711-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14666960
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A randomized, double-blind comparison of cerivastatin and lovastatin for treatment of primary hypercholesterolemia. Author(s): Yu WC, Chen CH, Tsao HM, Ding YA. Source: Zhonghua Yi Xue Za Zhi (Taipei). 2002 June; 65(6): 260-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12201566
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A single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia. Author(s): Koivisto UM, Palvimo JJ, Janne OA, Kontula K. Source: Proceedings of the National Academy of Sciences of the United States of America. 1994 October 25; 91(22): 10526-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7937987
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A splice mutation in a Syrian autosomal recessive hypercholesterolemia family causes a two-nucleotide deletion of mRNA. Author(s): Al-Kateb H, Bautz EK, Luft FC, Bahring S. Source: Circulation Research. 2003 September 5; 93(5): E49-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12958143
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Acyl-coenzyme A:cholesterol acyltransferase inhibitors for controlling hypercholesterolemia and atherosclerosis. Author(s): Miyazaki A, Sakai M, Sakamoto Y, Horiuchi S. Source: Curr Opin Investig Drugs. 2003 September; 4(9): 1095-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14582454
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An alanine29-serine variant in exon 2 of the low density lipoprotein receptor gene: no association with hypercholesterolemia. Author(s): Jensen HK, Jensen LG, Hansen PS, Petersen LS, Gerdes LU, Bolund L, Faergeman O, Gregersen N. Source: Clinical Genetics. 1994 August; 46(2): 214-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7820934
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Analysis of low-density lipoprotein receptor gene mutations in a Chinese patient with clinically homozygous familial hypercholesterolemia. Author(s): Cao S, Wang L, Qin Y, Lin J, Wu B, Liu S, Pan X, Du L, Chen B. Source: Chinese Medical Journal. 2003 October; 116(10): 1535-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14570618
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Apolipoprotein E polymorphism and heterozygous familial hypercholesterolemia. Sex-specific effects. Author(s): Ferrieres J, Sing CF, Roy M, Davignon J, Lussier-Cacan S. Source: Arterioscler Thromb. 1994 October; 14(10): 1553-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7918304
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Ask the doctor. I am a 64-year-old woman with high cholesterol caused by bad genes (familial hypercholesterolemia). Without medication, my cholesterol is above 450 mg/dL. So I am taking high-dose Lipitor (80 mg/day), WelChol, and Zetia to lower my cholesterol. I sometimes have pain and stiffness in my knees, and my shoulder, elbow, and wrist joints, plus the muscles in between, are stiff in the morning and hurt during the day. Two years ago I was diagnosed with bursitis in my hips. Could these problems be from the Lipitor? If so, is there another statin I could take that wouldn't do this? Author(s): Pasternak R. Source: Harvard Heart Letter : from Harvard Medical School. 2003 October; 14(2): 8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14576039
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Association of gene polymorphisms with coronary artery disease in individuals with or without nonfamilial hypercholesterolemia. Author(s): Shimokata K, Yamada Y, Kondo T, Ichihara S, Izawa H, Nagata K, Murohara T, Ohno M, Yokota M. Source: Atherosclerosis. 2004 January; 172(1): 167-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709372
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Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Author(s): Steinberg D. Source: Nature Medicine. 2002 November; 8(11): 1211-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12411947
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Atorvastatin reduces expression of leukocyte adhesion molecules in patients with hypercholesterolemia. Author(s): Stulc T, Vrablik M, Kasalova Z, Ceska R, Marinov I. Source: Atherosclerosis. 2003 January; 166(1): 197-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12482568
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Atorvastatin treatment does not affect gonadal and adrenal hormones in type 2 diabetes patients with mild to moderate hypercholesterolemia. Author(s): Santini SA, Carrozza C, Lulli P, Zuppi C, CarloTonolo G, Musumeci S. Source: J Atheroscler Thromb. 2003; 10(3): 160-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14564085
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Autosomal recessive hypercholesterolemia in a Sicilian kindred harboring the 432insA mutation of the ARH gene. Author(s): Barbagallo CM, Emmanuele G, Cefalu AB, Fiore B, Noto D, Mazzarino MC, Pace A, Brogna A, Rizzo M, Corsini A, Notarbartolo A, Travali S, Averna MR. Source: Atherosclerosis. 2003 February; 166(2): 395-400. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12535754
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Baseline lipid values partly determine the response to high-dose simvastatin in patients with familial hypercholesterolemia. The examination of probands and relatives in Statin studies with familial hypercholesterolemia (ExPRESS FH). Author(s): de Sauvage Nolting PR, Buirma RJ, Hutten BA, Kastelein JJ; Dutch ExPRESS investigators Group. Source: Atherosclerosis. 2002 October; 164(2): 347-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12204807
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Beneficial effect of cholesterol-lowering therapy on endothelium-dependent coronary vasodilation in patients with hypercholesterolemia. Author(s): Egashira K, Takeshita A. Source: Annals of the New York Academy of Sciences. 1995 January 17; 748: 622-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7695217
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Beneficial effect of lovastatin on sphincter of Oddi dyskinesia in hypercholesterolemia and hypertriglyceridemia. Author(s): Szilvassy Z, Nagy I, Madacsy L, Hajnal F, Velosy B, Takacs T, Lonovics J. Source: The American Journal of Gastroenterology. 1997 May; 92(5): 900-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9149215
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Benefits and costs of medical nutrition therapy by registered dietitians for patients with hypercholesterolemia. Massachusetts Dietetic Association. Author(s): McGehee MM, Johnson EQ, Rasmussen HM, Sahyoun N, Lynch MM, Carey M. Source: Journal of the American Dietetic Association. 1995 September; 95(9): 1041-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7657908
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Benefits of hypercholesterolemia treatment. Author(s): Soma M, Paoletti R. Source: Pharmacological Research : the Official Journal of the Italian Pharmacological Society. 1997 March; 35(3): 159. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9229398
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Beta-blocker effects on plasma lipids during prolonged treatment of hypertensive patients with hypercholesterolemia. Author(s): Fogari R, Zoppi A, Corradi L, Preti P, Mugellini A, Lusardi P. Source: Journal of Cardiovascular Pharmacology. 1999 April; 33(4): 534-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10218722
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Biliary lipid composition in heterozygous familial hypercholesterolemia and influence of treatment with probucol. Author(s): Tanno N, Oikawa S, Koizumi M, Kotake H, Hirakawa H, Kanazawa Y, Toyota T. Source: Digestive Diseases and Sciences. 1994 July; 39(7): 1586-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8026274
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Biliopancreatic diversion preserving the stomach and pylorus in the treatment of hypercholesterolemia and diabetes type II: results in the first 10 cases. Author(s): Noya G, Cossu ML, Coppola M, Tonolo G, Angius MF, Fais E, Ruggiu M. Source: Obesity Surgery : the Official Journal of the American Society for Bariatric Surgery and of the Obesity Surgery Society of Australia and New Zealand. 1998 February; 8(1): 67-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9562490
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Binding affinity and particle size of LDL in subjects with moderate hypercholesterolemia: relationship with in vivo LDL metabolism. Author(s): Yamane K, Kataoka S, Le NA, Paidi M, Howard WJ, Hannah JS, Howard BV. Source: Journal of Lipid Research. 1996 August; 37(8): 1646-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8864948
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Binding of 111In-labeled HDL to platelets from normolipemic volunteers and patients with heterozygous familial hypercholesterolemia. Author(s): Virgolini I, Li S, Yang Q, Banyai M, Koller E, Angelberger P, Sinzinger H. Source: Arterioscler Thromb. 1992 July; 12(7): 849-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1319736
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Binding of 111In-labeled LDL to platelets of normolipemic volunteers and patients with heterozygous familial hypercholesterolemia. Author(s): Virgolini I, Li S, Qiong Y, Koller E, Banyai M, Angelberger P, Sinzinger H. Source: Arterioscler Thromb. 1993 April; 13(4): 536-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8466889
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Biochemical and functional alterations associated with hypercholesterolemia in platelets from hypertensive patients. Author(s): Mazeaud MM, Driss F, Le Quan Sang KH, Duranthon V, Levenson J, Simon A, Devynck MA. Source: Atherosclerosis. 1992 June; 94(2-3): 201-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1321632
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Burden of disease from hypercholesterolemia in Portugal. Author(s): Gouveia M, Borges M, Costa J, Carneiro AV. Source: Rev Port Cardiol. 2004 February; 23(2): 255-70. English, Portuguese. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15116460
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Cardiovascular disease and mortality in statin-treated patients with familial hypercholesterolemia. Author(s): Mohrschladt MF, Westendorp RG, Gevers Leuven JA, Smelt AH. Source: Atherosclerosis. 2004 February; 172(2): 329-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15019543
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Carotid artery wall shear stress after LDL-apheresis in familial hypercholesterolemia. Author(s): Bardelli M, Cominotto F, Fazio M, Ussi D, Bordin P, Petrucco A, Fabris B, Fischetti F, Lapasin R, Carretta R. Source: Boll Soc Ital Biol Sper. 1994 October-November; 70(10-11): 295-7. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7702833
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Central nervous system effects of HMG CoA reductase inhibitors: lovastatin and pravastatin on sleep and cognitive performance in patients with hypercholesterolemia. Author(s): Kostis JB, Rosen RC, Wilson AC. Source: Journal of Clinical Pharmacology. 1994 October; 34(10): 989-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7836550
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Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia. Role of oxidized LDL. Author(s): Heitzer T, Yla-Herttuala S, Luoma J, Kurz S, Munzel T, Just H, Olschewski M, Drexler H. Source: Circulation. 1996 April 1; 93(7): 1346-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8641023
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Clinical and biochemical characterisation of patients with autosomal recessive hypercholesterolemia (ARH). Author(s): Fellin R, Zuliani G, Arca M, Pintus P, Pacifico A, Montali A, Corsini A, Maioli M. Source: Nutr Metab Cardiovasc Dis. 2003 October; 13(5): 278-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14717060
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Clinical effects of rosuvastatin, a new HMG-CoA reductase inhibitor, in Japanese patients with primary hypercholesterolemia: an early phase II study. Author(s): Yamamoto A, Arakawa K, Sasaki J, Matsuzawa Y, Takemura K, Tsushima M, Fujinami T, Mabuchi H, Itakura H, Yamada N, Toyota T, Oikawa S; Rosuvastatin DoseRanging Trialist Group. Source: J Atheroscler Thromb. 2002; 9(1): 48-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12238638
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Clinical features and genetic analysis of autosomal recessive hypercholesterolemia. Author(s): Harada-Shiba M, Takagi A, Miyamoto Y, Tsushima M, Ikeda Y, Yokoyama S, Yamamoto A. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 June; 88(6): 2541-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12788851
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Clinical implications of increased low-density lipoprotein oxidation in patients with hypercholesterolemia. Author(s): Stalenhoef AF. Source: Nutrition (Burbank, Los Angeles County, Calif.). 1994 November-December; 10(6): 564-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7703607
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Collateral formation and clinical variables in obstructive coronary artery disease: the influence of hypercholesterolemia and diabetes mellitus. Author(s): Kornowski R. Source: Coronary Artery Disease. 2003 February; 14(1): 61-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12629327
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Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial. Author(s): Illingworth DR, Stein EA, Mitchel YB, Dujovne CA, Frost PH, Knopp RH, Tun P, Zupkis RV, Greguski RA. Source: Archives of Internal Medicine. 1994 July 25; 154(14): 1586-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8031206
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Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Author(s): Schneck DW, Knopp RH, Ballantyne CM, McPherson R, Chitra RR, Simonson SG. Source: The American Journal of Cardiology. 2003 January 1; 91(1): 33-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12505568
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Comparison of forearm endothelial function between premenopausal and postmenopausal women with or without hypercholesterolemia. Author(s): Sanada M, Higashi Y, Nakagawa K, Kodama I, Tsuda M, Nagai N, Chayama K, Ohama K. Source: Maturitas. 2003 April 25; 44(4): 307-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12697372
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Comparison of lipid-lowering effects of low-dose fluvastatin and conventional-dose gemfibrozil in patients with primary hypercholesterolemia. Author(s): Betteridge DJ, Durrington PN, Fairhurst GJ, Jackson G, McEwan MS, McInnes GT, Miller JP, Mir MA, Reckless JP, Rees-Jones DI, et al. Source: The American Journal of Medicine. 1994 June 6; 96(6A): 45S-54S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8017467
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Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia. Author(s): Stein EA, Strutt K, Southworth H, Diggle PJ, Miller E; HeFH Study Group. Source: The American Journal of Cardiology. 2003 December 1; 92(11): 1287-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14636905
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Comparison of the effectiveness of lovastatin therapy for hypercholesterolemia after heart transplantation between patients with and without pretransplant atherosclerotic coronary artery disease. Author(s): Anguita M, Alonso-Pulpon L, Arizon JM, Cavero MA, Valles F, Segovia J, Perez-Jimenez F, Crespo M, Concha M. Source: The American Journal of Cardiology. 1994 October 15; 74(8): 776-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7942548
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Comparison of the efficacy, safety and tolerability of original policosanol versus other mixtures of higher aliphatic primary alcohols in patients with type II hypercholesterolemia. Author(s): Castano G, Fernandez L, Mas R, Illnait J, Fernandez J, Mesa M, Alvarez E, Lezcay M. Source: Int J Clin Pharmacol Res. 2002; 22(2): 55-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12503776
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Comparison of treatment with fluvastatin extended-release 80-mg tablets and immediate-release 40-mg capsules in patients with primary hypercholesterolemia. Author(s): Isaacsohn JL, LaSalle J, Chao G, Gonasun L. Source: Clinical Therapeutics. 2003 March; 25(3): 904-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12852707
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Compliance with National Cholesterol Education Program dietary and lifestyle guidelines among older women with self-reported hypercholesterolemia. The Women's Health Initiative. Author(s): Hsia J, Rodabough R, Rosal MC, Cochrane B, Howard BV, Snetselaar L, Frishman WH, Stefanick ML. Source: The American Journal of Medicine. 2002 October 1; 113(5): 384-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12401533
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Continuity of care and recognition of diabetes, hypertension, and hypercholesterolemia. Author(s): Koopman RJ, Mainous AG 3rd, Baker R, Gill JM, Gilbert GE. Source: Archives of Internal Medicine. 2003 June 9; 163(11): 1357-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796073
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CYP3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholesterolemia. Author(s): Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. Source: The American Journal of Cardiology. 2004 January 1; 93(1): 104-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14697480
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Daily dosing versus alternate-day dosing of simvastatin in patients with hypercholesterolemia. Author(s): Copher HR, Stewart RD. Source: Pharmacotherapy. 2002 September; 22(9): 1110-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12222546
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Damage to the structure of erythrocyte plasma membranes in patients with type-2 hypercholesterolemia. Author(s): Koter M, Franiak I, Strychalska K, Broncel M, Chojnowska-Jezierska J. Source: The International Journal of Biochemistry & Cell Biology. 2004 February; 36(2): 205-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14643886
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DEAE-Dextran in the treatment of primary hypercholesterolemia and/or hypercholesterolemia combined with hypertriglyceridemia. A multicentric randomized study on the efficacy of DEAE-Dextran compared with Cholestyramine. Author(s): Fedele F. Source: Clin Ter. 2003 July-August; 154(4): 231-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14618939
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Decreased macrophage paraoxonase 2 expression in patients with hypercholesterolemia is the result of their increased cellular cholesterol content: effect of atorvastatin therapy. Author(s): Rosenblat M, Hayek T, Hussein K, Aviram M. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2004 January; 24(1): 175-80. Epub 2003 October 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14592851
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Depressive mood accompanies hypercholesterolemia in young Japanese adults. Author(s): Nakao M, Ando K, Nomura S, Kuboki T, Uehara Y, Toyooka T, Fujita T. Source: Japanese Heart Journal. 2001 November; 42(6): 739-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11933923
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Detection and quantitation of calcific atherosclerosis by ultrafast computed tomography in children and young adults with homozygous familial hypercholesterolemia. Author(s): Hoeg JM, Feuerstein IM, Tucker EE. Source: Arterioscler Thromb. 1994 July; 14(7): 1066-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8018661
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Detection of a novel exon 4 low-density lipoprotein receptor gene deletion in a swiss family with severe familial hypercholesterolemia. Author(s): Neff D, Ruschitzka F, Hersberger M, Enseleit F, Hurlimann D, Noll G, Luscher T, Hanseler E. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2003 March; 41(3): 266-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12705331
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Detection of a novel mutation (stop 468) in exon 10 of the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians. Author(s): Simard J, Moorjani S, Vohl MC, Couture P, Torres AL, Gagne C, Despres JP, Labrie F, Lupien PJ. Source: Human Molecular Genetics. 1994 September; 3(9): 1689-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7833932
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Detection of familial defective apolipoprotein B-100 among patients clinically diagnosed with heterozygous familial hypercholesterolemia in maritime Canada. Author(s): Morash B, Guernsey DL, Tan MH, Dempsey G, Nassar BA. Source: Clinical Biochemistry. 1994 August; 27(4): 265-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8001287
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Diet first, then medication for hypercholesterolemia. Author(s): Anderson JW. Source: Jama : the Journal of the American Medical Association. 2003 July 23; 290(4): 531-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12876098
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Diet-dependent obesity and hypercholesterolemia in the New Zealand obese mouse: identification of a quantitative trait locus for elevated serum cholesterol on the distal mouse chromosome 5. Author(s): Giesen K, Plum L, Kluge R, Ortlepp J, Joost HG. Source: Biochemical and Biophysical Research Communications. 2003 May 16; 304(4): 812-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12727230
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Diet-induced hypercholesterolemia enhances brain A beta accumulation in transgenic mice. Author(s): Shie FS, Jin LW, Cook DG, Leverenz JB, LeBoeuf RC. Source: Neuroreport. 2002 March 25; 13(4): 455-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11930160
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Differential hs-CRP reduction in patients with familial hypercholesterolemia treated with aggressive or conventional statin therapy. Author(s): van Wissen S, Trip MD, Smilde TJ, de Graaf J, Stalenhoef AF, Kastelein JJ. Source: Atherosclerosis. 2002 December; 165(2): 361-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12417288
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Discovery of the hepatic canalicular and intestinal cholesterol transporters. New targets for treatment of hypercholesterolemia. Author(s): Zanlungo S, Nervi F. Source: Eur Rev Med Pharmacol Sci. 2003 March-April; 7(2): 33-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12911117
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Distinct patterns of lipoproteins with apoB defined by presence of apoE or apoC-III in hypercholesterolemia and hypertriglyceridemia. Author(s): Campos H, Perlov D, Khoo C, Sacks FM. Source: Journal of Lipid Research. 2001 August; 42(8): 1239-49. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11483625
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Disturbed regulation of cholesterol synthesis in monocytes of obese patients with hypercholesterolemia. Author(s): Paragh G, Balogh Z, Kovacs E, Szabolcs M, Szabo J, Csapo K, Foris G. Source: Metabolism: Clinical and Experimental. 2003 January; 52(1): 1-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12524654
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DNA testing for familial hypercholesterolemia: improving disease recognition and patient care. Author(s): Vergopoulos A, Knoblauch H, Schuster H. Source: American Journal of Pharmacogenomics : Genomics-Related Research in Drug Development and Clinical Practice. 2002; 2(4): 253-62. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12421096
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Dose response, safety, and efficacy of an extended-release formulation of lovastatin in adults with hypercholesterolemia. Author(s): Crouse JR 3rd, Lukacsko P, Niecestro R, Friedhoff L. Source: The American Journal of Cardiology. 2002 January 15; 89(2): 226-9. Erratum In: Am J Cardiol 2000 June 15; 89(12): 1452. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11792349
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Drug therapy of severe hypercholesterolemia in patients with coronary artery disease. Author(s): Parhofer KG, Richter WO, Schwandt P. Source: Artificial Organs. 1996 April; 20(4): 286-91. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8860708
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Dyslipidemia in young Japanese children: its relation to familial hypercholesterolemia and familial combined hyperlipidemia. Author(s): Ohta T, Kiwaki K, Endo F, Umehashi H, Matsuda I. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. 2002 December; 44(6): 602-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12421255
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E207K mutation of low-density lipoprotein receptor in familial hypercholesterolemia. Author(s): Tai DY, Chen GJ, Tso A, Chang HY, Shei SM. Source: J Formos Med Assoc. 2004 March; 103(3): 225-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15124051
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Early statin therapy restores endothelial function in children with familial hypercholesterolemia. Author(s): de Jongh S, Lilien MR, op't Roodt J, Stroes ES, Bakker HD, Kastelein JJ. Source: Journal of the American College of Cardiology. 2002 December 18; 40(12): 211721. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12505222
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Effect of fluvastatin therapy on coronary flow reserve in patients with hypercholesterolemia. Author(s): Fujimoto K, Hozumi T, Watanabe H, Shimada K, Takeuchi M, Sakanoue Y, Shimizu N, Ostuka R, Kawase Y, Sakamoto K, Yoshiyama M, Baba Y, Haze K, Yoshikawa J. Source: The American Journal of Cardiology. 2004 June 1; 93(11): 1419-21, A10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15165930
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Effect of HMG-CoA reductase inhibitor on plasma cholesteryl ester transfer protein activity in primary hypercholesterolemia: comparison among CETP/TaqIB genotype subgroups. Author(s): Kotake H, Sekikawa A, Tokita Y, Ishigaki Y, Oikawa S. Source: J Atheroscler Thromb. 2002; 9(5): 207-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12409629
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Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia. Author(s): Lu TM, Ding YA, Leu HB, Yin WH, Sheu WH, Chu KM. Source: The American Journal of Cardiology. 2004 July 15; 94(2): 157-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15246890
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Effect of simvastatin in familial hypercholesterolemia on the affinity of electronegative low-density lipoprotein subfractions to the low-density lipoprotein receptor. Author(s): Benitez S, Ordonez-Llanos J, Franco M, Marin C, Paz E, Lopez-Miranda J, Otal C, Perez-Jimenez F, Sanchez-Quesada JL. Source: The American Journal of Cardiology. 2004 February 15; 93(4): 414-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14969613
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Effects of atorvastatin and simvastatin on low-density lipoprotein subfraction profile, low-density lipoprotein oxidizability, and antibodies to oxidized low-density lipoprotein in relation to carotid intima media thickness in familial hypercholesterolemia. Author(s): van Tits LJ, Smilde TJ, van Wissen S, de Graaf J, Kastelein JJ, Stalenhoef AF. Source: Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research. 2004 April; 52(3): 177-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15222407
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Effects of rosuvastatin and atorvastatin compared over 52 weeks of treatment in patients with hypercholesterolemia. Author(s): Olsson AG, Istad H, Luurila O, Ose L, Stender S, Tuomilehto J, Wiklund O, Southworth H, Pears J, Wilpshaar JW; Rosuvastatin Investigators Group. Source: American Heart Journal. 2002 December; 144(6): 1044-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12486429
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Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Author(s): Dujovne CA, Ettinger MP, McNeer JF, Lipka LJ, LeBeaut AP, Suresh R, Yang B, Veltri EP; Esetimibe Study Group. Source: The American Journal of Cardiology. 2002 November 15; 90(10): 1092-7. Erratum In: Am J Cardiol. 2003 June 1; 91(11): 1399. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12423709
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Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Author(s): Gagne C, Bays HE, Weiss SR, Mata P, Quinto K, Melino M, Cho M, Musliner TA, Gumbiner B; Ezetimibe Study Group. Source: The American Journal of Cardiology. 2002 November 15; 90(10): 1084-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12423708
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Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. Author(s): Ballantyne CM, Blazing MA, King TR, Brady WE, Palmisano J. Source: The American Journal of Cardiology. 2004 June 15; 93(12): 1487-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15194018
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Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Author(s): Goldberg AC, Sapre A, Liu J, Capece R, Mitchel YB; Ezetimibe Study Group. Source: Mayo Clinic Proceedings. 2004 May; 79(5): 620-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15132403
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Efficacy and safety of fluvastatin therapy for hypercholesterolemia after heart transplantation: results of a randomised double blind placebo controlled study. Author(s): O'Rourke B, Barbir M, Mitchell AG, Yacoub MH, Banner NR. Source: International Journal of Cardiology. 2004 April; 94(2-3): 235-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15093987
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Efficacy and safety of rosuvastatin compared with pravastatin and simvastatin in patients with hypercholesterolemia: a randomized, double-blind, 52-week trial. Author(s): Brown WV, Bays HE, Hassman DR, McKenney J, Chitra R, Hutchinson H, Miller E; Rosuvastatin Study Group. Source: American Heart Journal. 2002 December; 144(6): 1036-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12486428
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Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. Author(s): Wiegman A, Hutten BA, de Groot E, Rodenburg J, Bakker HD, Buller HR, Sijbrands EJ, Kastelein JJ. Source: Jama : the Journal of the American Medical Association. 2004 July 21; 292(3): 331-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15265847
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Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin. Author(s): de Jongh S, Ose L, Szamosi T, Gagne C, Lambert M, Scott R, Perron P, Dobbelaere D, Saborio M, Tuohy MB, Stepanavage M, Sapre A, Gumbiner B, Mercuri M, van Trotsenburg AS, Bakker HD, Kastelein JJ; Simvastatin in Children Study Group. Source: Circulation. 2002 October 22; 106(17): 2231-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12390953
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Efficacy of extended-release niacin with lovastatin for hypercholesterolemia: assessing all reasonable doses with innovative surface graph analysis. Author(s): Insull W Jr, McGovern ME, Schrott H, Thompson P, Crouse JR, Zieve F, Corbelli J. Source: Archives of Internal Medicine. 2004 May 24; 164(10): 1121-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15159270
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Efficacy of folic acid when added to statin therapy in patients with hypercholesterolemia following acute myocardial infarction: a randomised pilot trial. Author(s): Liem AH, van Boven AJ, Veeger NJ, Withagen AJ, Robles de Medina RM, Tijssen JG, van Veldhuisen DJ; Folic Acid on Risk Diminishment After Acute Myocarial Infarction Study Group. Source: International Journal of Cardiology. 2004 February; 93(2-3): 175-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14975544
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Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. Author(s): Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, Suresh R, Sun S, Veltri EP. Source: Journal of the American College of Cardiology. 2002 December 18; 40(12): 212534. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12505224
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Familial homozygous hypercholesterolemia: effective long-term treatment with cascade double filtration plasmapheresis. Author(s): Demetriou K, H'Maltezou E, Pierides AM. Source: Blood Purification. 2001; 19(3): 308-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11244191
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Familial hypercholesterolemia (Type IIb) in a child: a case report with interesting features. Author(s): Prasad PV, Chidambaram N. Source: International Journal of Dermatology. 2004 March; 43(3): 173-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15009385
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Familial hypercholesterolemia due to ligand-defective apolipoprotein B100: first case report in a Mexican family. Author(s): Robles-Osorio L, Ordonez ML, Aguilar-Salinas CA, Auron-Gomez M, TusieLuna MT, Gomez-Perez FJ, Rull-Rodrigo JA. Source: Archives of Medical Research. 2003 January-February; 34(1): 70-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12604379
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Familial hypercholesterolemia from children to adults. Author(s): Ose L. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 2002 July; 16(4): 289-93. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12652097
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Familial hypercholesterolemia in Brazil. Author(s): Dos Santos JE, Zago MA. Source: Atherosclerosis. Supplements. 2003 November; 4(3): 1-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14615271
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Familial hypercholesterolemia in Morocco: first report of mutations in the LDL receptor gene. Author(s): El Messal M, Ait Chihab K, Chater R, Vallve JC, Bennis F, Hafidi A, Ribalta J, Varret M, Loutfi M, Rabes JP, Kettani A, Boileau C, Masana L, Adlouni A. Source: Journal of Human Genetics. 2003; 48(4): 199-203. Epub 2003 March 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12730724
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Familial hypercholesterolemia. Author(s): Seth RK, Gulati S, Seth S, Menon PS, Kalra V. Source: Indian J Pediatr. 2004 January; 71(1): 97-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14979394
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Familial hypercholesterolemia: stroke and the broader perspective. Author(s): Meschia JF. Source: Stroke; a Journal of Cerebral Circulation. 2003 January; 34(1): 22-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12511735
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Familial hypercholesterolemia--improving treatment and meeting guidelines. Author(s): Hopkins PN. Source: International Journal of Cardiology. 2003 May; 89(1): 13-23. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12727001
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Family history and cardiovascular risk in familial hypercholesterolemia: data in more than 1000 children. Author(s): Wiegman A, Rodenburg J, de Jongh S, Defesche JC, Bakker HD, Kastelein JJ, Sijbrands EJ. Source: Circulation. 2003 March 25; 107(11): 1473-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12654602
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Family history of cardiovascular events and endothelial dysfunction in children with familial hypercholesterolemia. Author(s): de Jongh S, Lilien MR, Bakker HD, Hutten BA, Kastelein JJ, Stroes ES. Source: Atherosclerosis. 2002 July; 163(1): 193-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12048139
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FH-Pyrgos: a novel mutation in the promoter (-45delT) of the low-density lipoprotein receptor gene associated with familial hypercholesterolemia. Author(s): Dedoussis GV, Pitsavos C, Kelberman D, Skoumas J, Prassa ME, Choumerianou DM, Stefanadis C, Humphries SE, Toutouzas P. Source: Clinical Genetics. 2003 November; 64(5): 414-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14616764
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Fibrinogen response with simvastatin versus atorvastatin in familial hypercholesterolemia. Author(s): Wierzbicki AS, Lumb PJ, Chik G, Crook MA. Source: The American Journal of Cardiology. 2001 February 1; 87(3): 338-40, A9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11165973
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Flow cytometric assay of platelet glycoprotein receptor numbers in hypercholesterolemia. Author(s): Ozsavci D, Yardimci T, Demirel GY, Demiralp E, Uras F, Onder E. Source: Platelets. 2002 June; 13(4): 223-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12189024
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Fluvastatin and niacin in hypercholesterolemia: a preliminary report on gender differences in efficacy. Author(s): Jacobson TA, Jokubaitis LA, Amorosa LF. Source: The American Journal of Medicine. 1994 June 6; 96(6A): 64S-68S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8017469
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Fluvastatin attenuates nitrate tolerance in patients with ischemic heart disease complicating hypercholesterolemia. Author(s): Inoue T, Takayanagi K, Hayashi T, Morooka S. Source: International Journal of Cardiology. 2003 August; 90(2-3): 181-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12957750
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Fluvastatin in primary hypercholesterolemia: efficacy and safety in patients at high risk. An analysis of a clinical trial database. Author(s): Peters TK, Muratti EN, Mehra M. Source: The American Journal of Medicine. 1994 June 6; 96(6A): 79S-83S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8017471
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Fluvastatin with and without niacin for hypercholesterolemia. Author(s): Jacobson TA, Chin MM, Fromell GJ, Jokubaitis LA, Amorosa LF. Source: The American Journal of Cardiology. 1994 July 15; 74(2): 149-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8023779
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Formation of isoprostanes in children with type IIa hypercholesterolemia. Author(s): Cracowski JL, Ploin D, Bessard J, Baguet JP, Stanke-Labesque F, Mallion JM, Bost M, Bessard G. Source: Journal of Cardiovascular Pharmacology. 2001 August; 38(2): 228-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11483872
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Frequency of the R3500Q mutation of the apolipoprotein B-100 gene in a sample screened clinically for familial hypercholesterolemia in Hungary. Author(s): Kalina A, Csaszar A, Czeizel AE, Romics L, Szaboki F, Szalai C, Reiber I, Nemeth A, Stephenson S, Williams RR. Source: Atherosclerosis. 2001 January; 154(1): 247-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11137107
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Garlic extract therapy in children with hypercholesterolemia. Author(s): McCrindle BW, Helden E, Conner WT. Source: Archives of Pediatrics & Adolescent Medicine. 1998 November; 152(11): 1089-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9811286
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Gastric obesity surgery combined with partial ileal bypass for hypercholesterolemia. Author(s): Buchwald H, Schone JL. Source: Obesity Surgery : the Official Journal of the American Society for Bariatric Surgery and of the Obesity Surgery Society of Australia and New Zealand. 1997 August; 7(4): 313-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9730516
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Gene therapy for familial hypercholesterolemia. Author(s): Rader DJ. Source: Nutr Metab Cardiovasc Dis. 2001 October; 11 Suppl 5: 40-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12063775
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Genetic and metabolic factors predicting risk of cardiovascular disease in familial hypercholesterolemia. Author(s): Smilde TJ, van Wissen S, Wollersheim H, Kastelein JJ, Stalenhoef AF. Source: The Netherlands Journal of Medicine. 2001 October; 59(4): 184-95. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11578794
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Genetic characterization of Swedish patients with familial hypercholesterolemia: a heterogeneous pattern of mutations in the LDL receptor gene. Author(s): Lind S, Rystedt E, Eriksson M, Wiklund O, Angelin B, Eggertsen G. Source: Atherosclerosis. 2002 August; 163(2): 399-407. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12052488
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Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol. Author(s): Chaves FJ, Real JT, Garcia-Garcia AB, Civera M, Armengod ME, Ascaso JF, Carmena R. Source: The Journal of Clinical Endocrinology and Metabolism. 2001 October; 86(10): 4926-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11600564
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Genetic investigation of patients with hypercholesterolemia type IIa. Author(s): Szalai C, Csaszar A, Czinner A, Palicz T, Halmos B, Romics L. Source: Clinical Genetics. 1999 January; 55(1): 67-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10066037
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Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. Author(s): Hunt SC, Hopkins PN, Bulka K, McDermott MT, Thorne TL, Wardell BB, Bowen BR, Ballinger DG, Skolnick MH, Samuels ME. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2000 April; 20(4): 1089-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10764678
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Genetic risk factors in the development of heart disease: familial hypercholesterolemia and hyperhomocysteinemia. Author(s): LaCharity LA. Source: Aacn Clinical Issues. 1998 November; 9(4): 531-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9855863
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Genetic tests for familial hypercholesterolemia. Author(s): Day I, Humphries S. Source: Nature Biotechnology. 1996 October; 14(10): 1227-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9631083
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Genetic variation at the apoA-IV gene locus and response to diet in familial hypercholesterolemia. Author(s): Carmena-Ramon R, Ascaso JF, Real JT, Ordovas JM, Carmena R. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 1998 August; 18(8): 1266-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9714133
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Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia. Author(s): Soutar AK, Naoumova RP, Traub LM. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 November 1; 23(11): 1963-70. Epub 2003 September 04. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12958046
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Global defects in the expression and function of the low density lipoprotein receptor (LDLR) associated with two familial hypercholesterolemia mutations resulting in misfolding of the LDLR epidermal growth factor-AB pair. Author(s): Boswell EJ, Jeon H, Blacklow SC, Downing AK. Source: The Journal of Biological Chemistry. 2004 July 16; 279(29): 30611-21. Epub 2004 April 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15100232
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Gout, bradycardia, and hypercholesterolemia after renal transplantation. Author(s): Kelleher SP, Davis WR, Paraskevopoulos N. Source: Southern Medical Journal. 2001 July; 94(7): 732-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11531183
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Growth hormone receptor variant (L526I) modifies plasma HDL cholesterol phenotype in familial hypercholesterolemia: intra-familial association study in an eight-generation hyperlipidemic kindred. 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: American Journal of Medical Genetics. 2003 August 30; 121A(2): 136-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12910492
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Guidance for industry: over-the-counter treatment of hypercholesterolemia. The international union of pharmcaology (IUPHAR). Author(s): Weintraub M. Source: The American Journal of Cardiology. 1998 April 23; 81(8A): 78F. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9604918
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Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Author(s): Civeira F; International Panel on Management of Familial Hypercholesterolemia. Source: Atherosclerosis. 2004 March; 173(1): 55-68. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15177124
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H.E.L.P. apheresis therapy in the treatment of severe hypercholesterolemia: 10 years of clinical experience. Author(s): Seidel D. Source: Artificial Organs. 1996 April; 20(4): 303-10. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8860711
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Heart disease in the assessment and treatment of hypercholesterolemia: coronary artery disease and other atherosclerotic disease, family history, and left ventricular hypertrophy. Author(s): Gotto AM Jr. Source: The American Journal of Medicine. 1994 June 6; 96(6A): 9S-18S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8017474
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High "population attributable fraction" for coronary heart disease mortality among relatives in monogenic familial hypercholesterolemia. Author(s): Austin MA, Zimmern RL, Humphries SE. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2002 July-August; 4(4): 275-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12172393
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Homozygous familial hypercholesterolemia. Author(s): Diwan AG, Krishna KK, Jain MM, Arafat M, Sardesai VR, Dube MN. Source: J Assoc Physicians India. 2002 May; 50(5): 738-9. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12186142
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Homozygous familial hypercholesterolemia: specific indication for domino liver transplantation. Author(s): Popescu I, Simionescu M, Tulbure D, Sima A, Catana C, Niculescu L, Hancu N, Gheorghe L, Mihaila M, Ciurea S, Vidu V. Source: Transplantation. 2003 November 15; 76(9): 1345-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627914
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Hypercholesterolemia and chronic rejection of renal allografts. Author(s): Blum CB. Source: Transplantation. 2001 August 27; 72(4): 751-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11544447
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Hypercholesterolemia associated with splice-junction variation of inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) gene. Author(s): Fujita Y, Ezura Y, Emi M, Sato K, Takada D, Iino Y, Katayama Y, Takahashi K, Kamimura K, Bujo H, Saito Y. Source: Journal of Human Genetics. 2004; 49(1): 24-8. Epub 2003 December 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14661079
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Hypercholesterolemia blunts forearm vasorelaxation and enhances the pressor response during acute systemic hypoxia. Author(s): Barreto-Filho JA, Consolim-Colombo FM, Guerra-Riccio GM, Santos RD, Chacra AP, Lopes HF, Teixeira SH, Martinez T, Krieger JE, Krieger EM. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 September 1; 23(9): 1660-6. Epub 2003 July 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12893690
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Hypercholesterolemia in children with Smith-Magenis syndrome: del (17) (p11.2p11.2). Author(s): Smith AC, Gropman AL, Bailey-Wilson JE, Goker-Alpan O, Elsea SH, Blancato J, Lupski JR, Potocki L. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2002 May-June; 4(3): 118-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12180145
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Hypercholesterolemia in elderly patients. Evidence-based medicine applied to a common clinical question. Author(s): Graham K. Source: Jaapa. 2001 January; 14(1): 16-21, 25-7. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11523194
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Hypercholesterolemia in undiagnosed non-insulin-dependent diabetes in southern Taiwan. Author(s): Chang CJ, Shin SJ, Lee WL, Lee YJ, Horng NC, Liu HW. Source: Kaohsiung J Med Sci. 1996 April; 12(4): 221-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8683643
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Hypercholesterolemia is a risk factor for bioprosthetic valve calcification and explantation. Author(s): Farivar RS, Cohn LH. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 October; 126(4): 96975. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14566234
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Hypercholesterolemia is common after pediatric heart transplantation: initial experience with pravastatin. Author(s): Seipelt IM, Crawford SE, Rodgers S, Backer C, Mavroudis C, Seipelt RG, Pahl E. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2004 March; 23(3): 317-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15019641
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Hypercholesterolemia promotes inflammation and microvascular dysfunction: role of nitric oxide and superoxide. Author(s): Stokes KY, Cooper D, Tailor A, Granger DN. Source: Free Radical Biology & Medicine. 2002 October 15; 33(8): 1026-36. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12374614
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Hypercholesterolemia treatment: a new hypothesis or just an accident? Author(s): Dzugan SA, Arnold Smith R. Source: Medical Hypotheses. 2002 December; 59(6): 751-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12445520
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Hypercholesterolemia underdiagnosis and undertreatment in psychiatric patients in Italy. Author(s): Cicero AF, Forghieri M, Arletti R. Source: European Journal of Epidemiology. 2003; 18(4): 373-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12803380
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Hypercholesterolemia with cholesterol-enriched LDL and normal levels of LDLapolipoprotein B. Effects of the step I diet and bile acid sequestrants on the cholesterol content of LDL. Author(s): Vega GL, Grundy SM. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 1996 April; 16(4): 517-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8624773
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Hypercholesterolemia. The evidence supports use of statins. Author(s): Aronow WS. Source: Geriatrics. 2003 August; 58(8): 18-20, 26-8, 31-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12938249
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Hypercholesterolemia. The NCEP Adult Treatment Panel III Guidelines. Author(s): Morgan JM, Capuzzi DM. Source: Geriatrics. 2003 August; 58(8): 33-8; Quiz 41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12938250
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Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia. Author(s): Singh RB, Niaz MA, Ghosh S. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 1994 August; 8(4): 659-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7848901
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Identification of a new mutation, S305C, in exon 7 of the low-density lipoprotein receptor gene in a Brazilian family with homozygous familial hypercholesterolemia. Author(s): van de Kerkhof L, Van Eijk SJ, Defesche JC, Dos-Santos JE. Source: Genetic Testing. 2003 Spring; 7(1): 77-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12820708
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Impact of the characteristics of patients and their clinical management on outcomes in children with homozygous familial hypercholesterolemia. Author(s): Al-Shaikh AM, Abdullah MH, Barclay A, Cullen-Dean G, McCrindle BW. Source: Cardiology in the Young. 2002 March; 12(2): 105-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12018713
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Incidence and prevalence of hypercholesterolemia in Portugal: a systematic review. Part I. Author(s): Costa J, Borges M, Oliveira E, Gouveia M, Carneiro AV. Source: Rev Port Cardiol. 2003 April; 22(4): 569-77. Review. English, Portuguese. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879647
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Incidence and prevalence of hypercholesterolemia in Portugal: a systematic review. Part III. Author(s): Costa J, Borges M, Oliveira E, Gouveia M, Carneiro AV. Source: Rev Port Cardiol. 2003 June; 22(6): 829-36. Review. English, Portuguese. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14526699
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Incidence and prevalence of hypercholesterolemia in Portugal: a systemic review. Part II. Author(s): Costa J, Borges M, Oliveira E, Gouveia M, Carneiro AV. Source: Rev Port Cardiol. 2003 May; 22(5): 683-702. Review. English, Portuguese. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12940181
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Increased levels of low-density lipoprotein oxidation in patients with familial hypercholesterolemia and in end-stage renal disease patients on hemodialysis. Author(s): Van Tits L, De Graaf J, Hak-Lemmers H, Bredie S, Demacker P, Holvoet P, Stalenhoef A. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2003 January; 83(1): 13-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12533682
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Increased levels of pregnancy-associated plasma protein-A in patients with hypercholesterolemia: the effect of atorvastatin treatment. Author(s): Stulc T, Malbohan I, Malik J, Fialova L, Soukupova J, Ceska R. Source: American Heart Journal. 2003 December; 146(6): E21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14661010
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Increasing the sensitivity of single-strand conformation polymorphism analysis of the LDLR gene mutations in brazilian patients with familial hypercholesterolemia. Author(s): Salazar LA, Hirata MH, Hirata RD. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 May; 40(5): 441-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12113284
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Indication of low-density lipoprotein apheresis in severe hypercholesterolemia and its atherosclerotic vascular complications: dextran sulfate cellulose low-density lipoprotein apheresis. Author(s): Keller C. Source: Ther Apher Dial. 2003 June; 7(3): 345-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12924611
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Individual responsiveness to a cholesterol-lowering diet in postmenopausal women with moderate hypercholesterolemia. Author(s): Denke MA. Source: Archives of Internal Medicine. 1994 September 12; 154(17): 1977-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8074602
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Influence of hypercholesterolemia and acute graft rejection on chronic nephropathy development in renal transplant recipients. Author(s): Boratynska M, Banasik M, Watorek E, Klinger M, Dorobisz A, Szyber P. Source: Transplantation Proceedings. 2003 September; 35(6): 2209-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14529891
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Influence of hypercholesterolemia on patient and graft survival in recipients of kidney transplants. Author(s): Booth JC, Joseph JT, Jindal RM. Source: Clinical Transplantation. 2003 April; 17(2): 101-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12709074
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Influence of simvastatin on LDL-subtypes in patients with heterozygous familial hypercholesterolemia and in patients with diabetes mellitus and mixed hyperlipoproteinemia. Author(s): Geiss HC, Schwandt P, Parhofer KG. Source: Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association. 2002 June; 110(4): 182-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12058342
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Influences of hypercholesterolemia on red cell indices and erythrocyte sedimentation rate in elderly persons. Author(s): Choi JW, Pai SH. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2004 March; 341(1-2): 117-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14967166
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Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred. Author(s): Takada D, Emi M, Ezura Y, Nobe Y, Kawamura K, Iino Y, Katayama Y, Xin Y, Wu LL, Larringa-Shum S, Stephenson SH, Hunt SC, Hopkins PN. Source: Journal of Human Genetics. 2002; 47(12): 656-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12522687
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Interactions between hypercholesterolemia and hypertension: implications for therapy. Author(s): Borghi C. Source: Current Opinion in Nephrology and Hypertension. 2002 September; 11(5): 48996. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12187312
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Interventional treatment of multiple vascular involvement in young male with heterozygous familial hypercholesterolemia. Author(s): Lubanda JC, Simek S, Linhart A, Aschermann M, Ceska R. Source: Cas Lek Cesk. 2003; 142(4): 248-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12841130
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Intima-media thickness and atherosclerotic plaques in familial defective apolipoprotein B-100 and familial hypercholesterolemia. Author(s): Kaiser M, Temelkova-Kurktschiev T, Hanefeld M. Source: Annals of the New York Academy of Sciences. 2002 June; 967: 528-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12079884
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Intravascular ultrasound evaluation of coronary plaque regression by low density lipoprotein-apheresis in familial hypercholesterolemia: the Low Density LipoproteinApheresis Coronary Morphology and Reserve Trial (LACMART). Author(s): Matsuzaki M, Hiramori K, Imaizumi T, Kitabatake A, Hishida H, Nomura M, Fujii T, Sakuma I, Fukami K, Honda T, Ogawa H, Yamagishi M. Source: Journal of the American College of Cardiology. 2002 July 17; 40(2): 220-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12106923
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Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia. Author(s): Amsellem S, Briffaut D, Carrie A, Rabes JP, Girardet JP, Fredenrich A, Moulin P, Krempf M, Reznik Y, Vialettes B, de Gennes JL, Brukert E, Benlian P. Source: Human Genetics. 2002 December; 111(6): 501-10. Epub 2002 September 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12436241
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Jaundice and extreme hypercholesterolemia after a stroke. Author(s): Fred HL, Hariharan R, Doucet J, Mehta N. Source: Hosp Pract (Off Ed). 1996 September 15; 31(9): 33-7. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8814119
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Knockout of the mouse apolipoprotein B gene results in embryonic lethality in homozygotes and protection against diet-induced hypercholesterolemia in heterozygotes. Author(s): Farese RV Jr, Ruland SL, Flynn LM, Stokowski RP, Young SG. Source: Proceedings of the National Academy of Sciences of the United States of America. 1995 February 28; 92(5): 1774-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7878058
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Lack of evidence for reduced plasma apo B48 catabolism in patients with heterozygous familial hypercholesterolemia carrying the same null LDL receptor gene mutation. Author(s): Tremblay AJ, Lamarche B, Ruel I, Hogue JC, Bergeron J, Gagne C, Couture P. Source: Atherosclerosis. 2004 February; 172(2): 367-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15019548
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Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia and coronary heart disease: secondary prevention cohort study of the Japan Lipid Intervention Trial (J-LIT). Author(s): Mabuchi H, Kita T, Matsuzaki M, Matsuzawa Y, Nakaya N, Oikawa S, Saito Y, Sasaki J, Shimamoto K, Itakura H; J-LIT Study Group. Japan Lipid Intervention Trial. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2002 December; 66(12): 1096-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12499612
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Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia. Author(s): Matsuzaki M, Kita T, Mabuchi H, Matsuzawa Y, Nakaya N, Oikawa S, Saito Y, Sasaki J, Shimamoto K, Itakura H; J-LIT Study Group. Japan Lipid Intervention Trial. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2002 December; 66(12): 1087-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12499611
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LDL Apheresis: an effective and safe treatment for refractory hypercholesterolemia. Author(s): Hudgins LC, Gordon BR, Parker TS, Saal SD, Levine DM, Rubin AL. Source: Cardiovasc Drug Rev. 2002 Winter; 20(4): 271-80. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12481200
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Lesion severity and hypercholesterolemia determine long-term prognosis of vasospastic angina treated with calcium channel antagonists. Author(s): Yamagishi M, Ito K, Tsutsui H, Miyazaki S, Goto Y, Nagaya N, Sumiyoshi T, Fukami K, Haze K, Kitakaze M, Nonogi H, Tomoike H. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 December; 67(12): 1029-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14639019
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Lipid levels and their genetic regulation in patients with familial hypercholesterolemia and familial defective apolipoprotein B-100: the MEDPED Slovakia Project. Author(s): Vohnout B, Raslova K, Gasparovic J, Franekova J, Fabryova L, Belosovicova M, Kovac G, Sebova C, Rajecova E, Stavny J, Babjak M, Donati MB, Iacoviello L. Source: Atherosclerosis. Supplements. 2003 November; 4(3): 3-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14615272
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Living-donor liver transplantation for homozygous familial hypercholesterolemia from a donor with heterozygous hypercholesterolemia. Author(s): Shirahata Y, Ohkohchi N, Kawagishi N, Syouji M, Tsukamoto S, Sekiguchi S, Koyamada N, Oikawa S, Satomi S. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 2003 April; 16(4): 276-9. Epub 2003 February 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12730809
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Locus on chromosome 6p linked to elevated HDL cholesterol serum levels and to protection against premature atherosclerosis in a kindred with familial hypercholesterolemia. Author(s): Canizales-Quinteros S, Aguilar-Salinas CA, Reyes-Rodriguez E, Riba L, Rodriguez-Torres M, Ramirez-Jimenez S, Huertas-Vazquez A, Fragoso-Ontiveros V, Zentella-Dehesa A, Ventura-Gallegos JL, Vega-Hernandez G, Lopez-Estrada A, AuronGomez M, Gomez-Perez F, Rull J, Cox NJ, Bell GI, Tusie-Luna MT. Source: Circulation Research. 2003 March 21; 92(5): 569-76. Epub 2003 February 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12609970
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Long-term compliance with lipid-lowering medication after genetic screening for familial hypercholesterolemia. Author(s): Umans-Eckenhausen MA, Defesche JC, van Dam MJ, Kastelein JJ. Source: Archives of Internal Medicine. 2003 January 13; 163(1): 65-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12523918
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Long-term effect of low-density lipoprotein apheresis in patients with heterozygous familial hypercholesterolemia. Author(s): Higashikata T, Mabuchi H. Source: Ther Apher Dial. 2003 August; 7(4): 402-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12887722
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Long-term effect of low-density lipoprotein apheresis in patients with homozygous familial hypercholesterolemia. Author(s): Makino H, Harada-Shiba M. Source: Ther Apher Dial. 2003 August; 7(4): 397-401. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12887721
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Long-term effect of simvastatin on the improvement of impaired myocardial flow reserve in patients with familial hypercholesterolemia without gender variance. Author(s): Yokoyama I, Yonekura K, Inoue Y, Ohtomo K, Nagai R. Source: Journal of Nuclear Cardiology : Official Publication of the American Society of Nuclear Cardiology. 2001 July-August; 8(4): 445-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11481566
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Long-term effects of pravastatin on serum lipid levels in elderly patients with hypercholesterolemia. Author(s): Morimoto S, Koh E, Fukuo K, Higaki J, Ikegami H, Miki T, Hata T, Ogihara T. Source: Clinical Therapeutics. 1994 September-October; 16(5): 793-803. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7859238
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Long-term outcome of liver transplantation for familial hypercholesterolemia. Author(s): Shrotri M, Fernando BS, Sudhindran S, Delriviere L, Watson CJ, Gibbs P, Alexander GJ, Gimson AE, Jamieson NV. Source: Transplantation Proceedings. 2003 February; 35(1): 381-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591450
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Long-term stable expression of human apolipoprotein A-I mediated by helperdependent adenovirus gene transfer inhibits atherosclerosis progression and remodels atherosclerotic plaques in a mouse model of familial hypercholesterolemia. Author(s): Belalcazar LM, Merched A, Carr B, Oka K, Chen KH, Pastore L, Beaudet A, Chan L. Source: Circulation. 2003 June 3; 107(21): 2726-32. Epub 2003 May 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742997
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Long-term treatment of hypercholesterolemia with fluvastatin: a 52-week multicenter safety and efficacy study. French-Dutch Fluvastatin Study Group. Author(s): Banga JD, Jacotot B, Pfister P, Mehra M. Source: The American Journal of Medicine. 1994 June 6; 96(6A): 87S-93S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8017473
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Low incidence of hypercholesterolemia among liver transplant patients under tacrolimus monotherapy immunosuppression. Author(s): Charco R, Bilbao I, Chavez R, Castells LI, Hidalgo E, Margarit C. Source: Transplantation Proceedings. 2002 August; 34(5): 1555-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176482
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Low-density lipoprotein apheresis versus lipid lowering drugs in the treatment of severe hypercholesterolemia: four years' experience. Author(s): Schiel R, Bambauer R, Muller U. Source: Artificial Organs. 1996 April; 20(4): 318-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8860713
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Lp(a) concentration and apo(a) isoform size. Relation to the presence of coronary artery disease in familial hypercholesterolemia. Author(s): Bowden JF, Pritchard PH, Hill JS, Frohlich JJ. Source: Arterioscler Thromb. 1994 October; 14(10): 1561-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7918305
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Lp(a) levels in Greek patients with heterozygous familial hypercholesterolemia. Author(s): Elisaf M, Bairaktari H, Siamopoulos KC. Source: International Journal of Cardiology. 1996 March; 53(3): 314-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8793588
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Magnitude of HDL cholesterol variation after high-dose atorvastatin is genetically determined at the LDL receptor locus in patients with homozygous familial hypercholesterolemia. Author(s): Sposito AC, Gonbert S, Bruckert E, Atassi M, Beucler I, Amsellem S, Khallouf O, Benlian P, Turpin G. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 November 1; 23(11): 2078-82. Epub 2003 September 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14512370
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Medical nutrition therapy for hypercholesterolemia positively affects patient satisfaction and quality of life outcomes. Author(s): Delahanty LM, Hayden D, Ammerman A, Nathan DM. Source: Annals of Behavioral Medicine : a Publication of the Society of Behavioral Medicine. 2002 Fall; 24(4): 269-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12434938
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Mice expressing the human CYP7A1 gene in the mouse CYP7A1 knock-out background lack induction of CYP7A1 expression by cholesterol feeding and have increased hypercholesterolemia when fed a high fat diet. Author(s): Chen JY, Levy-Wilson B, Goodart S, Cooper AD. Source: The Journal of Biological Chemistry. 2002 November 8; 277(45): 42588-95. Epub 2002 August 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12202481
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Microvascular reactivity in patients with hypercholesterolemia: effect of lipid lowering treatment. Author(s): Stulc T, Kasalova Z, Prazny M, Vrablik M, Skrha J, Ceska R. Source: Physiological Research / Academia Scientiarum Bohemoslovaca. 2003; 52(4): 439-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899656
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Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Author(s): Pappolla MA, Bryant-Thomas TK, Herbert D, Pacheco J, Fabra Garcia M, Manjon M, Girones X, Henry TL, Matsubara E, Zambon D, Wolozin B, Sano M, CruzSanchez FF, Thal LJ, Petanceska SS, Refolo LM. Source: Neurology. 2003 July 22; 61(2): 199-205. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12874399
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Modifying dietary fat intake can reduce serum cholesterol in HIV-associated hypercholesterolemia. Author(s): Batterham MJ, Brown D, Workman C. Source: Aids (London, England). 2003 June 13; 17(9): 1414-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12799574
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Molecular analysis of apo(a) fragmentation in polygenic hypercholesterolemia: characterization of a new plasma fragment pattern. Author(s): Gonbert S, Saint-Jore B, Giral P, Doucet C, Chapman J, Thillet J. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2001 August; 21(8): 1353-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11498465
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Molecular characterization of familial hypercholesterolemia in German and Greek patients. Author(s): Dedoussis GV, Genschel J, Bochow B, Pitsavos C, Skoumas J, Prassa M, Lkhagvasuren S, Toutouzas P, Vogt A, Kassner U, Thomas HP, Schmidt H. Source: Human Mutation. 2004 March; 23(3): 285-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14974088
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Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population. Author(s): Yu W, Nohara A, Higashikata T, Lu H, Inazu A, Mabuchi H. Source: Atherosclerosis. 2002 December; 165(2): 335-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12417285
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Molecular mechanisms of autosomal recessive hypercholesterolemia. Author(s): Wilund KR, Yi M, Campagna F, Arca M, Zuliani G, Fellin R, Ho YK, Garcia JV, Hobbs HH, Cohen JC. Source: Human Molecular Genetics. 2002 November 15; 11(24): 3019-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12417523
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Molecular mechanisms of autosomal recessive hypercholesterolemia. Author(s): Cohen JC, Kimmel M, Polanski A, Hobbs HH. Source: Current Opinion in Lipidology. 2003 April; 14(2): 121-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12642779
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Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Author(s): Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Source: Nature Genetics. 2003 June; 34(2): 154-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12730697
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Natural history of hypercholesterolemia in systemic lupus erythematosus. Author(s): Bruce IN, Urowitz MB, Gladman DD, Hallett DC. Source: The Journal of Rheumatology. 1999 October; 26(10): 2137-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10529129
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New guidelines for managing hypercholesterolemia. Author(s): McKenney JM. Source: Journal of the American Pharmaceutical Association (Washington,D.C. : 1996). 2001 July-August; 41(4): 596-607. Erratum In: J Am Pharm Assoc (Wash) 2002 MarchApril; 42(2): 157. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11486986
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Niacin-ER and lovastatin treatment of hypercholesterolemia and mixed dyslipidemia. Author(s): Yim BT, Chong PH. Source: The Annals of Pharmacotherapy. 2003 January; 37(1): 106-15. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12503944
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Nifedipine improves endothelial function in hypercholesterolemia, independently of an effect on blood pressure or plasma lipids. Author(s): Verhaar MC, Honing ML, van Dam T, Zwart M, Koomans HA, Kastelein JJ, Rabelink TJ. Source: Cardiovascular Research. 1999 June; 42(3): 752-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10533616
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Nitric oxide (NO) in the cardiovascular system: role in atherosclerosis and hypercholesterolemia. Author(s): Wennmalm A. Source: Blood Pressure. 1994 September; 3(5): 279-82. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7866590
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No effect of an L-arginine-enriched medical food (HeartBars) on endothelial function and platelet aggregation in subjects with hypercholesterolemia. Author(s): Abdelhamed AI, Reis SE, Sane DC, Brosnihan KB, Preli RB, Herrington DM. Source: American Heart Journal. 2003 March; 145(3): E15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12660684
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No effect of simvastatin treatment on insulin sensitivity in patients with primary hypercholesterolemia. Author(s): Altunbas H, Balci MK, Karayalcin U. Source: Endocrine Research. 2003 August; 29(3): 265-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14535628
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Normolipidemia and hypercholesterolemia in persons heterozygous for the same 1592 + 5G --> A splice site mutation in the low-density lipoprotein receptor gene. Author(s): Jensen HK, Jensen LG, Holst HU, Andreasen PH, Hansen PS, Larsen ML, Kolvraa S, Bolund L, Gregersen N, Faergeman O. Source: Clinical Genetics. 1999 November; 56(5): 378-88. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10668928
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Nurse case management of hypercholesterolemia in patients with coronary heart disease: results of a randomized clinical trial. Author(s): Allen JK, Blumenthal RS, Margolis S, Young DR, Miller ER 3rd, Kelly K. Source: American Heart Journal. 2002 October; 144(4): 678-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12360165
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Nutrient adequacy of diets of adults with hypercholesterolemia after a cholesterollowering intervention: long-term assessment. Author(s): Naglak MC, Mitchell DC, Shannon BM, Pearson TA, Harkness WL, KrisEtherton PM. Source: Journal of the American Dietetic Association. 2000 November; 100(11): 1385-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11103662
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Obesity, weight change and risks for hypertension, diabetes and hypercholesterolemia in Japanese men. Author(s): Ishikawa-Takata K, Ohta T, Moritaki K, Gotou T, Inoue S. Source: European Journal of Clinical Nutrition. 2002 July; 56(7): 601-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12080398
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Off-pump coronary artery bypass grafting for an 88-year-old man with familial hypercholesterolemia. Author(s): Kamiya H, Kanammori T, Watanabe G. Source: Ann Thorac Cardiovasc Surg. 2003 February; 9(1): 81. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12675036
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On the association between hypercholesterolemia, cardiovascular disease and severe periodontal disease. Author(s): Katz J, Chaushu G, Sharabi Y. Source: Journal of Clinical Periodontology. 2001 September; 28(9): 865-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11493357
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One-year community-based education program for hypercholesterolemia in middleaged Japanese: a long-term outcome at 8-year follow-up. Author(s): Iso H, Imano H, Nakagawa Y, Kiyama M, Kitamura A, Sato S, Naito Y, Shimamoto T, Iida M. Source: Atherosclerosis. 2002 September; 164(1): 195-202. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12119210
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Origin and migration of an Afrikaner founder mutation FHAfrikaner-2 (V408M) causing familial hypercholesterolemia. Author(s): Defesche JC, Van Diermen DE, Hayden MR, Kastelein JP. Source: Gene Geogr. 1996 April; 10(1): 1-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8913716
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Orlistat use in overweight women with mild hypercholesterolemia. Author(s): Petrogiannopoulos C, Kalogeropoulos S, Latsios GS, Hartzoulakis G, Kalogeropoulos G, Zaharof A. Source: Int J Clin Pharmacol Res. 2002; 22(3-4): 85-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12837045
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Overexpression of lipoprotein lipase in transgenic rabbits inhibits diet-induced hypercholesterolemia and atherosclerosis. Author(s): Fan J, Unoki H, Kojima N, Sun H, Shimoyamada H, Deng H, Okazaki M, Shikama H, Yamada N, Watanabe T. Source: The Journal of Biological Chemistry. 2001 October 26; 276(43): 40071-9. Epub 2001 July 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11477088
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Oxidative stress, F2-isoprostanes and endothelial dysfunction in hypercholesterolemia. Author(s): Palombo C, Lubrano V, Sampietro T. Source: Cardiovascular Research. 1999 December; 44(3): 474-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10690278
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Oxidizability of atherogenic low-density lipoprotein subspecies in severe familial hypercholesterolemia: impact of long-term low-density lipoprotein apheresis. Author(s): Lepage S, Nigon F, Bonnefont-Rousselot D, Assogba U, Goulinet S, Chancharme L, Delattre J, Bruckert E, Chapman MJ. Source: Journal of Cardiovascular Pharmacology and Therapeutics. 2000 April; 5(2): 87103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11150388
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Partial duplication of the EGF precursor homology domain of the LDL-receptor protein causing familial hypercholesterolemia (FH-Salerno). Author(s): Bertolini S, Patel DD, Coviello DA, Lelli N, Ghisellini M, Tiozzo R, Masturzo P, Elicio N, Knight BL, Calandra S. Source: Journal of Lipid Research. 1994 August; 35(8): 1422-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7989866
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Persistent hypercholesterolemia is associated with the development of obesity among girls: the Bogalusa Heart Study. Author(s): Tershakovec AM, Jawad AF, Stouffer NO, Elkasabany A, Srinivasan SR, Berenson GS. Source: The American Journal of Clinical Nutrition. 2002 October; 76(4): 730-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12324284
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Physician extenders for cost-effective management of hypercholesterolemia. Author(s): Schectman G, Wolff N, Byrd JC, Hiatt JG, Hartz A. Source: Journal of General Internal Medicine : Official Journal of the Society for Research and Education in Primary Care Internal Medicine. 1996 May; 11(5): 277-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8725976
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Plasma asymmetric dimethylarginine and hyperemic myocardial blood flow in young subjects with borderline hypertension or familial hypercholesterolemia. Author(s): Paiva H, Laakso J, Laine H, Laaksonen R, Knuuti J, Raitakari OT. Source: Journal of the American College of Cardiology. 2002 October 2; 40(7): 1241-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12383571
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Plasma levels of beta-amyloid(1-40), beta-amyloid(1-42), and total beta-amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins. Author(s): Hoglund K, Wiklund O, Vanderstichele H, Eikenberg O, Vanmechelen E, Blennow K. Source: Archives of Neurology. 2004 March; 61(3): 333-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15023808
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Polymorphisms at the SRBI locus are associated with lipoprotein levels in subjects with heterozygous familial hypercholesterolemia. Author(s): Tai ES, Adiconis X, Ordovas JM, Carmena-Ramon R, Real J, Corella D, Ascaso J, Carmena R. Source: Clinical Genetics. 2003 January; 63(1): 53-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12519372
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Pregnancy in a patient with homozygous familial hypercholesterolemia treated with long-term low-density lipoprotein apheresis. Author(s): Kroon AA, Swinkels DW, van Dongen PW, Stalenhoef AF. Source: Metabolism: Clinical and Experimental. 1994 September; 43(9): 1164-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8084291
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Prenatal diagnosis of familial hypercholesterolemia: importance of DNA analysis in the high-risk South African population. Author(s): Vergotine J, Thiart R, Langenhoven E, Hillermann R, De Jong G, Kotze MJ. Source: Genet Couns. 2001; 12(2): 121-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11491306
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Prevalence of hypercholesterolemia in Saudi Arabia, epidemiological study. Author(s): al-Nuaim AR, al-Rubeaan K, al-Mazrou Y, al-Attas O, al-Daghari N. Source: International Journal of Cardiology. 1996 April 19; 54(1): 41-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8792184
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Primary hypercholesterolemia: genetic causes and treatment of five monogenic disorders. Author(s): Pullinger CR, Kane JP, Malloy MJ. Source: Expert Rev Cardiovasc Ther. 2003 May; 1(1): 107-19. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15030301
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Quantity versus quality of LDL cholesterol in patients with familial hypercholesterolemia--which is more important? Author(s): Paiker JE, Raal FJ, Waisberg R, Buthelezi EP. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2001 December; 314(1-2): 167-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11718692
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Rapid effects of simvastatin on lipid profile and C-reactive protein in patients with hypercholesterolemia. Author(s): Li JJ, Chen MZ, Chen X, Fang CH. Source: Clin Cardiol. 2003 October; 26(10): 472-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14579918
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Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Author(s): Egashira K, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Inou T, Takeshita A. Source: Circulation. 1994 June; 89(6): 2519-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8205659
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Reduction in serum levels of adhesion molecules, interleukin-6 and C-reactive protein following short-term low-dose atorvastatin treatment in patients with nonfamilial hypercholesterolemia. Author(s): Nawawi H, Osman NS, Yusoff K, Khalid BA. Source: Hormone and Metabolic Research. Hormon- Und Stoffwechselforschung. Hormones Et Metabolisme. 2003 August; 35(8): 479-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12953165
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Relation of cholesterol-year score to severity of calcific atherosclerosis and tissue deposition in homozygous familial hypercholesterolemia. Author(s): Schmidt HH, Hill S, Makariou EV, Feuerstein IM, Dugi KA, Hoeg JM. Source: The American Journal of Cardiology. 1996 March 15; 77(8): 575-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8610605
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Relationship between hypercholesterolemia, lipid-lowering therapy and coronary flow velocity reserve evaluated by stress transesophageal echocardiography in patients with a negative coronary angiogram. Author(s): Nemes A, Neu K, Forster T, Gruber N, Csanady M. Source: Echocardiography (Mount Kisco, N.Y.). 2004 January; 21(1): 37-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14717719
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Relevance of homocysteine on brachial flow-mediated vasodilatation and carotid and femoral intima-media thickness in patients with hypercholesterolemia. Author(s): Vaudo G, Marchesi S, Siepi D, Bagaglia F, Paltriccia R, Pirro M, Schillaci G, Lupattelli G, Mannarino E. Source: The American Journal of Cardiology. 2004 June 1; 93(11): 1413-6, A9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15165928
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Response to HMG CoA reductase inhibitors in heterozygous familial hypercholesterolemia due to the 10-kb deletion ("French Canadian mutation") of the LDL receptor gene. Author(s): Karayan L, Qiu S, Betard C, Dufour R, Roederer G, Minnich A, Davignon J, Genest J Jr. Source: Arterioscler Thromb. 1994 August; 14(8): 1258-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8049186
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Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1. Author(s): Eden ER, Patel DD, Sun XM, Burden JJ, Themis M, Edwards M, Lee P, Neuwirth C, Naoumova RP, Soutar AK. Source: The Journal of Clinical Investigation. 2002 December; 110(11): 1695-702. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12464675
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Risk of fatal stroke in patients with treated familial hypercholesterolemia: a prospective registry study. Author(s): Huxley RR, Hawkins MH, Humphries SE, Karpe F, Neil HA; Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee. Source: Stroke; a Journal of Cerebral Circulation. 2003 January; 34(1): 22-5. Erratum In: Stroke. 2003 March; 34(3): 826. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12511745
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Risk perception of participants in a family-based genetic screening program on familial hypercholesterolemia. Author(s): van Maarle MC, Stouthard ME, Bonsel GJ. Source: American Journal of Medical Genetics. 2003 January 15; 116A(2): 136-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12494431
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Screening for point mutations in the LDL receptor gene in Bulgarian patients with severe hypercholesterolemia. Author(s): Mihaylov VA, Horvath AD, Savov AS, Kurshelova EF, Paskaleva ID, Goudev AR, Stoilov IR, Ganev VS. Source: Journal of Human Genetics. 2004; 49(4): 173-6. Epub 2004 March 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15015036
108
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Selective loss of microvascular endothelial function in human hypercholesterolemia. Author(s): Gilligan DM, Guetta V, Panza JA, Garcia CE, Quyyumi AA, Cannon RO 3rd. Source: Circulation. 1994 July; 90(1): 35-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8026018
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Serum total cholesterol concentrations and awareness, treatment, and control of hypercholesterolemia among US adults. Author(s): Folsom AR. Source: Circulation. 2003 November 25; 108(21): E152; Author Reply E152. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638534
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Serum total cholesterol concentrations and awareness, treatment, and control of hypercholesterolemia among US adults: findings from the National Health and Nutrition Examination Survey, 1999 to 2000. Author(s): Ford ES, Mokdad AH, Giles WH, Mensah GA. Source: Circulation. 2003 May 6; 107(17): 2185-9. Epub 2003 April 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12719276
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Severe hypercalcemia of an infant due to vitamin D toxicity associated with hypercholesterolemia. Author(s): Evliyaoglu O, Berberoglu M, Ocal G, Adiyaman P, Aycan Z. Source: J Pediatr Endocrinol Metab. 2001 July-August; 14(7): 915-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11515734
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Silent ischaemia in familial hypercholesterolemia. Author(s): Descamps OS, de Meester A, Cheron P, Kastelein JJ, Heller FR. Source: Atherosclerosis. Supplements. 2003 November; 4(3): 7-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14615273
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Simvastatin and pravastatin equally improve flow-mediated dilation in males with hypercholesterolemia. Author(s): Sebestjen M, Boh M, Keber I. Source: Wiener Klinische Wochenschrift. 2002 December 30; 114(23-24): 999-1003. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12635468
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Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred. Author(s): Sato K, Emi M, Ezura Y, Fujita Y, Takada D, Ishigami T, Umemura S, Xin Y, Wu LL, Larrinaga-Shum S, Stephenson SH, Hunt SC, Hopkins PN. Source: Journal of Human Genetics. 2004; 49(1): 29-34. Epub 2003 December 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14673705
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Study of causes underlying the low atherosclerotic response to dietary hypercholesterolemia in a selected strain of rabbits. Author(s): Thiery J, Teupser D, Walli AK, Ivandic B, Nebendahl K, Stein O, Stein Y, Seidel D. Source: Atherosclerosis. 1996 March; 121(1): 63-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8678925
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The apolipoprotein B R3500Q gene mutation in Spanish subjects with a clinical diagnosis of familial hypercholesterolemia. Author(s): Castillo S, Tejedor D, Mozas P, Reyes G, Civeira F, Alonso R, Ros E, Pocovi M, Mata P. Source: Atherosclerosis. 2002 November; 165(1): 127-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12208478
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The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery. Author(s): Mishra SK, Watkins SC, Traub LM. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 December 10; 99(25): 16099-104. Epub 2002 November 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12451172
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The effect of atorvastatin on erythrocyte membranes and serum lipids in patients with type-2 hypercholesterolemia. Author(s): Koter M, Broncel M, Chojnowska-Jezierska J, Klikczynska K, Franiak I. Source: European Journal of Clinical Pharmacology. 2002 November; 58(8): 501-6. Epub 2002 September 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12451426
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The effect of hypertension and hypercholesterolemia screening with subsequent intervention letter on the use of blood pressure and lipid lowering drugs. Author(s): Atthobari J, Monster TB, de Jong PE, de Jong-van den Berg LT; Prevend Study Group. Source: British Journal of Clinical Pharmacology. 2004 March; 57(3): 328-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14998429
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The effects of lovastatin and simvastatin on the diurnal periodicity of plasma mevalonate concentrations in patients with heterozygous familial hypercholesterolemia. Author(s): Pappu AS, Illingworth DR. Source: Atherosclerosis. 2002 November; 165(1): 137-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12208479
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The fetal origins of atherosclerosis: maternal hypercholesterolemia, and cholesterollowering or antioxidant treatment during pregnancy influence in utero programming and postnatal susceptibility to atherogenesis. Author(s): Palinski W, Napoli C. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2002 September; 16(11): 1348-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12205026
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Time-dependent lipid response on fluvastatin therapy of patients with hypercholesterolemia sensitive to apoE phenotype. Author(s): Dergunov AD, Perova NV, Visvikis S, Siest G. Source: Vascular Pharmacology. 2003 December; 40(5): 237-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15259790
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Treatment of children with familial hypercholesterolemia with colestilan, a newly developed bile acid-binding resin. Author(s): Asami T, Uchiyama M. Source: Atherosclerosis. 2002 October; 164(2): 381-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12204812
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Treatment of children with familial hypercholesterolemia. Author(s): Tonstad S. Source: Expert Rev Cardiovasc Ther. 2003 May; 1(1): 135-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15030303
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Treatment of hypercholesterolemia in patients with diabetes at a family practice office. Author(s): Camenga D, Gill JM. Source: Del Med J. 2003 November; 75(11): 415-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14870630
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Understanding risk in hypercholesterolemia. Author(s): LaRosa JC. Source: Clin Cardiol. 2003 January; 26(1 Suppl 1): I3-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12539815
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Undiagnosed hypertension and hypercholesterolemia among uninsured and insured adults in the Third National Health and Nutrition Examination Survey. Author(s): Ayanian JZ, Zaslavsky AM, Weissman JS, Schneider EC, Ginsburg JA. Source: American Journal of Public Health. 2003 December; 93(12): 2051-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14652333
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Unrecognized seropositive RA and SS in a patient with associated familial hypercholesterolemia type IIa and osseous xanthoma of the proximal femur. Author(s): Josipovic B, Jablanovic D, Josipovic A, Nedeljkovic R, Ilic S. Source: Clin Exp Rheumatol. 2003 September-October; 21(5): 678-9. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14611129
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Unstable angina during pregnancy in two patients with premature coronary atherosclerosis and aortic stenosis in association with familial hypercholesterolemia. Author(s): Hameed AB, Tummala PP, Goodwin TM, Nuno I, Wani OR, Karaalp IS, Elkayam U. Source: American Journal of Obstetrics and Gynecology. 2000 May; 182(5): 1152-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10819851
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Untreated hypercholesterolemia in an emergency department chest pain observation unit population. Author(s): Chandra A, Compton S, Sochor M, Puri S, Zalenski RJ. Source: Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. 2002 July; 9(7): 699-702. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12093710
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Update on managing hypercholesterolemia. The new NCEP guidelines. Author(s): Kuhar MB. Source: Aaohn Journal : Official Journal of the American Association of Occupational Health Nurses. 2002 August; 50(8): 360-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12227210
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Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia. Author(s): Garlichs CD, John S, Schmeisser A, Eskafi S, Stumpf C, Karl M, GoppeltStruebe M, Schmieder R, Daniel WG. Source: Circulation. 2001 November 13; 104(20): 2395-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11705814
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Use of denaturing HPLC to provide efficient detection of mutations causing familial hypercholesterolemia. Author(s): Bodamer OA, Bercovich D, Schlabach M, Ballantyne C, Zoch D, Beaudet AL. Source: Clinical Chemistry. 2002 November; 48(11): 1913-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12406975
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Use of homozygosity mapping to identify a region on chromosome 1 bearing a defective gene that causes autosomal recessive homozygous hypercholesterolemia in two unrelated families. Author(s): Eden ER, Naoumova RP, Burden JJ, McCarthy MI, Soutar AK. Source: American Journal of Human Genetics. 2001 March; 68(3): 653-60. Epub 2001 February 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11179013
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Variable expression of hypercholesterolemia in Apolipoprotein E2* (Arg136 --> Cys) heterozygotes. Author(s): Hubacek JA, Pitha J, Stavek P, Schmitz G, Poledne R. Source: Physiological Research / Academia Scientiarum Bohemoslovaca. 2000; 49(3): 307-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11043917
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Variation of apolipoprotein B as a possible cause of decreased low density lipoprotein clearance and hypercholesterolemia. Author(s): Korhonen T, Savolainen MJ, Kesaniemi YA. Source: Atherosclerosis. 1999 September; 146(1): 1-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10487480
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Visual disturbance due to carotid artery thrombosis in a patient with familial hypercholesterolemia; response to surgical thrombotectomy. Author(s): Shibasaki T, Uehara C, Ohno I, Ishimoto F. Source: Intern Med. 2001 May; 40(5): 421-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11393415
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Vitamin A in hypercholesterolemia. Author(s): Smith DK, Greene JM, Leonard SB, Kuske TT, Feldman DS, Feldman EB. Source: The American Journal of the Medical Sciences. 1992 July; 304(1): 20-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1642248
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Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia. Author(s): Ting HH, Timimi FK, Haley EA, Roddy MA, Ganz P, Creager MA. Source: Circulation. 1997 June 17; 95(12): 2617-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9193429
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Vitamin E in kidney transplantation: effect of treatment with simvastatin in hypercholesterolemia. Author(s): Cantarell C, Bonal J, Sierra C, Pastor C, Lauzurica R, Capdevila L. Source: Transplantation Proceedings. 1995 August; 27(4): 2222-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7652781
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VLDL and IDL apolipoprotein B-100 kinetics in familial hypercholesterolemia due to impaired LDL receptor function or to defective apolipoprotein B-100. Author(s): Zulewski H, Ninnis R, Miserez AR, Baumstark MW, Keller U. Source: Journal of Lipid Research. 1998 February; 39(2): 380-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9507998
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Wall thickening of carotid and femoral arteries in male subjects with isolated hypercholesterolemia. PCVMETRA Group. Prevention Cardio-Vasculaire en Medecine du Travail. Author(s): Gariepy J, Simon A, Massonneau M, Linhart A, Levenson J. Source: Atherosclerosis. 1995 March; 113(2): 141-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7605352
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Watanabe heritable hyperlipidemic rabbits. Familial hypercholesterolemia. Author(s): Atkinson JB, Swift LL, Virmani R. Source: American Journal of Pathology. 1992 March; 140(3): 749-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1546748
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Weekly treatment of diet/drug-resistant hypercholesterolemia with the heparininduced extracorporeal low-density lipoprotein precipitation (HELP) system by selective plasma low-density lipoprotein removal. Author(s): Lane DM, McConathy WJ, Laughlin LO, Comp PC, von Albertini B, Gibson SM, Bricker LA, Kozlovskis P, Dorrier C. Source: The American Journal of Cardiology. 1993 April 1; 71(10): 816-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8456760
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Weekly versus biweekly lipid removal and effect of statins in severe hypercholesterolemia. Author(s): Nuoffer JM, Zenklusen JM, Pfammatter JP, Wiesmann UN, Bianchetti MG. Source: American Journal of Therapeutics. 1998 November; 5(6): 393-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10099083
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When do we treat hypercholesterolemia? Author(s): Brown WV. Source: Clin Cardiol. 1992 November; 15(11 Suppl 3): Iii10-4; Discussion Iii 15-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1477992
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When do we treat hypercholesterolemia? Author(s): Brown WV. Source: Clin Cardiol. 1992 November; 15(11): Iii10-4; Discussion Iii15-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1458691
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When should patients with heterozygous familial hypercholesterolemia be treated? Author(s): Rifkind BM, Schucker B, Gordon DJ. Source: Jama : the Journal of the American Medical Association. 1999 January 13; 281(2): 180-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9917123
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Which statin is most efficient for the treatment of hypercholesterolemia? A costeffectiveness analysis. Author(s): Cobos A, Jovell AJ, Garcia-Altes A, Garcia-Closas R, Serra-Majem L. Source: Clinical Therapeutics. 1999 November; 21(11): 1924-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10890264
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Who should treat familial hypercholesterolemia? Author(s): Schonfeld G. Source: The American Journal of Cardiology. 1993 September 30; 72(10): 38D-41D. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8213495
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Women and men with hypercholesterolemia respond similarly to an American Heart Association step 1 diet. Author(s): Geil PB, Anderson JW, Gustafson NJ. Source: Journal of the American Dietetic Association. 1995 April; 95(4): 436-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7699185
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Xanthomas disappear rapidly after liver transplantation for familial hypercholesterolemia. Author(s): Onaca N, Goldstein RM, Klintmalm GB. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2003 December; 9(12): 1334-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14625835
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Xenopus autosomal recessive hypercholesterolemia protein couples lipoprotein receptors with the AP-2 complex in oocytes and embryos and is required for vitellogenesis. Author(s): Zhou Y, Zhang J, King ML. Source: The Journal of Biological Chemistry. 2003 November 7; 278(45): 44584-92. Epub 2003 August 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12944396
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Young adults with hypercholesterolemia. Author(s): Kwiterovich PO Jr. Source: The American Journal of Medicine. 1999 August 23; 107(2A): 40S-42S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10484240
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CHAPTER 2. NUTRITION AND HYPERCHOLESTEROLEMIA Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and hypercholesterolemia.
Finding Nutrition Studies on Hypercholesterolemia 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 “hypercholesterolemia” (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 hypercholesterolemia: •
Treatment of hypercholesterolemia and combined hyperlipidemia with simvastatin and gemfibrozil in patients with NIDDM. A multicenter comparison study. Author(s): Department of Medicine, University of Helsinki, Finland. Source: Tikkanen, M J Laakso, M Ilmonen, M Helve, E Kaarsalo, E Kilkki, E Saltevo, J Diabetes-Care. 1998 April; 21(4): 477-81 0149-5992
The following information is typical of that found when using the “Full IBIDS Database” to search for “hypercholesterolemia” (or a synonym): •
The effect of red beet (Beta vulgaris var. rubra) on alimentary hypercholesterolemia and chemically induced colon carcinogesis in rats. Source: Bobek, P. Galbavy, S. Mariassyova, M. Nahrung (Germany). (2000). volume 44(3) page 184-187.
Additional physician-oriented references include: •
Concurrent use of simvastatin and estrogen--progestin therapy compared with each therapy alone for hypercholesterolemia in postmenopausal women. Author(s): Jeans Hailes Foundation, Clayton, Australia. Source: Darling, G M Johns, J A McCloud, P I Davis, S R Climacteric. 1999 September; 2(3): 181-8 1369-7137
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Effect of experimental hypercholesterolemia on cavernosal structures. Author(s): Department of Urology, Ankara University School of Medicine, Ankara, Turkey. Source: Yesilli, C Yaman, O Anafarta, K Urology. 2001 June; 57(6): 1184-8 1527-9995
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Impaired testicular function in rats with diet-induced hypercholesterolemia and/or streptozotocin-induced diabetes mellitus. Author(s): Department of Pharmacology, St Marianna University School of Medicine, Kawasaki, Japan.
[email protected] Source: Tanaka, M Nakaya, S Kumai, T Watanabe, M Matsumoto, N Kobayashi, S Endocr-Res. 2001 Feb-May; 27(1-2): 109-17 0743-5800
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Relevance of hypercholesterolemia to fetal and pediatric atherosclerosis. Author(s): Department of Pathology and Molecular Medicine, Wellington School of Medicine, New Zealand.
[email protected] Source: Stehbens, W E Pediatr-Pathol-Mol-Med. 2002 May-June; 21(3): 259-78 1522-7952
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Stratification of risk in children with familial hypercholesterolemia with focus on psychosocial issues. Author(s): Department of Preventive Cardiology, Preventive Medicine Center, Ulleval University Hospital, N-0407 Oslo, Norway.
[email protected] Source: Tonstad, S Nutr-Metab-Cardiovasc-Dis. 2001 October; 11 Suppl 5: 64-7 0939-4753
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Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMDHealth: 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 hypercholesterolemia; 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 Niacin Source: Integrative Medicine Communications; www.drkoop.com Pantothenic Acid and Pantethine Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B3 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B3 (Niacin) Source: Integrative Medicine Communications; www.drkoop.com
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Minerals Atorvastatin Source: Healthnotes, Inc.; www.healthnotes.com Calcium Source: Healthnotes, Inc.; www.healthnotes.com Calcium Source: Prima Communications, Inc.www.personalhealthzone.com Fluvastatin Source: Healthnotes, Inc.; www.healthnotes.com Lovastatin Source: Healthnotes, Inc.; www.healthnotes.com Pravastatin Source: Healthnotes, Inc.; www.healthnotes.com Simvastatin Source: Healthnotes, Inc.; www.healthnotes.com
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Food and Diet Garlic Alternative names: Allium sativum Source: Healthnotes, Inc.; www.healthnotes.com High-Fiber Diet Source: Healthnotes, Inc.; www.healthnotes.com
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CHAPTER 3. ALTERNATIVE HYPERCHOLESTEROLEMIA
MEDICINE
AND
Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to hypercholesterolemia. 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 hypercholesterolemia 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 “hypercholesterolemia” (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 hypercholesterolemia: •
A dietary portfolio approach to cholesterol reduction: combined effects of plant sterols, vegetable proteins, and viscous fibers in hypercholesterolemia. Author(s): Jenkins DJ, Kendall CW, Faulkner D, Vidgen E, Trautwein EA, Parker TL, Marchie A, Koumbridis G, Lapsley KG, Josse RG, Leiter LA, Connelly PW. Source: Metabolism: Clinical and Experimental. 2002 December; 51(12): 1596-604. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12489074
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Additive effect of plant sterol-ester margarine and cerivastatin in lowering lowdensity lipoprotein cholesterol in primary hypercholesterolemia. Author(s): Simons LA. Source: The American Journal of Cardiology. 2002 October 1; 90(7): 737-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12356387
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Alternative therapies: Part II. Congestive heart failure and hypercholesterolemia. Author(s): Morelli V, Zoorob RJ. Source: American Family Physician. 2000 September 15; 62(6): 1325-30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11011861
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Apolipoprotein E gene polymorphism, hypercholesterolemia and glomerular filtration rate in type 2 diabetic subjects: a 9-year follow-up study. Author(s): Lehtinen S, Rantalaiho V, Wirta O, Pasternack A, Laippala P, Koivula T, Lehtimaki T. Source: Journal of Biomedical Science. 2003 March-April; 10(2): 260-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12595762
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Blockade of angiotensin signaling improves myocardial function in hypercholesterolemia independent of changes in eicosanoid release. Author(s): Schwemmer M, Sommer O, Bassenge E. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 2000 June; 14(3): 317-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10935154
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Carob pulp preparation for treatment of hypercholesterolemia. Author(s): Zunft HJ, Luder W, Harde A, Haber B, Graubaum HJ, Gruenwald J. Source: Adv Ther. 2001 September-October; 18(5): 230-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11783460
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Cholesterol-lowering effects of psyllium intake adjunctive to diet therapy in men and women with hypercholesterolemia: meta-analysis of 8 controlled trials. Author(s): Anderson JW, Allgood LD, Lawrence A, Altringer LA, Jerdack GR, Hengehold DA, Morel JG. Source: The American Journal of Clinical Nutrition. 2000 February; 71(2): 472-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10648260
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c-myc activation in early coronary lesions in experimental hypercholesterolemia. Author(s): de Nigris F, Lerman LO, Rodriguez-Porcel M, De Montis MP, Lerman A, Napoli C. Source: Biochemical and Biophysical Research Communications. 2001 March 9; 281(4): 945-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11237752
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Coronary endothelial function is preserved with chronic endothelin receptor antagonism in experimental hypercholesterolemia in vitro. Author(s): Best PJ, Lerman LO, Romero JC, Richardson D, Holmes DR Jr, Lerman A.
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Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 1999 November; 19(11): 2769-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10559024 •
Dietary linoleic acid-induced hypercholesterolemia and accumulation of very light HDL in steers. Author(s): Scislowski V, Durand D, Gruffat D, Bauchart D. Source: Lipids. 2004 February; 39(2): 125-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15134139
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Dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia. Author(s): Goodfellow J, Bellamy MF, Ramsey MW, Jones CJ, Lewis MJ. Source: Journal of the American College of Cardiology. 2000 February; 35(2): 265-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10676668
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Dietary supplementation with vitamins C and E prevents downregulation of endothelial NOS expression in hypercholesterolemia in vivo and in vitro. Author(s): Rodriguez JA, Grau A, Eguinoa E, Nespereira B, Perez-Ilzarbe M, Arias R, Belzunce MS, Paramo JA, Martinez-Caro D. Source: Atherosclerosis. 2002 November; 165(1): 33-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12208468
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Effect of dietary intervention and lipid-lowering treatment on brachial vasoreactivity in patients with ischemic heart disease and hypercholesterolemia. Author(s): Sondergaard E, Moller JE, Egstrup K. Source: American Heart Journal. 2003 May; 145(5): E19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766751
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Effect of garlic on lipid profile and psychopathologic parameters in people with mild to moderate hypercholesterolemia. Author(s): Peleg A, Hershcovici T, Lipa R, Anbar R, Redler M, Beigel Y. Source: Isr Med Assoc J. 2003 September; 5(9): 637-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14509153
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Effect of hydrogenated and saturated, relative to polyunsaturated, fat on immune and inflammatory responses of adults with moderate hypercholesterolemia. Author(s): Han SN, Leka LS, Lichtenstein AH, Ausman LM, Schaefer EJ, Meydani SN. Source: Journal of Lipid Research. 2002 March; 43(3): 445-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11893781
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Effect of Lactobacillus reuteri on the prevention of hypercholesterolemia in mice. Author(s): Taranto MP, Medici M, Perdigon G, Ruiz Holgado AP, Valdez GF.
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Source: Journal of Dairy Science. 2000 March; 83(3): 401-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10750094 •
Effects of curcumin on cyclosporine-induced cholestasis and hypercholesterolemia and on cyclosporine metabolism in the rat. Author(s): Deters M, Klabunde T, Meyer H, Resch K, Kaever V. Source: Planta Medica. 2003 April; 69(4): 337-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12709901
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Effects of microcrystalline plant sterol suspension and a powdered plant sterol supplement on hypercholesterolemia in genetically obese Zucker rats. Author(s): Summanen J, Yrjonen T, Christiansen L, Mervaala E, Vaskonen T, Lassila M, Ahotupa M, Yliruusi J, Karppanen H, Hiltunen R. Source: The Journal of Pharmacy and Pharmacology. 2003 December; 55(12): 1673-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14738595
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Effects of oral soy protein on markers of inflammation in postmenopausal women with mild hypercholesterolemia. Author(s): Blum A, Lang N, Peleg A, Vigder F, Israeli P, Gumanovsky M, Lupovitz S, Elgazi A, Ben-Ami M. Source: American Heart Journal. 2003 February; 145(2): E7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12595862
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Effects of phytosterol ester-enriched margarine on plasma lipoproteins in mild to moderate hypercholesterolemia are related to basal cholesterol and fat intake. Author(s): Mussner MJ, Parhofer KG, Von Bergmann K, Schwandt P, Broedl U, Otto C. Source: Metabolism: Clinical and Experimental. 2002 February; 51(2): 189-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11833047
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Effects of plant stanol and sterol esters on serum phytosterols in a family with familial hypercholesterolemia including a homozygous subject. Author(s): Ketomaki A, Gylling H, Miettinen TA. Source: The Journal of Laboratory and Clinical Medicine. 2004 April; 143(4): 255-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15085084
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Effects of psyllium on glucose and serum lipid responses in men with type 2 diabetes and hypercholesterolemia. Author(s): Anderson JW, Allgood LD, Turner J, Oeltgen PR, Daggy BP. Source: The American Journal of Clinical Nutrition. 1999 October; 70(4): 466-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10500014
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Effects of soy protein on endothelium-dependent vasodilatation and lipid profile in postmenopausal women with mild hypercholesterolemia.
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Author(s): Blum A, Lang N, Vigder F, Israeli P, Gumanovsky M, Lupovitz S, Elgazi A, Peleg A, Ben-Ami M. Source: Clinical and Investigative Medicine. Medecine Clinique Et Experimentale. 2003 February; 26(1): 20-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12659466 •
Endothelial dysfunction in hypercholesterolemia is reversed by a nutritional product designed to enhance nitric oxide activity. Author(s): Maxwell AJ, Anderson B, Zapien MP, Cooke JP. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 2000 June; 14(3): 309-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10935153
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Ethanol-extracted soy protein isolate does not modulate serum cholesterol in golden Syrian hamsters: a model of postmenopausal hypercholesterolemia. Author(s): Lucas EA, Khalil DA, Daggy BP, Arjmandi BH. Source: The Journal of Nutrition. 2001 February; 131(2): 211-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11160535
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Garlic for treating hypercholesterolemia. A meta-analysis of randomized clinical trials. Author(s): Stevinson C, Pittler MH, Ernst E. Source: Annals of Internal Medicine. 2000 September 19; 133(6): 420-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10975959
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Genetic defenses against hypercholesterolemia. Author(s): Hobbs HH, Graf GA, Yu L, Wilund KR, Cohen JC. Source: Cold Spring Harb Symp Quant Biol. 2002; 67: 499-505. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12858576
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Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial. Author(s): Szapary PO, Wolfe ML, Bloedon LT, Cucchiara AJ, DerMarderosian AH, Cirigliano MD, Rader DJ. Source: Jama : the Journal of the American Medical Association. 2003 August 13; 290(6): 765-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12915429
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HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. Author(s): Kurowska EM, Spence JD, Jordan J, Wetmore S, Freeman DJ, Piche LA, Serratore P.
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Source: The American Journal of Clinical Nutrition. 2000 November; 72(5): 1095-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11063434 •
High dose of simvastatin normalizes postprandial remnant-like particle response in patients with heterozygous familial hypercholesterolemia. Author(s): Twickler TB, Dallinga-Thie GM, de Valk HW, Schreuder PC, Jansen H, Cabezas MC, Erkelens DW. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2000 November; 20(11): 2422-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11073847
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Hypercholesterolemia: a look at low-cost treatment and treatment adherence. Author(s): Flannery J, Raulerson A. Source: Journal of the American Academy of Nurse Practitioners. 2000 November; 12(11): 462-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11930385
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Hypolipidemic effects and absorption of citrus polymethoxylated flavones in hamsters with diet-induced hypercholesterolemia. Author(s): Kurowska EM, Manthey JA. Source: Journal of Agricultural and Food Chemistry. 2004 May 19; 52(10): 2879-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15137829
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Impact of hypercholesterolemia on in vitro toxicity of N-nitrosodiethylamine: effect on lipidperoxidation of blood and tissue. Author(s): Mittal G, Kaur M, Soni G. Source: Indian J Exp Biol. 2002 September; 40(9): 1071-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12587740
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Improvement of early functional atherosclerotic changes in males with hypercholesterolemia after vitamin E supplementation. Author(s): Borovnicar A, Keber I, Stavljenic Rukavina A, Yaletel Kragelj L. Source: Pflugers Archiv : European Journal of Physiology. 2000; 440(5 Suppl): R126-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11005639
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Improving effect of dietary taurine on marked hypercholesterolemia induced by a high-cholesterol diet in streptozotocin-induced diabetic rats. Author(s): Mochizuki H, Takido J, Oda H, Yokogoshi H. Source: Bioscience, Biotechnology, and Biochemistry. 1999 November; 63(11): 1984-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10635563
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Ingestion of water-soluble soybean fiber prevents osteopenia and hypercholesterolemia induced by ovariectomy in rats. Author(s): Mitamura R, Hara H, Aoyama Y, Takahashi T, Furuta H. Source: Journal of Agricultural and Food Chemistry. 2003 February 12; 51(4): 1085-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12568577
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Isoflavones improve vascular reactivity in post-menopausal women with hypercholesterolemia. Author(s): Lissin LW, Oka R, Lakshmi S, Cooke JP. Source: Vascular Medicine (London, England). 2004 February; 9(1): 26-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15230485
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Japanese sisters associated with pseudohomozygous familial hypercholesterolemia and sitosterolemia. Author(s): Yoshida A, Naito M, Miyazaki K. Source: J Atheroscler Thromb. 2000; 7(1): 33-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11425042
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Konjac supplement alleviated hypercholesterolemia and hyperglycemia in type 2 diabetic subjects--a randomized double-blind trial. Author(s): Chen HL, Sheu WH, Tai TS, Liaw YP, Chen YC. Source: Journal of the American College of Nutrition. 2003 February; 22(1): 36-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12569112
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Long-term cholesterol-lowering effects of psyllium as an adjunct to diet therapy in the treatment of hypercholesterolemia. Author(s): Anderson JW, Davidson MH, Blonde L, Brown WV, Howard WJ, Ginsberg H, Allgood LD, Weingand KW. Source: The American Journal of Clinical Nutrition. 2000 June; 71(6): 1433-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10837282
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Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. Author(s): Rader DJ, Cohen J, Hobbs HH. Source: The Journal of Clinical Investigation. 2003 June; 111(12): 1795-803. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12813012
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Oats and soy in lipid-lowering diets for women with hypercholesterolemia: is there synergy? Author(s): Van Horn L, Liu K, Gerber J, Garside D, Schiffer L, Gernhofer N, Greenland P. Source: Journal of the American Dietetic Association. 2001 November; 101(11): 1319-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11716313
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Plant sterol ester-enriched spread lowers plasma total and LDL cholesterol in children with familial hypercholesterolemia. Author(s): Amundsen AL, Ose L, Nenseter MS, Ntanios FY. Source: The American Journal of Clinical Nutrition. 2002 August; 76(2): 338-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12145004
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Prickly pear induces upregulation of liver LDL binding in familial heterozygous hypercholesterolemia. Author(s): Palumbo B, Efthimiou Y, Stamatopoulos J, Oguogho A, Budinsky A, Palumbo R, Sinzinger H. Source: Nucl Med Rev Cent East Eur. 2003; 6(1): 35-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14600931
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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/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12897048
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Red cell and plasma plant sterols are related during consumption of plant stanol and sterol ester spreads in children with hypercholesterolemia. Author(s): Ketomaki AM, Gylling H, Antikainen M, Siimes MA, Miettinen TA. Source: The Journal of Pediatrics. 2003 May; 142(5): 524-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12756385
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Reduced platelet serotonin content in rabbits with dietary hypercholesterolemia. Author(s): Ogawa T, Sugidachi A, Asai F, Koike H. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. 2000 June; 11(4): 313-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10847417
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Renal vascular function in hypercholesterolemia is preserved by chronic antioxidant supplementation. Author(s): Stulak JM, Lerman A, Porcel MR, Caccitolo JA, Romero JC, Schaff HV, Napoli C, Lerman LO. Source: Journal of the American Society of Nephrology : Jasn. 2001 September; 12(9): 1882-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11518781
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Rescue of hypercholesterolemia-related impairment of angiogenesis by oral folate supplementation. Author(s): Sasaki K, Duan J, Murohara T, Ikeda H, Shintani S, Shimada T, Akita T, Egami K, Imaizumi T.
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Source: Journal of the American College of Cardiology. 2003 July 16; 42(2): 364-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12875777 •
Salvadora persica L.: hypolipidemic activity on experimental hypercholesterolemia in rat. Author(s): Galati EM, Monforte MT, Forestieri AM, Miceli N, Bader A, Trovato A, Bade A. Source: Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 1999 July; 6(3): 181-5. Erratum In: Phytomedicine 1999 November; 6(5): 389. Bade a [corrected to Bader A]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10439483
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Serum lipid response to n-3 fatty acid enriched eggs in persons with hypercholesterolemia. Author(s): Lewis NM, Schalch K, Scheideler SE. Source: Journal of the American Dietetic Association. 2000 March; 100(3): 365-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10719415
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Squalene and noncholesterol sterols in serum and lipoproteins of children with and without familial hypercholesterolemia. Author(s): Ketomaki A, Gylling H, Siimes MA, Vuorio A, Miettinen TA. Source: Pediatric Research. 2003 April; 53(4): 648-53. Epub 2003 January 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12612218
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Stress, stress reduction and hypercholesterolemia in African Americans: a review. Author(s): Calderon R Jr, Schneider RH, Alexander CN, Myers HF, Nidich SI, Haney C. Source: Ethn Dis. 1999 Autumn; 9(3): 451-62. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10600068
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Supplementation with 3 compositionally different tocotrienol supplements does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia. Author(s): Mustad VA, Smith CA, Ruey PP, Edens NK, DeMichele SJ. Source: The American Journal of Clinical Nutrition. 2002 December; 76(6): 1237-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12450888
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The effect of combining plant sterols, soy protein, viscous fibers, and almonds in treating hypercholesterolemia. Author(s): Jenkins DJ, Kendall CW, Marchie A, Faulkner D, Vidgen E, Lapsley KG, Trautwein EA, Parker TL, Josse RG, Leiter LA, Connelly PW. Source: Metabolism: Clinical and Experimental. 2003 November; 52(11): 1478-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624410
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The effect of dietary intervention through the modification of fatty acids composition and antioxidant vitamin intake on plasma TXB(2) level in Korean postmenopausal women with hypercholesterolemia. Author(s): Jung K, Kim S, Woo J, Chang Y. Source: Journal of Korean Medical Science. 2002 June; 17(3): 307-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12068132
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The effect of fiber supplementation on lipid profile in children with hypercholesterolemia. Author(s): Sanchez-Bayle M, Gonzalez-Requejo A, Asensio-Anton J, Ruiz-Jarabo C, Fernandez-Ruiz ML, Baeza J. Source: Clinical Pediatrics. 2001 May; 40(5): 291-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11388682
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The Hawaii Diet: ad libitum high carbohydrate, low fat multi-cultural diet for the reduction of chronic disease risk factors: obesity, hypertension, hypercholesterolemia, and hyperglycemia. Author(s): Shintani TT, Beckham S, Brown AC, O'Connor HK. Source: Hawaii Med J. 2001 March; 60(3): 69-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11320614
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Treatment of Familial Hypercholesterolemia and Other Genetic Dyslipidemias. Author(s): Dujovne CA. Source: Current Treatment Options in Cardiovascular Medicine. 2004 August; 6(4): 269278. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15212722
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Use of nutritional supplements for the prevention and treatment of hypercholesterolemia. Author(s): Steyer TE, King DE, Mainous AG 3rd, Gilbert G. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2003 May; 19(5): 415-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12714092
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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WebMDHealth: 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 hypercholesterolemia; 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 Diabetes Source: Healthnotes, Inc.; www.healthnotes.com Diabetes Mellitus Source: Integrative Medicine Communications; www.drkoop.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com Herpes Alternative names: Genital Herpes, Cold Sores Source: Prima Communications, Inc.www.personalhealthzone.com High Cholesterol 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
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TIAs Source: Integrative Medicine Communications; www.drkoop.com Transient Ischemic Attacks Source: Integrative Medicine Communications; www.drkoop.com •
Herbs and Supplements Angkak Source: Integrative Medicine Communications; www.drkoop.com Beni-Koji Source: Integrative Medicine Communications; www.drkoop.com Beta-Sitosterol Source: Healthnotes, Inc.; www.healthnotes.com Cynara Artichoke Alternative names: Artichoke; Cynara scolymus L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Eicosapentaenoic Acid (EPA) Source: Integrative Medicine Communications; www.drkoop.com EPA Source: Integrative Medicine Communications; www.drkoop.com Fiber Source: Healthnotes, Inc.; www.healthnotes.com Fiber Source: Integrative Medicine Communications; www.drkoop.com Hong Qu Source: Integrative Medicine Communications; www.drkoop.com Hung-Chu Source: Integrative Medicine Communications; www.drkoop.com Lysine Source: Healthnotes, Inc.; www.healthnotes.com Lysine Source: Prima Communications, Inc.www.personalhealthzone.com Monascus Source: Integrative Medicine Communications; www.drkoop.com Plantago Psyllium Alternative names: Psyllium, Ispaghula; Plantago psyllium/ovata Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
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Psyllium Alternative names: Plantago ovata, Plantago ispaghula Source: Healthnotes, Inc.; www.healthnotes.com Red Clover Alternative names: Trifolium pratense , beebread, cow clover, cow grass, meadow clover, purple clover Source: Integrative Medicine Communications; www.drkoop.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 Terminalia Alternative names: Myrobalans; Terminalia arjuna Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Tribulus Puncture Alternative names: Puncture Vine, Goathead; Tribulus terrestris L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org 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. PATENTS ON HYPERCHOLESTEROLEMIA Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “hypercholesterolemia” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on hypercholesterolemia, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Hypercholesterolemia By performing a patent search focusing on hypercholesterolemia, 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. 8Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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The following is an example of the type of information that you can expect to obtain from a patent search on hypercholesterolemia: •
Atorvastatin hemi-calcium form VII Inventor(s): Aronhime; Judith (Rehovot, IL), Lidor-Hadas; Ramy (Kafar-Saba, IL), Lifshitz; Revital (Herzlia, IL), Niddam; Valerie (Even-Yeouda, IL) Assignee(s): Teva Pharmaceutical Industries Ltd. (Petah Tiqva, IL) Patent Number: 6,605,636 Date filed: November 5, 2001 Abstract: The present invention provides a novel form of atorvastatin hemi-calcium designated Form VII and novel processes for its preparation whereby another crystalline form of atorvastatin hemi-calcium is suspended in ethanol, preferably absolute ethanol, and is converted to the new form, which is then isolated. The present invention further provides a method of reducing the plasma low density lipoprotein level in patients suffering from or susceptible to hypercholesterolemia and compositions and dosage forms for practicing the invention. Excerpt(s): The present invention relates to crystalline polymorphic forms of atorvastatin hemi-calcium and novel processes for preparing crystalline solids. Atorvastatin is a member of the class of drugs called statins. Statin drugs are currently the most therapeutically effective drugs available for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. A high level of LDL in the bloodstream has been linked to the formation of coronary lesions which obstruct the flow of blood and can rupture and promote thrombosis. Goodman and Gilman, The Pharmacological Basis of Therapeutics 879 (9th ed. 1996). Reducing plasma LDL levels has been shown to reduce the risk of clinical events in patients with cardiovascular disease and patients who are free of cardiovascular disease but who have hypercholesterolemia. Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b. The mechanism of action of statin drugs has been elucidated in some detail. They interfere with the synthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme ("HMG-CoA reductase"). HMG-CoA reductase catalyzes the conversion HMG to mevalonate, which is the rate determining step in the biosynthesis of cholesterol, and so, its inhibition leads to a reduction in the concentration of cholesterol in the liver. Very low density lipoprotein (VLDL) is the biological vehicle for transporting cholesterol and triglycerides from the liver to peripheral cells. VLDL is catabolized in the peripheral cells which releases fatty acids which may be stored in adopcytes or oxidized by muscle. The VLDL is converted to intermediate density lipoprotein (IDL), which is either removed by an LDL receptor, or is converted to LDL. Decreased production of cholesterol leads to an increase in the number of LDL receptors and corresponding reduction in the production of LDL particles by metabolism of IDL. Web site: http://www.delphion.com/details?pn=US06605636__
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Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors Inventor(s): Glenn; Kevin C. (Maryland Heights, MO), Keller; Bradley T. (Chesterfield, MO), Manning; Robert E. (St. Louis, MO) Assignee(s): G.D. Searle & Co. (Chicago, IL) Patent Number: 6,642,268 Date filed: February 15, 2002 Abstract: Provided are novel benzothiepines, derivatives, and analogs thereof; pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals. Also provided are compositions and methods for combination therapy employing ileal bile acid transport inhibitors and HMG Co--A reductase inhibitors for the treatment of hyperlipidemic conditions. Excerpt(s): The present invention relates to novel benzothiepines, derivatives and analogs thereof, in combination with HMG Co--A reductase inhibitors, pharmaceutical compositions containing them, and use of these compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia is mammals. It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the circulation of bile acids within the lumen of the intestinal tract is found to reduce the levels of serum cholesterol is a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of atherosclerosis. Stedronsky, in "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties," Biochimica et Biophysica Acta. 1210 (1994) 255-287 discusses the biochemistry, physiology and known active agents surrounding bile acids and cholesterol. Pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans by Heubi, J. E., et al. See "Primary Bile Acid Malabsorption: Defective in Vitro Ileal Active Bile Acid Transport", Gastroenterology, 1982:83:804-11. Web site: http://www.delphion.com/details?pn=US06642268__
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Hydrazones and analogs as cholesterol lowering agents Inventor(s): Hasegawa; Hirohiko (Osaka, JP), Medina; Julio C. (San Carlos, CA) Assignee(s): Tularik Inc. (South San Francisco, CA) Patent Number: 6,605,615 Date filed: March 1, 2001 Abstract: Hydrazones and hydrazone analogs are provided which are useful as upregulators of LDL receptors and can be used in the treatment of hypercholesterolemia and related disorders and conditions. Excerpt(s): Atherosclerosis is disease resulting from excess cholesterol accumulation in the arterial walls, which forms plaques that inhibit blood flow and promote clot formation, ultimately causing heart attacks, stroke and claudication. The principal
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source of these cholesterol deposits are low-density lipoprotein (LDL) particles that are present in the blood. There is a direct correlation between LDL concentration and plaque formation in the arteries. LDL concentration is itself largely regulated by the supply of active LDL cell surface receptors which bind LDL particles and translocate them from the blood into the cell interior. Accordingly, the regulation of LDL receptor expression provides an important therapeutic target. Lipoprotein disorders have been previously called hyperlipoproteinemias and defined as elevation of a lipoprotein level above normal. Hyperlipoproteinemias result in elevations of cholesterol, triglycerides or both and are clinically important because of their contribution to atherosclerotic diseases and pancreatitis. Lipoproteins are spherical macromolecular complexes of lipid and protein. The lipid constituents of lipoproteins are esterified and unesterified (free) cholesterol, triglycerides, and phospholipids. Lipoproteins transport cholesterol and triglycerides from sites of absorption and synthesis to sites of utilization. Cholesteryl ester and triglycerides are nonpolar and constitute the hydrophobic core of lipoproteins in varying proportions. The lipoprotein surface coat contains the polar constituents-free cholesterol, phospholipids, and apolipoproteins--that permit these particles to be miscible in plasma. Web site: http://www.delphion.com/details?pn=US06605615__ •
Method for treating hypercholesterolemia, hyperlipidemia, and atherosclerosis Inventor(s): Cherukuri; Reddy Sastry V. (Folsom, CA), Cheruvanky; Rukmini (Folsom, CA), Lynch; Ike (El Dorado Hills, CA), McPeak; Patricia (El Dorado Hills, CA), Qureshi; Asaf A. (Madison, WI) Assignee(s): The RiceX Company (El Dorado Hills, CA) Patent Number: 6,558,714 Date filed: November 16, 2001 Abstract: A method for reducing mammalian serum total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride levels, by ingesting a stabilized rice bran derivative selected from the group consisting of an enzyme treated stabilized rice bran, an insolubilized fraction and mixtures thereof, thereby reducing serum total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride levels in said mammal. Excerpt(s): The present invention relates to methods for treating hypercholesterolemia, hyperlipidemia, and atherosclerosis in mammals by ingesting a stabilized rice bran derivative. Hypercholesterolemia is a condition with elevated levels of circulating total cholesterol, LDL-cholesterol and VLDL-cholesterol as per the guidelines of the Expert Panel Report of the National Cholesterol Educational Program (NCEP) of Detection, Evaluation of Treatment of high cholesterol in adults (see, Arch. Int. Med. (1988) 148, 3639). In particular, high level of LDL and VLDL are positively associated with coronary arteriosclerosis while the high levels of high density lipoproteins (HDL) are negative risk factors. The role of LDL oxidation is gaining much attention in the literature. It is well documented that LDL becomes oxidatively stressed under pathological conditions and is no longer recognized by the LDL receptors. The oxidized LDL is taken up by macrophages within the subendothelial space, leading to the formation of fatty streaks which are the basis of most advanced lesions. Hypercholesterolemia is implicated as a high risk factor of cardiovascular disease (CVD), including arteriosclerosis, atherosclerosis and xanthomatosis in humans. Hypercholesterolemia is influenced by diet, heredity, environment, life style, diseases and stress, leading to heart attacks and strokes at an early age.
Patents 139
Web site: http://www.delphion.com/details?pn=US06558714__ •
Methods of treating obesity using a neurotensin receptor ligand Inventor(s): Hadcock; John R. (East Lyme, CT) Assignee(s): Pfizer Inc. (New York, NY) Patent Number: 6,699,832 Date filed: April 24, 2001 Abstract: The present invention relates to methods of treating obesity, diabetes, sexual dysfunction, atherosclerosis, insulin resistance, impaired glucose tolerance, hypercholesterolemia or hypertrigylceridemia using a neurotensin receptor ligand. The present invention also relates to pharmaceutical compositions and kits that comprise a neurotensin receptor ligand. Excerpt(s): The present invention relates to methods of treating obesity, diabetes, sexual dysfunction (including erectile dysfunction), atherosclerosis, insulin resistance, impaired glucose tolerance, hypercholesterolemia, or hypertrigylceridemia using a compound that is a neurotensin receptor ligand. The present invention also relates to compositions and kits that comprise a neurotensin receptor ligand. Obesity is a devastating disease. In addition to harming physical health, obesity can wreak havoc on mental health because obesity affects self-esteem, which ultimately can affect a person's ability to interact socially with others. Unfortunately, obesity is not well understood, and societal stereotypes and presumptions regarding obesity only tend to exacerbate the psychological effects of the disease. Because of the impact of obesity on individuals and society, much effort has been expended to find ways to treat obesity, but little success has been achieved in the long-term treatment and/or prevention of obesity. Neurotensin is a thirteen amino acid peptide that appears to have functions as a neurotransmitter and neuromodulator in the nervous system and as a local hormone in the periphery. Specifically, neurotensin is a neuromodulator of dopamine transmission and of anterior pituitary hormone secretion, and exerts potent hypothermic and analgesic effects in the brain. In the periphery, neurotensin is a paracrine and endocrine modulator of the digestive tract and acts as a growth factor on a variety of cells. Web site: http://www.delphion.com/details?pn=US06699832__
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Methyl analogs of simvastatin as novel HMG-CoA reductase inhibitors Inventor(s): Kumar; Saridi Madhava Dileep (Andhra Pradesh, IN), Kumar; Yatendra (Haryana, IN), Thaper; Rajesh Kumar (Hidersbad, IN) Assignee(s): Ranbaxy Laboratories Limited (New Delhi, IN) Patent Number: 6,541,511 Date filed: June 10, 2002 Excerpt(s): The present invention relates to a novel methyl analog of simvastatin, which has the ability to inhibit the synthesis of cholesterol. The compound of the present invention holds promise for the treatment and prophylaxis of hypercholesterolemia and of various cardiac disorders. The invention also relates to a process for making the novel compound. Hypercholesterolemia is a known primary risk factor for the progression of atherosclerosis. High serum cholesterol is regarded as a major risk factor
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for the development of ischaemic heart disease and there is, therefore, a need for drugs which have the effect of reducing the blood cholesterol levels. was preserved, thereby establishing it as a key structural feature responsible for its HMG-CoA reductase inhibitory activity. Soon afterwards, intense efforts were directed to the design and development of synthetic strategies for selectively modifying the side-chain ester and the lactone moieties of mevinolin. Web site: http://www.delphion.com/details?pn=US06541511__ •
Quinolinyl and benzothiazolyl modulators Inventor(s): Furukawa; Noboru (Osaka, JP), Hagiwara; Atsushi (Osaka, JP), Houze; Jonathan B. (San Mateo, CA), McGee; Lawrence R. (Pacifica, CA), Rubenstein; Steven M. (Pacifica, CA), Shinkai; Hisashi (Osaka, JP) Assignee(s): Japan Tobacco, Inc. (Tokyo, JP), Tularik Inc. (So. San Francisco, CA) Patent Number: 6,583,157 Date filed: June 27, 2001 Abstract: Compounds, compositions and methods are provided that are useful in the treatment or prevention of a condition or disorder mediated by PAPAR.gamma. In particular, the compounds of the invention modulate the function of PAPAR.gamma. The subject methods are particularly useful in the treatment and/or prevention of diabetes, obesity, hypercholesterolemia, rheumatoid arthritis and atherosclerosis. Excerpt(s): The present invention relates to compounds that modulate the PAPAR.gamma. receptor and are useful in the diagnosis and treatment of type II diabetes (and complications thereof), hypercholesterolemia (and related disorders associated with abnormally high or low plasma lipoprotein or triglyceride levels) and inflammatory disorders. The peroxisome proliferator-activated receptors (PPARs) are transducer proteins belonging to the steroid/thyroid/retinoid receptor superfamily. The PPARs were originally identified as orphan receptors, without known ligands, but were named for their ability to mediate the pleiotropic effects of fatty acid peroxisome proliferators. These receptors function as ligand-regulated transcription factors that control the expression of target genes by binding to their responsive DNA sequence as heterodimers with RXR. The target genes encode enzymes involved in lipid metabolism and differentiation of adipocytes. Accordingly, the discovery of transcription factors involved in controlling lipid metabolism has provided insight into regulation of energy homeostasis in vertebrates, and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes and dyslipidemia. In an effort to understand the role of PAPAR.gamma. in adipocyte differentiation, several investigators have focused on the identification of PAPAR.gamma. activators. One class of compounds, the thiazolidinediones, which were known to have adipogenic effects on preadipocyte and mesenchymal stem cells in vitro, and antidiabetic effects in animal models of non-insulin-dependent diabetes mellitus (NIDDM) were also demonstrated to be PAPAR.gamma.-selective ligands. More recently, compounds that selectively activate murine PAPAR.gamma. were shown to possess in vivo antidiabetic activity in mice. Web site: http://www.delphion.com/details?pn=US06583157__
Patents 141
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Use of growth hormone or analogues thereof for the treatment of mammals with familial hypercholesterolemia Inventor(s): Angelin; Bo (Stockholm, SE), Rudling; Mats (Sollentuna, SE) Assignee(s): Salhtech I Goteborg AB (SE) Patent Number: 6,559,289 Date filed: April 23, 2001 Abstract: The invention relates to the use of compounds selected from GH, analogues thereof, and GH-releasing compounds, optionally in combination with lipid-lowering agents or therapy, for the preparation of a drug for treatment of mammals with familial hypercholesterolemia of homozygous form. Excerpt(s): The present invention relates to the use of biologically active compounds selected from GH, analogues thereof and GH-releasing compounds, as lipid lowering agents for the preparation of a drug for the treatment of mammals with homozygous familial hypercholesterolemia. By the furnishing of a drug comprising compounds selected from GH, analogues thereof and GH-releasing compounds, optionally in combination with further lipid lowering treatment, elevated plasma cholesterol in LDLR deficient mammals with familial hypercholesterolemia of the homozygous form may be treated. Growth hormone (GH) has pleiotropic effects on cholesterol metabolism. GH stimulates the expression of hepatic low density lipoprotein (LDL)-receptors and the activity of cholesterol 7.alpha.-hydroxylase (C7.alpha.OH), a key regulatory step in bile acid synthesis. According to the present invention it is shown that GH treatment reduces plasma cholesterol in the situation of homozygous familial hypercholesterolemia as represented by the recently developed LDL-receptor knockout mouse strain. In this specification and the appended claims the following abbreviations are used: C7.alpha.OH, represents cholesterol 7.alpha. hydroxylase; HMG CoA reductase, represents 3-hydroxy-3-methyl-glutaryl coenzyme A reductase; FPLC, represents fast performance liquid chromatography; GH, represents growth hormone; HDL, represents high density lipoprotein; LDL, represents low density lipoprotein; LDLR, represents low density lipoprotein receptor; LDLRKO, represents low density lipoprotein receptor knockout; SDS-PAGE, represents sodium dodecyl sulphatepolyacrylamide gel electrophoresis; TNA, represents total nucleic acid; VLDL, represents very low density lipoprotein. Web site: http://www.delphion.com/details?pn=US06559289__
Patent Applications on Hypercholesterolemia As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to hypercholesterolemia:
9
This has been a common practice outside the United States prior to December 2000.
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Bioavailable fenofibrate compositions, methods for treating hyperlipidemia and hypercholesterolemia and processes for the preparation of such compositions Inventor(s): Femia, Robert A.; (Kinnelon, NJ), Fishkis, Oscar I.; (White Plains, NY), Patel, Damodar P.; (Elmwood Park, NJ), Ragunathan, Narayan; (West Nyack, NY) Correspondence: The Firm OF Karl F Ross; 5676 Riverdale Avenue; PO Box 900; Riverdale (bronx); NY; 10471-0900; US Patent Application Number: 20040142903 Date filed: January 16, 2003 Abstract: Pharmaceutical compositions for treating hyperlipidemia or hypercholesterolemia in mammals are described which comprise: 1 (a) fenofibrate 5 to 35 wt. -% (b) a cyclodextrin 4 to 30 wt. -% (c) an alkali metal or 0.1 to 10 wt. -%; and alkaline earth metal docusate and/or alkali metal or alkaline earth metal lauryl sulfate (d) a water-insoluble, wettable 5 to 30 wt. -% inorganic carrier capable of forming a dispersion of the fenofibrate and a pharmaceutically acceptable inert carrier or diluent.A therapeutically effective amount of the compositions are orally administered to mammals to treat hyperlipidemia or hypercholesterolemia. Excerpt(s): This invention relates to novel fenofibrate compositions with bioavailability. The invention further relates to compositions containing fenofibrate, a cyclodextrin, an alkaline metal or alkaline earth metal docusate and/or an alkali metal or alkaline earth metal lauryl sulfate, and a water-insoluble, wettable carrier which provide fenofibrate to patients in a highly bioavailable form without the need for co-micronization of fenofibrate with any of the other ingredients. Fenofibrate is a well known antihyperlipoproteinemic agent. See U.S. Pat. No. 4,058,552. Experience with oral administration of fenofibrate has shown that the bioavailability of the drug has not been as high as would be desirable. A good deal of research has been carried out over the years to obtain compositions containing fenofibrate that are orally administered to patients and which have improved bioavailability. According to U.S. Pat. No. 4,895,726 to CURTET et al compositions containing fenofibrate with improved bioavailability have been prepared in which the fenofibrate has been co-micronized in an intimate mixture with a solid surfactant such as sodium lauryl sulfate. CURTET et al expressly state that it is possible to improve the bioavailability to a significantly greater extent than that which would be achieved either by adding a surfactant, or by micronizing the fenofibrate on its own, or by intimately mixing the separately micronized fenofibrate and surfactant. Such a fenofibrate-containing composition is currently available on the market under the mark TRICOR.sup.R. Among the compositions actually exemplified in CURTET et al, all such compositions contain alpha-lactose monohydrate, a well known hydrosoluble carrier. The alpha-lactose monohydrate is added to the co-micronizate of fenofibrate and solid surfactant. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Combinations of cholesteryl ester transfer protein inhibitors and bile acid sequestering agents for cardiovascular indications Inventor(s): Glenn, Kevin C.; (Maryland Heights, MO), Sikorski, James A.; (Des Peres, MO) Correspondence: Banner & Witcoff; 1001 G Street N W; Suite 1100; Washington; DC; 20001; US Patent Application Number: 20040028644 Date filed: April 14, 2003 Abstract: The present invention provides combinations of cardiovascular therapeutic compounds for the prophylaxis or treatment of cardiovascular disease including hypercholesterolemia and atherosclerosis. Combinations disclosed include an cholesteryl ester transfer protein inhibitor combined with a bile acid sequestrant. Excerpt(s): This application claims priority of U.S. provisional application Ser. No. 60/142,682 filed Jul. 7, 1999 and of U.S. provisional application Ser. No. 60/113,955 filed Dec. 23, 1998. The present invention relates to methods of treating cardiovascular diseases, and specifically relates to combinations of compounds, compositions, and methods for their use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as are associated with atherosclerosis, hypercholesterolemia, and other coronary artery disease in mammals. More particularly, the invention relates to cholesteryl ester transfer protein (CETP) activity inhibiting compounds. The invention also relates to bile acid sequestering compounds. It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein (LDL) cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Numerous studies have demonstrated that a low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Barter and Rye, Atherosclerosis, 121, 1-12 (1996). HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL), intermediate density lipoprotein (IDL), and very low density lipoprotein (VLDL). Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels. These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compositions for reducing hypercholesterolemia and controlling of postprandial blood glucose and insulin levels Inventor(s): Christmas, Kevin Patrick; (Mason, OH), Elsen, Joseph James; (St. Bernard, OH), Helmers, Ralph Lawrence JR.; (Cincinnati, OH), Kester, Jeffrey John; (West Chester, OH), Prosise, Robert Lawrence; (Cincinnati, OH), Wehmejer, Thomas Joseph; (Cincinnati, OH) Correspondence: Michael Best & Friedrich, Llp; 100 E Wisconsin Avenue; Milwaukee; WI; 53202; US Patent Application Number: 20040086547 Date filed: October 21, 2003 Abstract: Beta-glucan soluble fiber and non-digestible fats are administered orally to reduce blood cholesterol levels and to control postprandial blood glucose and insulin levels. The beta-glucan soluble fiber and non-digestible fat may be administered as separate compounds, as a mixture, or combined with other materials and administered in the form of an appealing food. Excerpt(s): This application claims the benefit of U.S. Provisional Application Serial No. 60/196,410 filed on Apr. 12, 2000, in the name of Prosise et al. The present invention relates to methods and compositions for reducing blood cholesterol levels, and for controlling of postprandial blood glucose and insulin levels, by oral administration of beta-glucan soluble fiber and a non-digestible fat. High blood cholesterol (hypercholesterolemia) is recognized as a risk factor for coronary heart disease, which is a major health care problem. Epidemiological studies have demonstrated that, with few exceptions, populations consuming large quantities of saturated fat and cholesterol have a relatively high concentration of serum cholesterol and a high mortality rate from coronary heart disease. While it is recognized that other factors can also contribute to the development of cardiovascular disease, there appears to be a causal relationship between the concentration of serum cholesterol, in which hypercholesterolemia results in the accumulation of undesirable amounts of cholesterol in various parts of the circulatory system (arteriosclerosis) or in soft tissues (xanthomatosis), and coronary disease and coronary mortality rates. It is well accepted that lowering of blood cholesterol levels will reduce the risk of heart disease, as well as slow the progression of this chronic disease in individuals already suffering its effects. Typical therapy for persons with hypercholesterolemia includes strict control of dietary intake of fat, saturated fat, and cholesterol. In certain cases, this dietary regimen may be combined with a treatment of cholesterol lowering drugs, such as the bile acid sequestrants (e.g., colestipol and cholestyramine). Patient adherence to a stringent and prolonged dietary and drug regimen is often poor. The cholesterol lowering drugs can have unpleasant side effects and palatability is often extremely poor. Therefore, it would be particularly advantageous to have palatable food products that can replace or enhance the effectiveness of cholesterol lowering drugs. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Controlled release pharmaceutical composition Inventor(s): Inagi, Toshio; (Mishima-shi, JP), Kawashima, Hiroyuki; (Fuji-shi, JP), Ogawa, Hirotada; (Fuji-shi, JP), Ohashi, Chihiro; (Fuji-shi, JP), Shimokawa, Tatsuharu; (Fuji-shi, JP), Shinoda, Yasuo; (Shizuoka-shi, JP), Tanizawa, Yoshio; (Fuji-shi, JP), Watanabe, Mayumi; (Fuji-shi, JP) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20040018235 Date filed: June 16, 2003 Abstract: The present invention is drawn to a pharmaceutical composition characterized by containing a composition (A) which contains pitavastatin, a salt thereof, or an ester thereof and which initiates release thereof at least in the stomach, and an enteric composition (B) which contains pitavastatin, a salt thereof, or an ester thereof. By use of the controlled release pharmaceutical composition of the present invention, the blood level of pitavastatin can be maintained at an appropriate level immediately after administration over a long period of time. Thus, highly safety and effective treatment of hypercholesterolemia can be performed. Excerpt(s): The present invention relates to a controlled release pharmaceutical composition containing pitavastatin, which is an HMG-CoA reductase inhibitor, a salt thereof, or an ester thereof. Pitavastatin and salts and esters thereof are known to be useful as drugs for treating hypercholesterolemia, by virtue of their excellent HMGCoA reductase inhibitory activity (U.S. Pat. No. 5,856,336 and EP 0,304,063). Hypercholesterolemia treatment drugs such as the pitavastatin-containing drugs are used in the form of peroral preparations such as tablets, granules and capsules (U.S. Pat. No. 6,465,477 and WO 97/23200). In general, peroral drug preparations are designed such that the blood level of the active ingredient reaches its peak 0.5 to 3 hours after ingestion, and the level rapidly decreases afterward. However, since cholesterol is synthesized in the body during the period from midnight to morning, it is highly likely that blood level of the active ingredient does not match the time at which biosynthesis of cholesterol occurs. Although pitavastatin and salts and esters thereof are also known to exert high activity and have high safety, an excessively high blood level thereof is not preferred, from the viewpoint of prevention against the side effects. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Crystalline bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino]pyrimidin -5-yl] (3R,5S)-3, 5-dihydroxyhept -6-enoic acid]calcium salt Inventor(s): Taylor, Nigel P.; (MacClesfield, GB) Correspondence: Morgan Lewis & Bockius Llp; 1111 Pennsylvania Avenue NW; Washington; DC; 20004; US Patent Application Number: 20040009997 Date filed: April 10, 2003 Abstract: The present invention relates to a crystalline form of the compound bis[(E)-7[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S)-3, 5-dihydroxyhept-6-enoic acid]calcium salt, as well as processes for its manufacture and pharmaceutical compositions comprising the crystalline form, which is
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useful as an atherosclerosis.
agent
for
treating
hyperlipidemia,
hypercholesterolemia
and
Excerpt(s): The present invention relates to a novel crystalline chemical compound and more particularly to a novel crystalline form of bis[(E)-7-[4-(4-fluorophenyl)-6isopropyl-2-[methyl(methylsulfonyl)amino]- pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept6-enoic acid] calcium salt, hereinafter referred to as "the Agent", and illustrated in Formula I hereinafter, which compound is an inhibitor of the enzyme 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMG CoA reductase) and is useful as a pharmaceutical agent, for example in the treatment of hyperlipidemia, hypercholesterolemia and atherosclerosis, as well as other diseases or conditions in which HMG CoA reductase is implicated. The invention also relates to processes for the manufacture of the crystalline form, pharmaceutical compositions comprising the crystalline form and the use of the crystalline form in medical treatment. European Patent Application, Publication No. 521471 (hereinafter EPA 521471), which is herein incorporated by reference, discloses an amorphous (powder) form of the Agent, prepared by dissolving the corresponding sodium salt in water, adding calcium chloride and collecting the resultant precipitate by filtration. An amorphous form of a compound intended for pharmaceutical use may give rise to manufacturing problems and there is a need to identify crystalline forms of such compounds which have different physical characteristics compared to the amorphous form which may assist in the manufacture of the compound, or formulation of the compound, to the purity levels and uniformity required for regulatory approval. Crystalline for ms of such compounds may also possess improved pharmacological characteristics, for example, improved bioavailability. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Fenofibrate tablets Inventor(s): Blouquin, Pascale; (Talant, FR), Reginault, Philippe; (Fontaine les Dijon, FR) Correspondence: Merchant & Gould; PO Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20040115264 Date filed: October 16, 2003 Abstract: The invention concerns a novel galenic formulation of fenofibrate for oral administration and its method of preparation. The invention is characterised in that it consists of a tablet obtained by compressing a mixture comprising: a) a granular material containing: 1 to 5% of a surfactant, micronized fenofibrate, at least a solid support selected among starch, cellulose or their derivatives, except C.sub.12 disaccharides; said granular material being obtained by granulating the mixture using an aqueous polyvinylpyrrolidone solution; b) crosslinked polyvinylpyrrolidone; c) optionally flow or lubricating agents, the amount of fenofibrate being more than 50 wt. %, expressed relative to the tablet weight. The invention is useful for treating hypercholesterolemia and hypertriglyceridemia. Excerpt(s): The present invention relates to a novel galenic formulation of fenofibrate for oral administration, to the process for its preparation and to the drugs manufactured from these formulations. Fenofibrate (INN), which belongs to the fibrate family, has been known for many years as a medicinal active principle because of its efficacy in lowering the blood triglyceride and cholesterol levels. Thus fenofibrate is widely prescribed in numerous countries when there is a need to reduce the risk of
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atherogenesis. It is also known that, to obtain a satisfactory hypocholesterolemic effect, it is desirable to maintain a circulating level of fenofibric acid (which is the active metabolite of fenofibrate) in the order of 6 to 10 mg/l. Such a level is obtained in particular with a unit dose of fenofibrate of 300 mg in gelatin capsule form (cf. Drugs 40 (2) pp 260-290 (1990)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Hypoestoxides, derivatives and agonists thereof for use in the treatment and prophylaxis of hyperlipidemia Inventor(s): Cottam, Howard B.; (Escondido, CA), Nchekwube, Emeka J.; (Morgan Hill, CA), Ojo-Amaize, Emmanuel A.; (Glendora, CA) Correspondence: Pillsbury Winthrop Llp; Intellectual Property Group; P.O. Box 10500; Mclean; VA; 22102; US Patent Application Number: 20040087553 Date filed: October 28, 2003 Abstract: Methods for treatment and prophylaxis of hyperlipidemias, including hypertriglyceridemia and hypercholesterolemia, are provided. The methods include administering to a host a therapeutically or prophylactically effective amount of a diterpene compound, such as a hypoestoxide. Excerpt(s): This application claims the benefit of priority under 35 U.S.C.sctn. 119 of provisional U.S. application Serial No. 60/421,533, filed Oct. 28, 2002, the contents of which are hereby incorporated by reference in their entirety, as if fully set forth. This invention relates to the use of diterpene compounds, in particular, hypoestoxides, derivatives and agonists thereof for treatment and prophylaxis of hyperlipidemias, including hypercholesterolemia and hypertriglyceridemia. Hyperlipidemias are conditions of abnormal plasma lipids, lipoproteins, and/or cholesterol levels, and include hypercholesterolemia and hypertriglyceridemia. Hyperlipidemias commonly accelerate atherosclerosis and predispose individuals to coronary heart disease. Hyperlipidemias can be inherited conditions or can be the result of a lifestyle that includes dietary excess, increased body weight and little or no vigorous exercise. (Jay H. Stein et al., Eds., Internal Medicine, 5.sup.th Ed., 1998, p. 1892.) References of interest providing background information on hyperlipidemia include: Foxton et al., Hyperlipidemia, Nursing Standard (Jun. 13, 1998) 12:49-56 and Krauss, Triglycerides and Atherogenic Lipoproteins: Rationale for Lipid Management, The American Journal of Medicine (Jul. 6, 1998) 105:58S-62S. All publications, patents, and patent documents referenced herein are incorporated by reference in their entirety as if fully set forth. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method of diagnosing statin myopathy Inventor(s): Phillips, Paul S; (Coronado, CA) Correspondence: Brown, Martin, Haller & Mcclain Llp; 1660 Union Street; San Diego; CA; 92101-2926; US Patent Application Number: 20030224470 Date filed: March 12, 2003
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Abstract: The use of statins for the control of hypercholesterolemia is continually increasing. Although the side effects of statins are relatively uncommon, muscle myopathies may develop in response to statin therapy. The invention is the discovery of a correlation between statin related myopathy based on the presence of 3methylglutaconic acid (3MGA) in the urine. This correlation allows for the screening of both symptomatic and asymptomatic individuals for statin related myopathy. Excerpt(s): This application claims the benefit of priority of United States provisional application Serial No. 60/363,435 filed Mar. 12, 2002 which is incorporated herein by reference in its entirety. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the mainstay of therapy for hypercholesterolemia because of their effectiveness and exceptional safety profile. Nonetheless, many patients treated with statins have muscle symptoms, and some patients develop severe muscle toxicity. Little is known about the mechanism by which statin therapy leads to muscle toxicity. The recent withdrawal of cerivastatin from the U.S. market has highlighted both our ignorance and the need for postmarketing surveillance of these therapies (Farmer Lancet 358:1383-5; 2001). There are credible reports of patients who have muscle symptoms and normal serum creatine kinase levels while receiving statins. However, there is no way to determine if the source of the myopathy is the statin or a non-related cause. As statin therapy becomes used more aggressively in larger groups of patients, the importance of even minor toxic side effects of this therapy is magnified. Early detection of patients who may suffer toxic muscular reactions to these drugs would be extremely useful. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method of reducing cholesterol Inventor(s): Roh-Schmidt, Haeri; (Ada, MI), Roufs, James B.; (Santa Monica, CA) Correspondence: G. Peter Nichols; Brinks Hofer Gilson & Lione; Nbc Tower, Suite 3600; P.O. Box 10395; Chicago; IL; 60610; US Patent Application Number: 20040097432 Date filed: November 3, 2003 Abstract: A method of treating elevated cholesterol levels, hyperlipidemia and/or hypercholesterolemia in a mammal includes administering an effective amount of theaflavins, thearubigins, and their mixture. The theaflavins include theaflavin and gallate esters of theaflavin, particularly those obtained from tea. The gallate esters include theaflavin-3-gallate, theaflavin-3'-gallate, and theaflavin-3,3'-digallate. Excerpt(s): The present invention claims priority to U.S. Ser. No. 60/423,612 filed Nov. 4, 2002, the entire contents of which are incorporated herein by reference. The present invention relates to compositions containing theaflavins, thearubigins, or their combination for reducing cholesterol and for the treatment of hyperlipidemia and/or hypercholesterolemia. In particular, the present invention is directed to the method of reducing cholesterol or treating hyperlipidemia and/or hypercholesterolemia in a mammal by administering an anti-hyperlipidemia and/or anti-hypercholesterolemia effective amount of theaflavins, thearubigin, or their mixture. A desired composition includes a neutriceutically acceptable diluent or carrier and an active ingredient that is selected from the group consisting of theaflavin, a gallate ester of theaflavin, or their mixture, wherein the theaflavin and gallate ester of theaflavin are derived from tea. There is ongoing interest in reducing, treating or regulating cholesterol levels in the
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body because of the known link between hyperlipidemia and hypercholesterolamia and cardiovascular disease. A popular drug, Lipitor.RTM., is prescribed to lower the lipid content in hyperlipidemic people. Despite the success of Lipitor.RTM., many people desire a natural alternative to the widely available prescription drugs. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Stable pharmaceutical formulation comprising a HMG-CoA reductase inhibitor Inventor(s): Kerc, Janez; (Ljubljana, SI) Correspondence: Bromberg & Sunstein Llp; 125 Summer Street; Boston; MA; 02110-1618; US Patent Application Number: 20040072894 Date filed: September 4, 2003 Abstract: Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, and derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, and some are obtained by treating the fermentation products using the methods of chemical synthesis or they are the products of total chemical synthesis.The aforementioned active substances may be destabilised by the environmental factors, their degradation may also be accelerated by interactions with other pharmaceutical ingredients, such as fillers, binders, lubricants, glidants and disintegrating agents, therefore the pharmaceutical ingredients and the process for preparation of the pharmaceutical formulation should be meticulously chosen to avoid the aforementioned undesired interactions and reactions.The present invention relates to a stable solid pharmaceutical formulation for the treatment of hypercholesterolemia and hyperlipidemia. More precisely, the present invention relates to the new stable solid pharmaceutical formulation containing as an active ingredient a HMG-CoA reductase inhibitor, such as atorvastatin, pravastatin, fluvastatin and cerivastatin or pharmaceutically acceptable salts thereof. Excerpt(s): The present invention relates to a new stable solid pharmaceutical formulation which is particularly suitable for the treatment of hypercholesterolemia and hyperlipidemia. More precisely, the present invention relates to the new stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor, such as atorvastatin, pravastatin, fluvastatin and cerivastatin, or pharmaceutically active salts thereof. Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, fluvastatin and cerivastatin, derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus. Some are obtained by treating the fermentation products using the methods of chemical synthesis like simvastatin or they are the products of total chemical synthesis like fluvastatin, atorvastatin and cerivastatin. The purity of the active substance is an important factor for manufacturing a safe and effective pharmaceutical formulation. Maximum possible purity of the product is of particular importance if the pharmaceutical product must be taken on a longer term basis in the treatment or prevention of high cholesterol levels in blood. Accumulation of impurities from drugs of a lower level of purity may cause a variety of side effects during treatment. Besides impurities, that cannot be completely eliminated
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in the process of preparation of the active substance, degradation products occurring by subjecting the final pharmaceutical formulation to various environmental factors such as temperature, moisture, low pH and light, may also impose a problem. HMG-CoA reductase inhibitors occurring in the form of salts in the final pharmaceutical formulation, such as atorvastatin, pravastatin, fluvastatin and cerivastatin, are particularly sensitive to an acidic environment in which hydroxy acids are degraded into a lactone. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Use of rosuvastatin hypercholesterolemia
(zd-4522)
in
the
treatment
of
heterozygous
familial
Inventor(s): Hutchinson, Howard Gerard; (Delaware, DE), Raza, Ali; (Cheshire, GB) Correspondence: Morgan Lewis & Bockius Llp; 1111 Pennsylvania Avenue NW; Washington; DC; 20004; US Patent Application Number: 20040072852 Date filed: November 6, 2003 Abstract: The invention provides a method for the treatment of heterozygous familial hypercholesterolemia by administering the compound (E)-7-[4-(4-fluorphenyl)-6isopropyl-2-[methyl(methylsulfonyl)amino]pyrim- idin-5-yl](3R,5S)-3,5-dihydroxy-hept6-enoic acid or a pharmaceutically acceptable salt thereof. Excerpt(s): The present invention relates to a new use of a statin drug in the treatment of severe heterozygous familial hypercholesterolemia (HeFH)and in particular patients with baseline LDL-C>220 mg/dL. There is now a large body of evidence obtained from clinical trials demonstrating that pharmacological agents (particularly the statins) that reduce low density lipoprotein-cholesterol LDL-C levels also decrease Chronic Heart Disease (CHD) risk (Lipid Research Clinics Program 1984, Gould et al 1998). Taken together, the trials published to date support the concept that lowering LDL-C levels should be the principal goal of lipid altering therapy (Ansell et al 1999), and that the reduction in coronary risk that occurs during treatment with statins is directly related to these agents' LDL-C lowering effects (Gould et al 1998, Pedersen et al 1998). Primary hyperlipidemia is a term used to describe a defect in lipoprotein metabolism. The lipoproteins commonly affected are LDL-C, which transports mainly cholesterol, and VLDL-C, which transports mainly TG. Most subjects with hyperlipidemia have a defect in LDL metabolism, characterised by raised cholesterol, LDL-C, levels, with or without raised triglyceride levels; such subjects are termed hypercholesterolemic (Fredrickson Type IL). Familial hypercholesterolemia (FH) is caused by any one of a number of genetically determined defects in the LDL receptor, which is important for the entry of cholesterol into cells. The condition is characterised by a reduced number of functional LDL receptors, and is therefore associated with raised serum LDL-C levels due to an increase in LDL. In its heterozygous form (HeFH) it is one of the commonest genetic diseases, with a frequency of about 1 in 500 in the United Kingdom (US), the United States (US), and Japan (Myant 1981, Mabuchi et al 1979). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Keeping Current In order to stay informed about patents and patent applications dealing with hypercholesterolemia, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “hypercholesterolemia” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on hypercholesterolemia. You can also use this procedure to view pending patent applications concerning hypercholesterolemia. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 5. BOOKS ON HYPERCHOLESTEROLEMIA Overview This chapter provides bibliographic book references relating to hypercholesterolemia. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on hypercholesterolemia include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.
Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “hypercholesterolemia” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on hypercholesterolemia: •
PDR for Herbal Medicines. 1st ed Source: Montvale, NJ: Medical Economics Company. 1998. 1244 p. Contact: Available from Medical Economics Publishing Inc. P.O. Box 10689, Des Moines, IA 50336. (800) 922-0937. Fax (515) 284-6714. Website: www.medecbookstore.com. PRICE: $59.99. ISBN: 1563632926. Summary: Most of today's herbal remedies exhibit varying degrees of therapeutic value. Some, such as ginkgo, valerian, and saw palmetto, seem genuinely useful, while others, such as ephedra, tansy, and nightshade, can actually be dangerous. As the use of unfamiliar botanicals spreads, the need to steer patients toward the few truly useful preparations and warn them away from ineffective, dangerous alternatives is becoming an increasingly significant priority. This volume, from the publishers of Physicians Desk Reference, brings together the findings of the German Regulatory Authority's herbal
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watchdog agency (commonly caused Commission E). This agency conducted an intensive assessment of the peer-reviewed literature on some 300 common botanicals, weighing the quality of the clinical evidence and identifying the uses for which the herb can reasonably be considered effective. This reference book contains profiles of over 600 medicinal herbs. Each entry contains up to 9 standard sections: name(s), description, actions and pharmacology, indications and usage, contraindications, precautions and adverse reactions, overdosage, dosage, and literature. The entries have also been indexed by scientific and common name, indications, therapeutic category, and side effects. To assist in identification, the reference book includes a section of full-color plates of the plants included. The book concludes with a glossary of the specialized botanical nomenclature and other unfamiliar terminology, a list of poison control centers, and a list of drug information centers. Some of the herbs are listed for use for abdominal cramps or distress, acid indigestion, appetite stimulation, rectal bleeding, various bowel disorders, stomach cancer, cholelithiasis (gallstones), colic, colitis, constipation, dehydration, diarrhea, digestive disorders, dysentery, enteritis, anal fissure, flatulence (intestinal gas), gastritis, gastroenteritis, gastrointestinal disorders, gout, helminthiasis, hemorrhage, hemorrhoids, hepatitis, hypercholesterolemia, jaundice, liver and gall bladder complaints, liver disorders, malaria, nausea, abdominal pain, and vomiting.
Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “hypercholesterolemia” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “hypercholesterolemia” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “hypercholesterolemia” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
Treatment of Severe Hypercholesterolemia in the Prevention of Coronary Heart Disease (Contributions to Infusion Therapy Beitrage Zur Infusionstherapi) by A.M. Gotto, et al; ISBN: 3805549059; http://www.amazon.com/exec/obidos/ASIN/3805549059/icongroupinterna
•
Treatment of Severe Hypercholesterolemia in the Prevention of Coronary Heart Disease 2 by A.M. Gotto, M. Mancini; ISBN: 3805550855; http://www.amazon.com/exec/obidos/ASIN/3805550855/icongroupinterna
Chapters on Hypercholesterolemia In order to find chapters that specifically relate to hypercholesterolemia, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and hypercholesterolemia using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type
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“hypercholesterolemia” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on hypercholesterolemia: •
Focal Segmental Glomerulosclerosis Source: in Schena, F.P., ed. Nephrology. New York, NY: McGraw-Hill, Inc. 2001. p. 141148. Contact: Available from McGraw-Hill, Inc. Shoppenhangers Road, Maidenhead, Berkshire SL6 2QL. 44 (0)1628 502700. Fax: +44 (0)1628 635895 E-mail:
[email protected]. Website: www.mcgraw-hill.co.uk. PRICE: $79.95; plus shipping and handling. ISBN: 0077095251. Summary: Focal segmental glomerulosclerosis (FSGS) is not a disease but a pathologic lesion, a scarring of a portion of the glomerulus (a group of capillaries that are part of the filtering units of the kidney). This chapter on focal segmental glomerulosclerosis(FSGS) is from a book on nephrology (the study of the kidney and kidney diseases) designed for general practitioners and family care providers that offers strategies for the management of patients with renal (kidney) damage. Among glomerular disorders that affect children and young adults, FSGS is the most common disorder leading to end stage renal disease (ESRD). The lesion is more frequent and the severity of the disease is greater in patients of African-American origin. Clinically, the lesions of FSGS can be observed in a wide variety of disorders. In the idiopathic (of unknown cause) variety, there is proteinuria (protein in the urine), hypoalbuminemia (low levels of protein in the blood), and generalized edema (fluid accumulation), together with varying degrees of hypertriglyceridemia and hypercholesterolemia (high levels of fats in the blood). Since FSGS is a histologic diagnosis, a renal biopsy is necessary. The pathogenesis of this disease continues to be elusive; however, in recent years studies point to the role of transforming growth factor beta (TGF-b) in inducing the sclerosis. Most cases of FSGS tend to be resistant to steroid therapy as well as to therapy with alkylating agents such as cyclophosphamide. Controlled trials have documented the efficacy of cyclosporine in inducing a remission of the proteinuria, particularly in children; however, relapses tend to occur upon withdrawal of cyclosporine. In severe edema, intravenous furosemide often is necessary. Antihypertensive (high blood pressure medications) therapy should consist of ACE inhibitors and calcium channel blockers. 2 tables. 15 references.
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Nephrotic Syndrome Source: in Kher, K.K.; Makker, S.P., eds. Clinical Pediatric Nephrology. New York, NY: McGraw-Hill. 1992. p. 137-174. Contact: Available from McGraw-Hill, Inc. P.O. Box 545, Blacklick, OH 43004. (800) 2624729. PRICE: $85.00 plus $3.00 shipping and handling. ISBN: 0070345430. Summary: Nephrotic syndrome, one of the most common renal diseases in childhood, is characterized by proteinuria, hypoalbulinemia, hypercholesterolemia, and edema. This chapter, from a book on clinical pediatric nephrology, discusses nephrotic syndrome. Topics covered include the classification of nephrotic syndrome, clinical features, pathophysiology, etiology, chronic glomerulonephritis as a cause of nephrotic syndrome, focal glomerulosclerosis, congenital nephrotic syndrome, secondary nephrotic syndrome, the laboratory evaluation of nephrotic syndrome, when to perform renal biopsy, treatment of nephrotic syndrome, complications of nephrotic syndrome, and growth in children with nephrotic syndrome. A final section, written in question and answer format, addresses management issues. Appended to the chapter is a
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commentary by H. William Schnaper about the questions remaining in the understanding of childhood nephrotic syndrome. 11 figures. 3 tables. 126 references. •
Primary Biliary Cirrhosis Source: in Feldman, M.; Friedman, L.S.; Sleisenger, M.H. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 7th ed. [2-volume set]. St. Louis, MO: Saunders. 2002. p. 1474-1485. Contact: Available from Elsevier. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 545-2522. Fax (800) 568-5136. Website: www.us.elsevierhealth.com. PRICE: $229.00 plus shipping and handling. ISBN: 0721689736. Summary: Primary biliary cirrhosis (PBC) is an autoimmune liver disease that generally affects middle-aged women and that is characterized by ongoing inflammatory destruction of the bile ducts. This destruction leads to chronic cholestasis (lack of bile flow) and biliary cirrhosis, with consequent complications such as portal hypertension and liver failure. This chapter on PBC is from a comprehensive and authoritative textbook that covers disorders of the gastrointestinal tract, biliary tree, pancreas, and liver, as well as the related topics of nutrition and peritoneal disorders. Topics include epidemiology; pathogenesis; clinical features (symptoms); diagnosis; natural history; medical treatment; complications of chronic cholestasis and their management, including bone disease, fat-soluble vitamin deficiency, hypercholesterolemia, hyperlipidemia, pruritus (itching), and steatorrhea; liver transplantation; and autoimmune cholangitis or antimitochondrial antibody-negative PBC. The chapter includes a mini-outline with page citations, full-color illustrations, and extensive references. 2 figures. 4 tables. 95 references.
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Gene Therapy for Metabolic Disease Source: in LeRoith, D.; Taylor, S.I.; Olefsky, J.M., eds. Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia, PA: Lippincott-Raven Publishers. 1996. p. 432-438. Contact: Available from Lippincott-Raven Publishers. 12107 Insurance Way, Hagerstown, MD 21740-5184. (800) 777-2295. Fax (301) 824-7390. PRICE: $199.00. ISBN: 0397514565. Summary: Somatic gene therapy refers to the introduction of genetic material into a specific organ or tissue in order to treat an inherited or acquired disease. This chapter, from a medical textbook on diabetes, presents an overview of the current status of somatic gene therapy for metabolic disease. The authors focus on liver-directed gene transfer for the purpose of illustration and uses homozygous familial hypercholesterolemia as a model. A final section of the chapter covers some of the issues related to somatic gene therapy for Type 1 diabetes mellitus (insulin-dependent or IDDM). The authors note that most of the issues relating to the successful development of gene therapy for diabetes mellitus are technical issues similar to those encountered in other diseases: targeting of the transgene to the appropriate tissue and achieving stable, regulated expression of the transgene. Another important issue for diabetes mellitus is the choice of gene for gene transfer. For most patients with IDDM, the insulin gene would appear to be the appropriate therapeutic gene for transfer. Another approach would be to transduce immunomodulatory cytokines into the pancreatic islets to prevent the autoimmune destruction that causes Type 1 diabetes. 1 figure. 2 tables. 66 references.
Books
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Genetics of Human Disease, Longevity, and Aging Source: in Hazzard, W.R., et al., eds. Principles of Geriatric Medicine and Gerontology. 2nd ed. New York, NY: McGraw-Hill, Inc. 1990. p. 22-36. Contact: This publication may be available from your local medical library. Call for information. ISBN: 0070275009. Summary: The authors of this chapter suggest that, to a considerable extent, future progress in geriatric medicine is likely to be coupled to progress in basic and medical genetics. Specific attention is given to two specific areas: (1) basic considerations of genetics and aging; and (2) genetic syndromes that modulate aspects of the senescent phenotype. The former considers such aspects as maximum life span as a constitutional feature of speciation, the association between heredity and longevity, estimation of the number of genetic loci involved in human aging, sex differences in longevity, and genetic mechanisms and aging. The latter covers progeroid syndromes, Werner's syndrome, the Hutchinson-Gilford syndrome, ataxia telangiectasia (an autosomal, recessively-inherited disorder), Down's syndrome, other segmental progeroid syndromes, familial hypercholesterolemia, hereditary amyloidosis, familial Alzheimer's disease, Huntington's disease, and antigeroid syndromes. Consideration also is given to the potential association between parental age and mutation, including point mutations, and maternal age and aneuploidy. 150 references.
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High-Fiber Diet Source: in American Dietetic Association. Manual of Clinical Dietetics, Sixth Edition. Chicago, IL: American Dietetic Association. 2000. p.709-717. Contact: Available from American Dietetic Association. 216 West Jackson Boulevard, Chicago, IL 60606. (800) 877-1600 or (312) 899-0040. Fax (312) 899-4899. PRICE: $59.95 for members, $70.00 for nonmembers. ISBN: 0880911875. Summary: This chapter describing a high-fiber diet is from a comprehensive manual of clinical dietetics designed to help dietitians, physicians, and nurses deliver quality nutrition care. The chapter includes the purpose of the high-fiber diet, the indications for use, a description of the diet, meal planning approaches, and a discussion section. The high-fiber diet is used to increase fecal bulk and promote regularity, to normalize serum lipid (fats) levels, and to blunt postprandial (after a meal) blood glucose response. A high-fiber diet can be used in the prevention or treatment of various gastrointestinal, cardiovascular, and metabolic diseases and conditions including diverticular disease, cancer of the colon, diabetes mellitus, endometrial cancer, constipation, irritable bowel syndrome, Crohn's disease, hypercholesterolemia, and obesity. 2 tables. 20 references.
•
Lipid Metabolism in Renal Disease and Renal Failure Source: in Kopple, J.D. and Massry, S.G. Nutritional Management of Renal Disease. Baltimore, MD: Williams and Wilkins. 1997. p. 35-62. Contact: Available from Williams and Wilkins. 351 West Camden Street, Baltimore, MD 21201-2436. (800) 638-0672 or (410) 528-4223. Fax (800) 447-8438 or (410) 528-8550. PRICE: $99.00. ISBN: 068304740X. Summary: This chapter on lipid metabolism is from a medical textbook on nutrition and metabolism of individuals with renal disease or renal failure. In uremia, the distribution of lipid and apolipoproteins in the lipoprotein density classes is distorted. The disorder is complex and varies substantially within groups of patients treated with different renal
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replacement methods (e.g., hemodialysis, CAPD, transplantation). Abnormalities in lipid metabolism can be detected in the patient early as renal function begins to decline. The author summarizes the most characteristic patterns of serum lipids in patients with renal disease and renal failure. Guidelines for the detection, evaluation, and treatment of hypercholesterolemia in adults have been established in the U.S. and Europe. These guidelines recommend that total cholesterol levels be used for screening purposes. All persons in the so-called high category (cholesterol greater than 240 mg per dL) require measurements of low-density lipoprotein (LDL) cholesterol levels; the measurements are used as a guide to the selection of treatment. The chapter concludes with recommended treatment and patient care management strategies. 4 figures. 3 tables. 153 references. (AA-M). •
Nutritional and Metabolic Liver Diseases Source: in Sherlock, S.; Dooley, J. Diseases of the Liver and Biliary System. Malden, MA: Blackwell Science, Inc. 2002. p.423-452. Contact: Available from Blackwell Science, Inc. 350 Main Street, Commerce Place, Malden, MA 02148. (800) 215-1000 or (617) 388-8250. Fax (617) 388-8270. E-mail:
[email protected]. Website: www.blackwell-science.com. PRICE: $178.95. ISBN: 0632055820. Summary: This chapter on nutritional and metabolic liver diseases is from a textbook that presents a comprehensive and up-to-date account of diseases of the liver and biliary system. The chapter covers malnutrition; fatty liver, including diagnosis and classification; non-alcoholic fatty liver disease, including hepatic steatosis, steatonecrosis, the effects of the jejuno-ileal bypass, parenteral nutrition, and vitamins; carbohydrate metabolism in liver disease, including hypoglycemia and hyperglycemia; the liver in diabetes mellitus, including insulin and the liver, hepatic histology, clinical features, and liver function tests; hepatobiliary disease and diabetes, including the glucose intolerance of cirrhosis and the treatment of diabetes in patients with cirrhosis; glycogen storage disease (types I through VI) and hepatic glycogen synthetase deficiency; hereditary fructose intolerance; glutaric aciduria type II, galactosemia; mucopolysaccharidoses; familial hypercholesterolemia; amyloidosis; alpha1-antitrypsin deficiency; hereditary tyrosinemia; cystic fibrosis; liver and thyroid, including thyrotoxicosis, myxoedema, and changes with hepatocellular disease; liver and adrenal; liver and growth hormone; hepatic porphyrias, including acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, porphyria cutanea tarda, erythropoietic protoporphyria, hepato-erythropoietic porphyria, and secondary coproporphyrias; hereditary hemorrhagic teleangiectasia; and dystrophic myotonica. Each section includes its own list of references for further reading. 19 figures. 6 tables. 184 references.
•
Classification, Diagnostic Criteria, and Screening for Diabetes Source: in Harris, M.I., et al., eds., for the National Diabetes Data Group (NDDG). Diabetes in America. 2nd ed. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. 1995. p. 15-36. Contact: Available from National Diabetes Information Clearinghouse (NDIC). 1 Information Way, Bethesda, MD 20892-3560. (800) 860-8747 or (301) 654-3327. E-mail:
[email protected]. Also available at http://www.niddk.nih.gov/. PRICE: Fulltext available online at no charge. Summary: This chapter on the classification, diagnostic criteria, and screening for diabetes is from a compilation and assessment of data on diabetes and its complications
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in the United States. Four major types of diabetes have been defined: insulin dependent diabetes mellitus (Type 1 Diabetes), noninsulin dependent diabetes mellitus (Type 2 Diabetes), gestational diabetes mellitus (GDM), and diabetes secondary to other conditions. Impaired glucose tolerance (IGT) is a class that encompasses persons whose glucose tolerance is intermediate between normal and diabetes ranges. Screening is most appropriately carried out in groups at high risk for NIDDM. Major risk factors for NIDDM include older age, obesity, family history of diabetes, race or ethnicity of black, Hispanic or American Indian, and the presence of complications related to diabetes. The author outlines the scientific basis for the diagnostic criteria, the circumstances and methods for the diagnosis of diabetes in the United States, the use of the oral glucose tolerance test, the frequency and methods of screening for diabetes in the United States, the principles of screening for undiagnosed NIDDM, controversies in screening for NIDDM, and screening in high risk populations. The author concludes that the choice of screening method and criteria to be used depends on the screening situation. In public screening programs, considerations of cost and efficiency are important and it might be considered important to screen only very high risk groups to ensure high yields of positive screenees, although this would miss significant numbers of persons with NIDDM. In physicians' offices, where the focus is on care of the individual patient, it would appear appropriate to relax the screening exclusions and be more inclusive. Screening for undiagnosed NIDDM can also be accomplished in the context of programs directed toward other medical conditions that are frequent in people with diabetes, such as hypertension and hypercholesterolemia. 15 figures. 13 tables. 87 references. •
Management of the Hyperlipidemia of the Nephrotic Syndrome Source: in Andreucci, V.E. International Yearbook of Nephrology 1990. Hingham, MA: Kluwer Academic Publishers. 1990. p. 53-69. Contact: Available from Kluwer Academic Publishers. P.O. Box 358, Accord Station, Hingham, MA02018-0358. (617) 871-6600. Summary: This chapter summarizes and discusses various aspects associated with the effective management of patients with hyperlipidemia of the nephrotic syndrome, a syndrome representing a renal disorder characterized by proteinuria, hypoalbuminemia, sometimes edema, and hyperlipidemia. Specific attention is given to mechanisms of nephrotic hyperlipidemia (NH) (hypercholesterolemia; hypertriglyceridemia) and to drug therapy of NH (bile acid resins; nicotinic acid; 3hydroxy-3- methylglutaryl coenzyme A reductase inhibitors; fibric acids; probucol). The utility of combined drug therapy also is discussed. 56 references.
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CHAPTER 6. PERIODICALS HYPERCHOLESTEROLEMIA
AND
NEWS
ON
Overview In this chapter, we suggest a number of news sources and present various periodicals that cover hypercholesterolemia.
News Services and Press Releases One of the simplest ways of tracking press releases on hypercholesterolemia is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “hypercholesterolemia” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to hypercholesterolemia. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “hypercholesterolemia” (or synonyms). The following was recently listed in this archive for hypercholesterolemia: •
Statins for children with hypercholesterolemia reverses early vascular thickening Source: Reuters Medical News Date: November 12, 2003
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•
Hypertension, hypercholesterolemia should prompt screening for diabetes Source: Reuters Medical News Date: February 03, 2003
•
Hypertension and hypercholesterolemia undertreated in type 2 diabetics Source: Reuters Medical News Date: June 26, 2002
•
Mortality risk for those with familial hypercholesterolemia may have been overestimated Source: Reuters Medical News Date: April 27, 2001 The NIH
Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “hypercholesterolemia” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “hypercholesterolemia” (or synonyms). If you know the name of a company that is relevant to hypercholesterolemia, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/.
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BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “hypercholesterolemia” (or synonyms).
Academic Periodicals covering Hypercholesterolemia Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to hypercholesterolemia. In addition to these sources, you can search for articles covering hypercholesterolemia that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”
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CHAPTER 7. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for hypercholesterolemia. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a non-profit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with hypercholesterolemia. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.).
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The following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to hypercholesterolemia: Anabolic Steroids •
Systemic - U.S. Brands: Anadrol-50; Deca-Durabolin; Durabolin; Durabolin-50; Hybolin Decanoate; Hybolin-Improved; Kabolin; Oxandrin; Winstrol http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202035.html
Cerivastatin •
Systemic - U.S. Brands: Not commercially available http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203060.html
Colestipol •
Oral - U.S. Brands: Colestid http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202161.html
Diethylcarbamazine •
Systemic - U.S. Brands: Hetrazan http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202192.html
Diethyltoluamide •
Topical - U.S. Brands: Backwoods Cutter; Cutter Pleasant Protection; Deep Woods OFF!; Deep Woods OFF! For Sportsmen; Muskol; OFF!; OFF! For Maximum Protection; OFF! Skintastic; OFF! Skintastic For Children; OFF! Skintastic For Kids; Ultra Muskol http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202749.html
Fenofibrate •
Systemic - U.S. Brands: Lofibra; Tricor http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203516.html
HMG-CoA Reductase Inhibitors •
Systemic - U.S. Brands: Baycol; Lescol; Lipitor; Mevacor; Pravachol; Zocor http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202284.html
Indapamide •
Systemic - U.S. Brands: Lozol http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202296.html
Laxatives •
Oral - U.S. Brands: Agoral; Alophen; Alphamul; Alramucil Orange; Alramucil Regular; Bisac-Evac; Black-Draught; Black-Draught Lax-Senna; Carter's Little Pills; Cholac; Citroma; Citrucel Orange Flavor; Citrucel Sugar-Free Orange Flavor; Colace; Constilac; Constulose; Correctol; Correctol Caplets; Correctol Herbal Tea; Correctol Stool Softener Soft Gels; D.O.S. Softgels; DC Softgels; Diocto; Diocto-C; Dioeze; Diosuccin; Docu-K Plus; DOK; DOK Softgels; Dr. Caldwell Senna Laxative; D-S-S; D-S-S plus; Dulcolax; Emulsoil; Enulose; Epsom salts; Equalactin; Evac-U-Gen; Ex-Lax; Ex-Lax Chocolate; FemiLax; Fiberall; Fibercon Caplets; Fiber-Lax; FiberNorm; Fleet Laxative; Fleet Mineral Oil; Fleet
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Phospho-Soda; Fleet Soflax Gelcaps; Fleet Soflax Overnight Gelcaps; Fletcher's Castoria; Genasoft Plus Softgels; Gentle Laxative; Haley's M-O; Herbal Laxative; Hydrocil Instant; Kondremul Plain; Konsyl; Konsyl Easy Mix; Konsyl-D; KonsylOrange; Konsyl-Orange Sugar Free; Laxinate 100; Liqui-Doss; Mag-Ox 400; Maltsupex; Metamucil; Metamucil Apple Crisp Fiber Wafers; Metamucil Cinnamon Spice Fiber Wafers; Metamucil Orange Flavor; Metamucil Smooth Sugar-Free, Citrus Flavor; Metamucil Smooth Sugar-Free, Orange Flavor; Metamucil Smooth Sugar-Free, Regular Flavor; Metamucil Smooth, Citrus Flavor; Metamucil Smooth, Orange Flavor; Metamucil Sugar-Free, Lemon-Lime Flavor; Metamucil Sugar-Free, Orange Flavor; MiraLax; Modane; Modane Bulk; Mylanta Natural Fiber Supplement; Mylanta Sugar Free Natural Fiber Supplement; Nature's Remedy; Neoloid; Perdiem; Perdiem Fiber; Peri-Colace; Peri-Dos Softgels; Phillips' Chewable; Phillips' Concentrated; Phillips' Milk of Magnesia; Phillips' Stool Softner Laxative Softgels; Prompt; Purge; Reguloid Natural; Reguloid Natural Sugar Free; Reguloid Orange; Reguloid Orange Sugar Free; Senexon; Senna-Gen; Senokot; Senokot Children's Syrup; Senokot-S; SenokotXTRA; Senolax; Serutan; Serutan Toasted Granules; Silace; Silace-C; Sulfolax; Surfak; Syllact; Veracolate; V-Lax; X-Prep Liquid http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202319.html Progestins for Contraceptive Use •
Systemic - U.S. Brands: Depo-Provera Contraceptive Injection; Micronor; NORPLANT System; Nor-QD; Ovrette; Plan B http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202757.html
Progestins for Noncontraceptive Use •
Systemic - U.S. Brands: Amen; Aygestin; Crinone; Curretab; Cycrin; DepoProvera; Gesterol 50; Gesterol LA 250; Hy/Gestrone; Hylutin; Megace; Prodrox; Prometrium; Pro-Span; Provera http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202758.html
Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.
Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information
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adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.
Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to hypercholesterolemia by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “hypercholesterolemia” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for hypercholesterolemia: •
Sodium dichloroacetate http://www.rarediseases.org/nord/search/nodd_full?code=56
If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.
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APPENDICES
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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.
NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute10: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
•
National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
•
National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
•
National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
•
National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
•
National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
•
National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
•
National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
10
These publications are typically written by one or more of the various NIH Institutes.
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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
•
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
•
National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
•
National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
•
National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
•
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
•
National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
•
National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
•
National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
•
National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
•
National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
•
National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
•
Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
•
National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
•
National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
•
Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
•
Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.11 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:12 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
•
HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
•
NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
•
Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
•
Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
•
Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
•
Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
•
MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
11
Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 12 See http://www.nlm.nih.gov/databases/databases.html.
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•
Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
•
Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
The NLM Gateway13 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “hypercholesterolemia” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total
Items Found 24304 201 132 97 109 24843
HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.17 Simply search by “hypercholesterolemia” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
13
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
14
The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17
The HSTAT URL is http://hstat.nlm.nih.gov/.
Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.
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Coffee Break: Tutorials for Biologists18 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.19 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
18 Adapted 19
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 20 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.
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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on hypercholesterolemia can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.
Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to hypercholesterolemia. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to hypercholesterolemia. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “hypercholesterolemia”:
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Genetic Disorders http://www.nlm.nih.gov/medlineplus/geneticdisorders.html Heart Attack http://www.nlm.nih.gov/medlineplus/heartattack.html Liver Transplantation http://www.nlm.nih.gov/medlineplus/livertransplantation.html Metabolic Disorders http://www.nlm.nih.gov/medlineplus/metabolicdisorders.html Stroke http://www.nlm.nih.gov/medlineplus/stroke.html Weight Loss and Dieting http://www.nlm.nih.gov/medlineplus/weightlossanddieting.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on hypercholesterolemia. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •
Managing High Cholesterol Source: Palo Alto, CA: FastMark, Inc. 2001. 4 p. Contact: Available from FastMark, Inc. 125 University Avenue, Suite 250, Palo Alto, CA 94301. (800) 406-2035. (650) 327-7700. Fax: (650) 327-7734. Email:
[email protected]. Website: www.fastmark.com. PRICE: $1.45 each; discounts available for large orders. Item number: 1245. Summary: This brochure helps readers understand high cholesterol and how it can be managed. Topics include the risk factors for high cholesterol (hypercholesterolemia), complications associated with high cholesterol levels, a recommended healthy diet strategy (eat less fat and dietary cholesterol, eat more fiber, eating plenty of complex carbohydrates, make good choices at restaurants), quitting smoking, weight loss, drug therapy for high cholesterol, and the importance of getting aerobic exercise, including exercise tips. Each of the sections offers specific, practical tips for readers. The brochure is printed on heavy weight card stock and illustrated with colorful graphics. The brochure is also available in Spanish. 2 figures. 4 tables.
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Preventing Progression of Renal Disease: News Briefings for Science Writers on Transplantation, Dialysis and Kidney Research (memorandum) Source: New York, NY: National Kidney Foundation, Inc. March 26-27, 1990. 7 p. Contact: Available from National Kidney Foundation, Inc. 30 East 33rd Street, New York, NY 10016. (800) 622-9010 or (212) 889-2210. Summary: This technical paper prepared for the National Kidney Foundation's 1990 science writers news briefing on transplantation, dialysis, and kidney/urology research discusses the mechanisms underlying the progression of renal disease. Accumulating evidence indicates that the risk factors underlying the progression of chronic renal disease include hypertension, hypercholesterolemia, invasion of the kidney by inflammatory cells, proteinuria and/or persistence of the initial pathogenic insult responsible for renal damage. The theorized participation of each risk factor is discussed. The author concludes that the risk factors may be interrelated and may potentiate each other at different stages of the evolution and progression of renal disease. The NIH Search Utility
The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to hypercholesterolemia. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. NORD (The National Organization of Rare Disorders, Inc.) NORD provides an invaluable service to the public by publishing short yet comprehensive guidelines on over 1,000 diseases. NORD primarily focuses on rare diseases that might not be covered by the previously listed sources. NORD’s Web address is http://www.rarediseases.org/. A complete guide on hypercholesterolemia can be purchased from NORD for a nominal fee. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
•
Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
•
WebMDHealth: http://my.webmd.com/health_topics
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to hypercholesterolemia. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with hypercholesterolemia. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about hypercholesterolemia. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “hypercholesterolemia” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “hypercholesterolemia”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format
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option “Organization Resource Sheet.” Type “hypercholesterolemia” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “hypercholesterolemia” (or a synonym) into the search box, and click “Submit Query.”
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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.21
Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.
Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of
21
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)22: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
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California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
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California: Gateway Health Library (Sutter Gould Medical Foundation)
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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
•
Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
22
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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•
Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
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Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm
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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp
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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm
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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
•
National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
•
Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
•
Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on hypercholesterolemia: •
Basic Guidelines for Hypercholesterolemia Diabetes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001214.htm Diabetes mellitus Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001214.htm Hypothyroidism Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000353.htm Nephrotic syndrome Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000490.htm
•
Diagnostics and Tests for Hypercholesterolemia HDL Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003496.htm
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LDL Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003495.htm Low density lipoprotein Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003495.htm Total cholesterol Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003492.htm •
Nutrition for Hypercholesterolemia Cholesterol Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002472.htm Fat Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002468.htm Niacin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002409.htm
•
Background Topics for Hypercholesterolemia Autosomal dominant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002049.htm Bile Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002237.htm Genetics Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002048.htm Hepatic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002378.htm Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Smoking Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002032.htm Smoking cessation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001992.htm
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
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•
MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
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Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
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Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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HYPERCHOLESTEROLEMIA DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Cramps: Abdominal pain due to spasmodic contractions of the bowel. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology,
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nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerobic Exercise: A type of physical activity that includes walking, jogging, running, and dancing. Aerobic training improves the efficiency of the aerobic energy-producing systems that can improve cardiorespiratory endurance. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]
Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Ageing: A physiological or morphological change in the life of an organism or its parts, generally irreversible and typically associated with a decline in growth and reproductive vigor. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low
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serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]
Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha-Linolenic Acid: A fatty acid that is found in plants and involved in the formation of prostaglandins. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Amaurosis: Partial or total blindness from any cause. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH]
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Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Anal Fissure: A small tear in the anus that may cause itching, pain, or bleeding. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anastomosis: A procedure to connect healthy sections of tubular structures in the body after the diseased portion has been surgically removed. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Anginal: Pertaining to or characteristic of angina. [EU] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angiogram: An x-ray of blood vessels; the person receives an injection of dye to outline the
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vessels on the x-ray. [NIH] Angiography: Radiography of blood vessels after injection of a contrast medium. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Anode: Electrode held at a positive potential with respect to a cathode. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antidiabetic: An agent that prevents or alleviates diabetes. [EU] Antidote: A remedy for counteracting a poison. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU]
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Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]
Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antipruritic: Relieving or preventing itching. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Aortic Valve: The valve between the left ventricle and the ascending aorta which prevents backflow into the left ventricle. [NIH] Apheresis: Components plateletpheresis. [NIH]
being
separated
out,
as
leukapheresis,
plasmapheresis,
Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the
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walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspartate: A synthetic amino acid. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atherogenic: Causing the formation of plaque in the lining of the arteries. [NIH] Atrial: Pertaining to an atrium. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Neuropathy: A disease of the nerves affecting mostly the internal organs such as the bladder muscles, the cardiovascular system, the digestive tract, and the genital organs. These nerves are not under a person's conscious control and function automatically. Also called visceral neuropathy. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]
Axillary Artery: The continuation of the subclavian artery; it distributes over the upper limb, axilla, chest and shoulder. [NIH] Backcross: A cross between a hybrid and either one of its parents. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH]
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Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Basilar Artery: The artery formed by the union of the right and left vertebral arteries; it runs from the lower to the upper border of the pons, where it bifurcates into the two posterior cerebral arteries. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Beta-Galactosidase: A group of enzymes that catalyzes the hydrolysis of terminal, nonreducing beta-D-galactose residues in beta-galactosides. Deficiency of beta-Galactosidase A1 may cause gangliodisosis GM1. EC 3.2.1.23. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH]
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Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biphasic: Having two phases; having both a sporophytic and a gametophytic phase in the life cycle. [EU] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or
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animal to another. [NIH] Boron: A trace element with the atomic symbol B, atomic number 5, and atomic weight 10.81. Boron-10, an isotope of boron, is used as a neutron absorber in boron neutron capture therapy. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Artery: The continuation of the axillary artery; it branches into the radial and ulnar arteries. [NIH] Bradycardia: Excessive slowness in the action of the heart, usually with a heart rate below 60 beats per minute. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Bronchoconstriction: Diminution of the caliber of a bronchus physiologically or as a result of pharmacological intervention. [NIH] Bursitis: Inflammation of a bursa, occasionally accompanied by a calcific deposit in the underlying supraspinatus tendon; the most common site is the subdeltoid bursa. [EU] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium channel blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools. Since they are inducers of vascular and other smooth muscle relaxation, they are used in the drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms. [NIH] Calcium Chloride: A salt used to replenish calcium levels, as an acid-producing diuretic, and as an antidote for magnesium poisoning. [NIH] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually
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composed of mineral salts. Also called stones. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary Fragility: The lack of resistance, or susceptibility, of capillaries to damage or disruption under conditions of increased stress. [NIH] Capillary Permeability: Property of blood capillary walls that allows for the selective exchange of substances. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (tight junctions) which may limit large molecule movement. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Cardiac: Having to do with the heart. [NIH] Cardiology: The study of the heart, its physiology, and its functions. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carotenoids: Substance found in yellow and orange fruits and vegetables and in dark green, leafy vegetables. May reduce the risk of developing cancer. [NIH] Carotid Artery Thrombosis: Blood clot formation in the common, internal, or external carotid artery which may produce stenosis or occlusion of the vessel, leading to ischemia or
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infarction of tissue supplied by these arteries. Thrombosis of the common and internal carotid arteries may result in ischemic attacks, transient; cerebral infarction; or amaurosis fugax. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Carrier State: The condition of harboring an infective organism without manifesting symptoms of infection. The organism must be readily transmissable to another susceptible host. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catechin: Extracted from Uncaria gambier, Acacia catechu and other plants; it stabilizes collagen and is therefore used in tanning and dyeing; it prevents capillary fragility and abnormal permeability, but was formerly used as an antidiarrheal. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caveolae: Endocytic/exocytic cell membrane structures rich in glycosphingolipids, cholesterol, and lipid-anchored membrane proteins that function in endocytosis (potocytosis), transcytosis, and signal transduction. Caveolae assume various shapes from open pits to closed vesicles. Caveolar coats are composed of caveolins. [NIH] Caveolins: The main structural proteins of caveolae. Several distinct genes for caveolins have been identified. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Adhesion Molecules: Surface ligands, usually glycoproteins, that mediate cell-to-cell adhesion. Their functions include the assembly and interconnection of various vertebrate systems, as well as maintenance of tissue integration, wound healing, morphogenic movements, cellular migrations, and metastasis. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Membrane Structures: Structures which are part of the cell membrane or have cell membrane as a major part of their structure. [NIH] Cell motility: The ability of a cell to move. [NIH]
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Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cellobiose: A disaccharide consisting of two glucose units in beta (1-4) glycosidic linkage. Obtained from the partial hydrolysis of cellulose. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Arteries: The arteries supplying the cerebral cortex. [NIH] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemokines, C: Group of chemokines without adjacent cysteines that are chemoattractants for lymphocytes only. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chest Pain: Pressure, burning, or numbness in the chest. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH]
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Cholangitis: Inflammation of a bile duct. [NIH] Cholelithiasis: Presence or formation of gallstones. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [NIH]
Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Cholesterol, Dietary: Cholesterol present in food, especially in animal products. [NIH] Cholestyramine: Strongly basic anion exchange resin whose main constituent is polystyrene trimethylbenzylammonium as Cl(-) anion. It exchanges chloride ions with bile salts, thus decreasing their concentration and that of cholesterol. It is used as a hypocholesteremic in diarrhea and biliary obstruction and as an antipruritic. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chronotropic: Affecting the time or rate, as the rate of contraction of the heart. [EU] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] Circulatory system: The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH]
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Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clathrin: The main structural coat protein of coated vesicles which play a key role in the intracellular transport between membranous organelles. Clathrin also interacts with cytoskeletal proteins. [NIH] Claudication: Limping or lameness. [EU] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]
Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coated Vesicles: Vesicles formed when cell-membrane coated pits invaginate and pinch off. The outer surface of these vesicles are covered with a lattice-like network of coat proteins, such as clathrin, coat protein complex proteins, or caveolins. [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH] Colestipol: Highly crosslinked and insoluble basic anion exchange resin used as anticholesteremic. It may also may reduce triglyceride levels. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and
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leaves the body through the anus. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computer Simulation: Computer-based representation of physical systems and phenomena such as chemical processes. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized
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tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confidence Intervals: A range of values for a variable of interest, e.g., a rate, constructed so that this range has a specified probability of including the true value of the variable. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contrast medium: A substance that is introduced into or around a structure and, because of the difference in absorption of x-rays by the contrast medium and the surrounding tissues, allows radiographic visualization of the structure. [EU] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]
Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH]
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Coronary Disease: Disorder of cardiac function due to an imbalance between myocardial function and the capacity of the coronary vessels to supply sufficient flow for normal function. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Coronary Vessels: The veins and arteries of the heart. [NIH] Corpuscle: A small mass or body; a sensory nerve end bulb; a cell, especially that of the blood or the lymph. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Creatine: An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. [NIH]
Creatine Kinase: A transferase that catalyzes formation of phosphocreatine from ATP + creatine. The reaction stores ATP energy as phosphocreatine. Three cytoplasmic isoenzymes have been identified in human tissues: MM from skeletal muscle, MB from myocardial tissue, and BB from nervous tissue as well as a mitochondrial isoenzyme. Macro-creatine kinase refers to creatine kinase complexed with other serum proteins. EC 2.7.3.2. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH]
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Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Curcumin: A dye obtained from tumeric, the powdered root of Curcuma longa Linn. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. [NIH] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cystathionine beta-Synthase: A multifunctional pyridoxal phosphate enzyme. In the second stage of cysteine biosynthesis it catalyzes the reaction of homocysteine with serine to form cystathionine with the elimination of water. Deficiency of this enzyme leads to hyperhomocysteinemia and homocystinuria. EC 4.2.1.22. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]
Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]
Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH]
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Cytotoxins: Substances elaborated by microorganisms, plants or animals that are specifically toxic to individual cells; they may be involved in immunity or may be contained in venoms. [NIH]
Dairy Products: Raw and processed or manufactured milk and milk-derived products. These are usually from cows (bovine) but are also from goats, sheep, reindeer, and water buffalo. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Deoxyguanosine: A nucleoside consisting of the base guanine and the sugar deoxyribose. [NIH]
Dermal: Pertaining to or coming from the skin. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Dextran Sulfate: Long-chain polymer of glucose containing 17-20% sulfur. It has been used as an anticoagulant and also has been shown to inhibit the binding of HIV-1 to CD4+ Tlymphocytes. It is commonly used as both an experimental and clinical laboratory reagent and has been investigated for use as an antiviral agent, in the treatment of hypolipidemia, and for the prevention of free radical damage, among other applications. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastolic: Of or pertaining to the diastole. [EU]
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Dichloroacetate: A derivative of acetic acid which increases the activity of pyruvate dehydrogenase and rate of lipogenesis. It is used in organic synthesis, pharmaceuticals, and medicine. [NIH] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Dietary Fats: Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. [NIH]
Dietary Fiber: The remnants of plant cell walls that are resistant to digestion by the alimentary enzymes of man. It comprises various polysaccharides and lignins. [NIH] Dietary Proteins: Proteins obtained from foods. They are the main source of the essential amino acids. [NIH] Dietetics: The study and regulation of the diet. [NIH] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disaccharides: Sugars composed of two monosaccharides linked by glycoside bonds. [NIH] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Disease Susceptibility: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the individual more than usually susceptible to certain diseases. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal
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consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diuretic: A drug that increases the production of urine. [NIH] Diurnal: Occurring during the day. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dysentery: Any of various disorders marked by inflammation of the intestines, especially of the colon, and attended by pain in the abdomen, tenesmus, and frequent stools containing blood and mucus. Causes include chemical irritants, bacteria, protozoa, or parasitic worms. [EU]
Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dyslipidemia: Disorders in the lipoprotein metabolism; classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high-density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol predispose to premature atherosclerosis. [NIH]
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Dyspepsia: Impaired digestion, especially after eating. [NIH] Dystrophic: Pertaining to toxic habitats low in nutrients. [NIH] Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]
Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emollient: Softening or soothing; called also malactic. [EU] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocrine Glands: Ductless glands that secrete substances which are released directly into the circulation and which influence metabolism and other body functions. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endoderm: The inner of the three germ layers of the embryo. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous)
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production. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]
Endometrium: The layer of tissue that lines the uterus. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelins: 21-Amino-acid peptides produced by vascular endothelial cells and functioning as potent vasoconstrictors. The endothelin family consists of three members, endothelin-1, endothelin-2, and endothelin-3. All three peptides contain 21 amino acids, but vary in amino acid composition. The three peptides produce vasoconstrictor and pressor responses in various parts of the body. However, the quantitative profiles of the pharmacological activities are considerably different among the three isopeptides. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxemia: A condition characterized by the presence of endotoxins in the blood. If endotoxemia is the result of gram-negative rod-shaped bacteria, shock may occur. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH]
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Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH] Enteritis: Inflammation of the intestine, applied chiefly to inflammation of the small intestine; see also enterocolitis. [EU] Enterocolitis: Inflammation of the intestinal mucosa of the small and large bowel. [NIH] Enterocytes: Terminally differentiated cells comprising the majority of the external surface of the intestinal epithelium (see intestinal mucosa). Unlike goblet cells, they do not produce or secrete mucins, nor do they secrete cryptdins as do the paneth cells. [NIH] Enterohepatic: Of or involving the intestine and liver. [EU] Enterohepatic Circulation: Recycling through liver by excretion in bile, reabsorption from intestines into portal circulation, passage back into liver, and re-excretion in bile. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]
Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Environmental Pollutants: Substances which pollute the environment. Use environmental pollutants in general or for which there is no specific heading. [NIH]
for
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH]
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Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitopes: Sites on an antigen that interact with specific antibodies. [NIH] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythrocyte Membrane: The semipermeable outer portion of the red corpuscle. It is known as a 'ghost' after hemolysis. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]
Esterification: The process of converting an acid into an alkyl or aryl derivative. Most frequently the process consists of the reaction of an acid with an alcohol in the presence of a trace of mineral acid as catalyst or the reaction of an acyl chloride with an alcohol. Esterification can also be accomplished by enzymatic processes. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]
Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU]
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Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracorporeal: Situated or occurring outside the body. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Family Practice: A medical specialty concerned with the provision of continuing, comprehensive primary health care for the entire family. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]
Fatty Liver: The buildup of fat in liver cells. The most common cause is alcoholism. Other causes include obesity, diabetes, and pregnancy. Also called steatosis. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Fetal Development: Morphologic and physiologic growth and development of the mammalian embryo or fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of
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other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Flatulence: Production or presence of gas in the gastrointestinal tract which may be expelled through the anus. [NIH] Flatus: Gas passed through the rectum. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Foam Cells: Lipid-laden macrophages originating from monocytes or from smooth muscle cells. [NIH] Focus Groups: A method of data collection and a qualitative research tool in which a small group of individuals are brought together and allowed to interact in a discussion of their opinions about topics, issues, or questions. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Fructose Intolerance: An autosomal recessive fructose metabolism disorder due to deficient fructose-1-phosphate aldolase (EC 2.1.2.13) activity, resulting in accumulation of fructose-1phosphate. The accumulated fructose-1-phosphate inhibits glycogenolysis and gluconeogenesis, causing severe hypoglycemia following ingestion of fructose. Prolonged fructose ingestion in infants leads ultimately to hepatic failure and death. Patients develop a strong distaste for sweet food, and avoid a chronic course of the disease by remaining on a fructose- and sucrose-free diet. [NIH] Furosemide: A sulfamyl saluretic and diuretic. It has a fast onset and short duration of
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action and is used in edema and chronic renal insufficiency. [NIH] Galactosemia: Buildup of galactose in the blood. Caused by lack of one of the enzymes needed to break down galactose into glucose. [NIH] Galactosides: Glycosides formed by the reaction of the hydroxyl group on the anomeric carbon atom of galactose with an alcohol to form an acetal. They include both alpha- and beta-galactosides. [NIH] Gallate: Antioxidant present in tea. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gangrenous: A circumscribed, deep-seated, suppurative inflammation of the subcutaneous tissue of the eyelid discharging pus from several points. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gasoline: Volative flammable fuel (liquid hydrocarbons) derived from crude petroleum by processes such as distillation reforming, polymerization, etc. [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastritis: Inflammation of the stomach. [EU] Gastroenteritis: An acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhoea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Called also enterogastritis. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gemfibrozil: A lipid-regulating agent that lowers elevated serum lipids primarily by decreasing serum triglycerides with a variable reduction in total cholesterol. These decreases occur primarily in the VLDL fraction and less frequently in the LDL fraction. Gemfibrozil increases HDL subfractions HDL2 and HDL3 as well as apolipoproteins A-I and A-II. Its mechanism of action has not been definitely established. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH]
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Gene Expression Profiling: The determination of the pattern of genes expressed i.e., transcribed, under specific circumstances or in a specific cell. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] General practitioner: A medical practitioner who does not specialize in a particular branch of medicine or limit his practice to a specific class of diseases. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Screening: Searching a population or individuals for persons possessing certain genotypes or karyotypes that: (1) are already associated with disease or predispose to disease; (2) may lead to disease in their descendants; or (3) produce other variations not known to be associated with disease. Genetic screening may be directed toward identifying phenotypic expression of genetic traits. It includes prenatal genetic screening. [NIH] Genetic Techniques: Chromosomal, biochemical, intracellular, and other methods used in the study of genetics. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]
Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geriatric: Pertaining to the treatment of the aged. [EU] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]
Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH]
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Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and kidney failure. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Gluconeogenesis: The process by which glucose is formed from a non-carbohydrate source. [NIH]
Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]
Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]
Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycogen Storage Disease: A group of inherited metabolic disorders involving the enzymes
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responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycan: A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Goblet Cells: Cells of the epithelial lining that produce and secrete mucins. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]
Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Graft Survival: The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH]
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Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Health Behavior: Behaviors expressed by individuals to protect, maintain or promote their health status. For example, proper diet, and appropriate exercise are activities perceived to influence health status. Life style is closely associated with health behavior and factors influencing life style are socioeconomic, educational, and cultural. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heart Transplantation: The transference of a heart from one human or animal to another. [NIH]
Heartbeat: One complete contraction of the heart. [NIH] Heartburn: Substernal pain or burning sensation, usually associated with regurgitation of gastric juice into the esophagus. [NIH] Helminthiasis: Infestation with parasitic worms of the helminth class. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of
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glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhoids: Varicosities of the hemorrhoidal venous plexuses. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatobiliary: Pertaining to the liver and the bile or the biliary ducts. [EU] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocyte: A liver cell. [NIH] Hepatocyte Growth Factor: Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is proto-oncogene protein C-met. [NIH] Hepatoma: A liver tumor. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterodimers: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH]
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Histology: The study of tissues and cells under a microscope. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]
Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygote: An individual in which both alleles at a given locus are identical. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Antagonists: Chemical substances which inhibit the function of the endocrine glands, the biosynthesis of their secreted hormones, or the action of hormones upon their specific sites. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Human Development: Continuous sequential changes which occur in the physiological and psychological functions during the individual's life. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH]
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Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxy Acids: Organic compounds containing both the hydroxyl and carboxyl radicals. [NIH]
Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hypercapnia: A clinical manifestation of abnormal increase in the amount of carbon dioxide in arterial blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperhomocysteinemia: An inborn error of methionone metabolism which produces an excess of homocysteine in the blood. It is often caused by a deficiency of cystathionine betasynthase and is a risk factor for coronary vascular disease. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperlipoproteinemia: Metabolic disease characterized by elevated plasma cholesterol and/or triglyceride levels. The inherited form is attributed to a single gene mechanism. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hyperthyroidism: Excessive functional activity of the thyroid gland. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Hypoglycemia: Abnormally low blood sugar [NIH] Hypoglycemic: An orally active drug that produces a fall in blood glucose concentration. [NIH]
Hypoglycemic Agents: Agents which lower the blood glucose level. [NIH] Hypolipidemic: A drug that lowers abnormally high plasma concentrations of cholesterol or triglycerides or both. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH]
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Hypothyroidism: Deficiency of thyroid activity. In adults, it is most common in women and is characterized by decrease in basal metabolic rate, tiredness and lethargy, sensitivity to cold, and menstrual disturbances. If untreated, it progresses to full-blown myxoedema. In infants, severe hypothyroidism leads to cretinism. In juveniles, the manifestations are intermediate, with less severe mental and developmental retardation and only mild symptoms of the adult form. When due to pituitary deficiency of thyrotropin secretion it is called secondary hypothyroidism. [EU] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Idiopathic: Describes a disease of unknown cause. [NIH] Ileal: Related to the ileum, the lowest end of the small intestine. [NIH] Ileitis: Inflammation of the ileum. [EU] Ileum: The lower end of the small intestine. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunochemistry: Field of chemistry that pertains to immunological phenomena and the study of chemical reactions related to antigen stimulation of tissues. It includes physicochemical interactions between antigens and antibodies. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH]
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Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indigestion: Poor digestion. Symptoms include heartburn, nausea, bloating, and gas. Also called dyspepsia. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Inferior vena cava: A large vein that empties into the heart. It carries blood from the legs and feet, and from organs in the abdomen and pelvis. [NIH] Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and
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severe, often generalized, myalgia. [NIH] Information Centers: Facilities for collecting and organizing information. They may be specialized by subject field, type of source material, persons served, location, or type of services. [NIH] Infuse: To pour (a liquid) into something. [EU] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inotropic: Affecting the force or energy of muscular contractions. [EU] Inpatients: Persons admitted to health facilities which provide board and room, for the purpose of observation, care, diagnosis or treatment. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Interindividual: Occurring between two or more individuals. [EU] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis,
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secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Intermediate Filaments: Cytoplasmic filaments intermediate in diameter (about 10 nanometers) between the microfilaments and the microtubules. They may be composed of any of a number of different proteins and form a ring around the cell nucleus. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Intrinsic Factor: A glycoprotein secreted by the cells of the gastric glands that is required for the absorption of vitamin B 12. Deficiency of intrinsic factor results in pernicious anemia. [NIH]
Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Irritants: Drugs that act locally on cutaneous or mucosal surfaces to produce inflammation; those that cause redness due to hyperemia are rubefacients; those that raise blisters are vesicants and those that penetrate sebaceous glands and cause abscesses are pustulants; tear gases and mustard gases are also irritants. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Isopropyl: A gene mutation inducer. [NIH] Isozymes: The multiple forms of a single enzyme. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile
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pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]
Kallidin: A decapeptide bradykinin homolog produced by the action of tissue and glandular kallikreins on low-molecular-weight kininogen. It is a smooth-muscle stimulant and hypotensive agent that functions through vasodilatation. [NIH] Karyotypes: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney stone: A stone that develops from crystals that form in urine and build up on the inner surfaces of the kidney, in the renal pelvis, or in the ureters. [NIH] Kidney Transplantation: The transference of a kidney from one human or animal to another. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lamivudine: A reverse transcriptase inhibitor and zalcitabine analog in which a sulfur atom replaces the 3' carbon of the pentose ring. It is used to treat HIV disease. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from
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fat cells in the feedback system that controls body fat stores. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethargy: Abnormal drowsiness or stupor; a condition of indifference. [EU] Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligaments: Shiny, flexible bands of fibrous tissue connecting together articular extremities of bones. They are pliant, tough, and inextensile. [NIH] Ligands: A RNA simulation method developed by the MIT. [NIH] Linear Models: Statistical models in which the value of a parameter for a given value of a factor is assumed to be equal to a + bx, where a and b are constants. The models predict a linear regression. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipodystrophy: A collection of rare conditions resulting from defective fat metabolism and characterized by atrophy of the subcutaneous fat. They include total, congenital or acquired, partial, abdominal infantile, and localized lipodystrophy. [NIH] Lipolysis: The hydrolysis of lipids. [NIH] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Lipoprotein Lipase: An enzyme of the hydrolase class that catalyzes the reaction of
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triacylglycerol and water to yield diacylglycerol and a fatty acid anion. The enzyme hydrolyzes triacylglycerols in chylomicrons, very-low-density lipoproteins, low-density lipoproteins, and diacylglycerols. It occurs on capillary endothelial surfaces, especially in mammary, muscle, and adipose tissue. Genetic deficiency of the enzyme causes familial hyperlipoproteinemia Type I. (Dorland, 27th ed) EC 3.1.1.34. [NIH] Lipoprotein(a): A family of lipoprotein particles varying in density and size depending on the protein-lipid ratio and the protein composition. These particles consist of apolipoprotein B-100 covalently linked to apolipoprotein-a by one or two disulfide bonds. There is a correlation between high plasma levels of this lipoprotein and increased risk for atherosclerotic cardiovascular disease. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Lod: The lowest analyte content which, if actually present, will be detected with reasonable statistical certainty and can be identified according to the identification criteria of the method. If both accuracy and precision are constant over a concentration range. [NIH] Lod Score: The total relative probability, expressed on a logarithmic scale, that a linkage relationship exists among selected loci. Lod is an acronym for "logarithmic odds." [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Lovastatin: A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lubricants: Oily or slippery substances. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH]
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Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]
Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lysosomal Storage Diseases: Inborn errors of metabolism characterized by defects in specific lysosomal hydrolases and resulting in intracellular accumulation of unmetabolized substrates. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macula: A stain, spot, or thickening. Often used alone to refer to the macula retinae. [EU] Macula Lutea: An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the superior pole of the eye and slightly below the level of the optic disk. [NIH] Macular Degeneration: Degenerative changes in the macula lutea of the retina. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe
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than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]
Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Melanin: The substance that gives the skin its color. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Fluidity: The motion of phospholipid molecules within the lipid bilayer, dependent on the classes of phospholipids present, their fatty acid composition and degree of unsaturation of the acyl chains, the cholesterol concentration, and temperature. [NIH] Membrane Lipids: Lipids, predominantly phospholipids, cholesterol and small amounts of glycolipids found in membranes including cellular and intracellular membranes. These lipids may be arranged in bilayers in the membranes with integral proteins between the layers and peripheral proteins attached to the outside. Membrane lipids are required for active transport, several enzymatic activities and membrane formation. [NIH] Membrane Microdomains: Detergent-insoluble cell membrane components. They are enriched in sphingolipids and cholesterol and clustered with glycosyl-phosphatidylinositol (GPI)-anchored proteins. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning,
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(2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Micronutrients: Essential dietary elements or organic compounds that are required in only small quantities for normal physiologic processes to occur. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microtubule-Associated Proteins: High molecular weight proteins found in the
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microtubules of the cytoskeletal system. Under certain conditions they are required for tubulin assembly into the microtubules and stabilize the assembled microtubules. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Middle Cerebral Artery: The largest and most complex of the cerebral arteries. Branches of the middle cerebral artery supply the insular region, motor and premotor areas, and large regions of the association cortex. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mineralization: The action of mineralizing; the state of being mineralized. [EU] Miscible: Susceptible of being mixed. [EU] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitogen-Activated Protein Kinase Kinases: A serine-threonine protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate mitogen-activated protein kinases and are themselves phosphorylated by MAP kinase kinase kinases. JNK kinases (also known as SAPK kinases) are a subfamily. EC 2.7.10.- [NIH] Mitogen-Activated Protein Kinases: A superfamily of protein-serine-threonine kinases that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by mitogen-activated protein kinase kinases which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP kinase kinase kinases). Families of these mitogen-activated protein kinases (MAPKs) include extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs) (also known as c-jun terminal kinases (JNKs)), and p38-mitogen-activated protein kinases. EC 2,7,1.- [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other
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procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monocyte: A type of white blood cell. [NIH] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [NIH] Monotherapy: A therapy which uses only one drug. [EU] Morphological: Relating to the configuration or the structure of live organs. [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucopolysaccharidoses: Group of lysosomal storage diseases each caused by an inherited deficiency of an enzyme involved in the degradation of glycosaminoglycans (mucopolysaccharides). The diseases are progressive and often display a wide spectrum of clinical severity within one enzyme deficiency. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Mutagenic: Inducing genetic mutation. [EU] Myalgia: Pain in a muscle or muscles. [EU] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myopathy: Any disease of a muscle. [EU] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neocortex: The largest portion of the cerebral cortex. It is composed of neurons arranged in six layers. [NIH]
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Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. [NIH] Nephrology: A subspecialty of internal medicine concerned with the anatomy, physiology, and pathology of the kidney. [NIH] Nephropathy: Disease of the kidneys. [EU] Nephrosis: Descriptive histopathologic term for renal disease without an inflammatory component. [NIH] Nephrotic: Pertaining to, resembling, or caused by nephrosis. [EU] Nephrotic Syndrome: Clinical association of heavy proteinuria, hypoalbuminemia, and generalized edema. [NIH] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neurofibrillary Tangles: Abnormal structures located in various parts of the brain and composed of dense arrays of paired helical filaments (neurofilaments and microtubules). These double helical stacks of transverse subunits are twisted into left-handed ribbon-like filaments that likely incorporate the following proteins: (1) the intermediate filaments: medium- and high-molecular-weight neurofilaments; (2) the microtubule-associated proteins map-2 and tau; (3) actin; and (4) ubiquitin. As one of the hallmarks of Alzheimer disease, the neurofibrillary tangles eventually occupy the whole of the cytoplasm in certain classes of cell in the neocortex, hippocampus, brain stem, and diencephalon. The number of these tangles, as seen in post mortem histology, correlates with the degree of dementia during life. Some studies suggest that tangle antigens leak into the systemic circulation both in the course of normal aging and in cases of Alzheimer disease. [NIH] Neurofilaments: Bundle of neuronal fibers. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neurotensin: A biologically active tridecapeptide isolated from the hypothalamus. It has been shown to induce hypotension in the rat, to stimulate contraction of guinea pig ileum and rat uterus, and to cause relaxation of rat duodenum. There is also evidence that it acts as both a peripheral and a central nervous system neurotransmitter. [NIH] Neurotic: 1. Pertaining to or characterized by neurosis. 2. A person affected with a neurosis. [EU]
Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]
Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel
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across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]
Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nursing Care: Care given to patients by nursing service personnel. [NIH] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Omega-3 fatty acid: A type of fat obtained in the diet and involved in immunity. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH]
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Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Ophthalmic: Pertaining to the eye. [EU] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Hygiene: The practice of personal hygiene of the mouth. It includes the maintenance of oral cleanliness, tissue tone, and general preservation of oral health. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteoblasts: Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovariectomy: The surgical removal of one or both ovaries. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdosage: 1. The administration of an excessive dose. 2. The condition resulting from an excessive dose. [EU] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens
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rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]
Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]
Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parenteral Nutrition: The administering of nutrients for assimilation and utilization by a patient who cannot maintain adequate nutrition by enteral feeding alone. Nutrients are administered by a route other than the alimentary canal (e.g., intravenously, subcutaneously). [NIH] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]
Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU]
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Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Care Management: Generating, planning, organizing, and administering medical and nursing care and services for patients. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
Patient Satisfaction: The degree to which the individual regards the health care service or product or the manner in which it is delivered by the provider as useful, effective, or beneficial. [NIH] Pedigree: A record of one's ancestors, offspring, siblings, and their offspring that may be used to determine the pattern of certain genes or disease inheritance within a family. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Periodicity: The tendency of a phenomenon to recur at regular intervals; in biological systems, the recurrence of certain activities (including hormonal, cellular, neural) may be annual, seasonal, monthly, daily, or more frequently (ultradian). [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontal Index: A numerical rating scale for classifying the periodontal status of a person or population with a single figure which takes into consideration prevalence as well as severity of the condition. It is based upon probe measurement of periodontal pockets and on gingival tissue status. [NIH] Periodontal Pocket: An abnormal extension of a gingival sulcus accompanied by the apical migration of the epithelial attachment and bone resorption. [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH]
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Peripheral Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [NIH] Peristalsis: The rippling motion of muscles in the intestine or other tubular organs characterized by the alternate contraction and relaxation of the muscles that propel the contents onward. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Pernicious anemia: A type of anemia (low red blood cell count) caused by the body's inability to absorb vitamin B12. [NIH] Peroral: Performed through or administered through the mouth. [EU] Peroxisome Proliferators: A class of nongenotoxic carcinogens that induce the production of hepatic peroxisomes and induce hepatic neoplasms after long-term administration. [NIH] Personality Assessment: The determination and evaluation of personality attributes by interviews, observations, tests, or scales. Articles concerning personality measurement are considered to be within scope of this term. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor
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of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phosphatidic Acids: Fatty acid derivatives of glycerophosphates. They are composed of glycerol bound in ester linkage with 1 mole of phosphoric acid at the terminal 3-hydroxyl group and with 2 moles of fatty acids at the other two hydroxyl groups. [NIH] Phosphatidylcholines: Derivatives of phosphatidic acids in which the phosphoric acid is bound in ester linkage to a choline moiety. Complete hydrolysis yields 1 mole of glycerol, phosphoric acid and choline and 2 moles of fatty acids. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] Physical Fitness: A state of well-being in which performance is optimal, often as a result of physical conditioning which may be prescribed for disease therapy. [NIH] Physicochemical: Pertaining to physics and chemistry. [EU] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]
Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plant Proteins: Proteins found in plants (flowers, herbs, shrubs, trees, etc.). The concept does not include proteins found in vegetables for which vegetable proteins is available. [NIH] Plant sterols: Plant-based compounds that can compete with dietary cholesterol to be absorbed by the intestines. This results in lower blood cholesterol levels. They may have some effect in cancer prevention. Also known as phytosterols. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH]
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Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Platelet Activating Factor: A phospholipid derivative formed by platelets, basophils, neutrophils, monocytes, and macrophages. It is a potent platelet aggregating agent and inducer of systemic anaphylactic symptoms, including hypotension, thrombocytopenia, neutropenia, and bronchoconstriction. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Plateletpheresis: The preparation of platelet concentrates with the return of red cells and platelet-poor plasma to the donor. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poison Control Centers: Facilities which provide information concerning poisons and treatment of poisoning in emergencies. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Pollen: The male fertilizing element of flowering plants analogous to sperm in animals. It is released from the anthers as yellow dust, to be carried by insect or other vectors, including wind, to the ovary (stigma) of other flowers to produce the embryo enclosed by the seed. The pollens of many plants are allergenic. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU]
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Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] Porphyria: A group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [NIH]
Porphyria Cutanea Tarda: A form of hepatic porphyria (porphyria, hepatic) characterized by photosensitivity resulting in bullae that rupture easily to form shallow ulcers. This condition occurs in two forms: a sporadic, nonfamilial form that begins in middle age and has normal amounts of uroporphyrinogen decarboxylase with diminished activity in the liver; and a familial form in which there is an autosomal dominant inherited deficiency of uroporphyrinogen decarboxylase in the liver and red blood cells. [NIH] Porphyria, Hepatic: Porphyria in which the liver is the site where excess formation of porphyrin or its precursors is found. Acute intermittent porphyria and porphyria cutanea tarda are types of hepatic porphyria. [NIH] Porphyrins: A group of compounds containing the porphin structure, four pyrrole rings connected by methine bridges in a cyclic configuration to which a variety of side chains are attached. The nature of the side chain is indicated by a prefix, as uroporphyrin, hematoporphyrin, etc. The porphyrins, in combination with iron, form the heme component in biologically significant compounds such as hemoglobin and myoglobin. [NIH] Portacaval: Surgical creation of an anastomosis between the portal and caval veins. [NIH] Portal Hypertension: High blood pressure in the portal vein. This vein carries blood into the liver. Portal hypertension is caused by a blood clot. This is a common complication of cirrhosis. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] Postprandial Blood Glucose: Blood taken 1-2 hours after eating to see the amount of glucose (sugar) in the blood. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH]
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Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Pravastatin: An antilipemic fungal metabolite isolated from cultures of Nocardia autotrophica. It acts as a competitive inhibitor of HMG CoA reductase (hydroxymethylglutaryl CoA reductases). [NIH] Precipitation: The act or process of precipitating. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection, as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential
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component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandins: A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent. [NIH]
Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Kinase C: An enzyme that phosphorylates proteins on serine or threonine residues in the presence of physiological concentrations of calcium and membrane phospholipids. The additional presence of diacylglycerols markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by phorbol esters and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. EC 2.7.1.-. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors. EC 2.7.10. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that
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promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]
Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU] Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psyllium: Dried, ripe seeds of Plantago psyllium, P. indica, and P. ovata (Plantaginaceae). Plantain seeds swell in water and are used as demulcents and bulk laxatives. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]
Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Pupil: The aperture in the iris through which light passes. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Pylorus: The opening in a vertebrate from the stomach into the intestine. [EU]
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Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quercetin: Aglucon of quercetrin, rutin, and other glycosides. It is widely distributed in the plant kingdom, especially in rinds and barks, clover blossoms, and ragweed pollen. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radioactive: Giving off radiation. [NIH] Ramipril: A long-acting angiotensin-converting enzyme inhibitor. It is a prodrug that is transformed in the liver to its active metabolite ramiprilat. [NIH] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reabsorption: 1. The act or process of absorbing again, as the selective absorption by the kidneys of substances (glucose, proteins, sodium, etc.) already secreted into the renal tubules, and their return to the circulating blood. 2. Resorption. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been
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recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reference Values: The range or frequency distribution of a measurement in a population (of organisms, organs or things) that has not been selected for the presence of disease or abnormality. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal Artery: A branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Renin-Angiotensin System: A system consisting of renin, angiotensin-converting enzyme, and angiotensin II. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. The converting enzyme contained in the lung acts on angiotensin I in the plasma converting it to angiotensin II, the most powerful directly pressor substance known. It causes contraction of the arteriolar smooth muscle and has other indirect actions mediated through the adrenal cortex. [NIH]
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Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Research Support: Financial support of research activities. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rheology: The study of the deformation and flow of matter, usually liquids or fluids, and of the plastic flow of solids. The concept covers consistency, dilatancy, liquefaction, resistance to flow, shearing, thixotrophy, and viscosity. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH]
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Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rickets: A condition caused by deficiency of vitamin D, especially in infancy and childhood, with disturbance of normal ossification. The disease is marked by bending and distortion of the bones under muscular action, by the formation of nodular enlargements on the ends and sides of the bones, by delayed closure of the fontanelles, pain in the muscles, and sweating of the head. Vitamin D and sunlight together with an adequate diet are curative, provided that the parathyroid glands are functioning properly. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rutin: 3-((6-O-(6-Deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranosyl)oxy)-2-(3,4dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one. Found in many plants, including buckwheat, tobacco, forsythia, hydrangea, pansies, etc. It has been used therapeutically to decrease capillary fragility. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Saturated fat: A type of fat found in greatest amounts in foods from animals, such as fatty cuts of meat, poultry with the skin, whole-milk dairy products, lard, and in some vegetable oils, including coconut, palm kernel, and palm oils. Saturated fat raises blood cholesterol more than anything else eaten. On a Step I Diet, no more than 8 to 10 percent of total calories should come from saturated fat, and in the Step II Diet, less than 7 percent of the day's total calories should come from saturated fat. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH]
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Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segmentation: The process by which muscles in the intestines move food and wastes through the body. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septicaemia: A term originally used to denote a putrefactive process in the body, but now usually referring to infection with pyogenic micro-organisms; a genus of Diptera; the severe type of infection in which the blood stream is invaded by large numbers of the causal. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serotypes: A cause of haemorrhagic septicaemia (in cattle, sheep and pigs), fowl cholera of birds, pasteurellosis of rabbits, and gangrenous mastitis of ewes. It is also commonly found in atrophic rhinitis of pigs. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral
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upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Shunt: A surgically created diversion of fluid (e.g., blood or cerebrospinal fluid) from one area of the body to another area of the body. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Simvastatin: A derivative of lovastatin and potent competitive inhibitor of 3-hydroxy-3methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic LDL receptors, it increases breakdown of LDL-cholesterol (lipoproteins, LDL cholesterol). [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Soybean Oil: Oil from soybean or soybean plant. [NIH] Spasmodic: Of the nature of a spasm. [EU] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles
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are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Sphincter: A ringlike band of muscle fibres that constricts a passage or closes a natural orifice; called also musculus sphincter. [EU] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinous: Like a spine or thorn in shape; having spines. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [EU] Steatorrhea: A condition in which the body cannot absorb fat. Causes a buildup of fat in the stool and loose, greasy, and foul bowel movements. [NIH] Steatosis: Fatty degeneration. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] Stent: A device placed in a body structure (such as a blood vessel or the gastrointestinal tract) to provide support and keep the structure open. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU]
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Steroid therapy: Treatment with corticosteroid drugs to reduce swelling, pain, and other symptoms of inflammation. [NIH] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Substrate: A substance upon which an enzyme acts. [EU] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Sudden death: Cardiac arrest caused by an irregular heartbeat. The term "death" is somewhat misleading, because some patients survive. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppositories: A small cone-shaped medicament having cocoa butter or gelatin at its basis and usually intended for the treatment of local conditions in the rectum. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in
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which the process of exclusion is not conscious. [NIH] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]
Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. [NIH] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telomerase: Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase appears to be repressed in normal human somatic tissues but reactivated in cancer, and thus may be necessary for malignant transformation. EC 2.7.7.-. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Tendon: A discrete band of connective tissue mainly composed of parallel bundles of collagenous fibers by which muscles are attached, or two muscles bellies joined. [NIH] Tenesmus: Straining, especially ineffectual and painful straining at stool or in urination. [EU] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH]
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Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyrotoxicosis: The clinical syndrome that reflects the response of the peripheral tissues to an excess of thyroid hormone. [NIH] Thyrotropin: A peptide hormone secreted by the anterior pituitary. It promotes the growth of the thyroid gland and stimulates the synthesis of thyroid hormones and the release of thyroxine by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH]
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Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme
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"donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGFbeta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. [NIH]
Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocate: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Transport Vesicles: Vesicles that are involved in shuttling cargo from the interior of the cell to the cell surface, from the cell surface to the interior, across the cell or around the cell to various locations. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]
Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is
Dictionary 265
also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]
Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urology: A surgical specialty concerned with the study, diagnosis, and treatment of diseases of the urinary tract in both sexes and the genital tract in the male. It includes the specialty of andrology which addresses both male genital diseases and male infertility. [NIH] Uroporphyrinogen Decarboxylase: One of the enzymes active in heme biosynthesis. It catalyzes the decarboxylation of uroporphyrinogen III to coproporphyrinogen III by the conversion of four acetic acid groups to four methyl groups. EC 4.1.1.37. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [NIH]
Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Valerian: Valeriana officinale, an ancient, sedative herb of the large family Valerianaceae. The roots were formerly used to treat hysterias and other neurotic states and are presently used to treat sleep disorders. [NIH] Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Vasa Vasorum: Nutrient blood vessels which supply the walls of large arteries or veins. [NIH]
266
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Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasculitis: Inflammation of a blood vessel. [NIH] Vasodilatation: A state of increased calibre of the blood vessels. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vegetable Proteins: Proteins which are present in or isolated from vegetables or vegetable products used as food. The concept is distinguished from plant proteins which refers to nondietary proteins from plants. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Vena: A vessel conducting blood from the capillary bed to the heart. [NIH] Venoms: Poisonous animal secretions forming fluid mixtures of many different enzymes, toxins, and other substances. These substances are produced in specialized glands and secreted through specialized delivery systems (nematocysts, spines, fangs, etc.) for disabling prey or predator. [NIH] Venous: Of or pertaining to the veins. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Very low-density lipoprotein: The lipoprotein particles that initially leave the liver, carrying cholesterol and lipid. VLDLs contain 10 to 15 percent of the total serum cholesterol along with most of the triglycerides in the fasting serum; VLDLs are precursors of LDL, and some forms of VLDL, particularly VLDL remnants, appear to be atherogenic. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body,
Dictionary 267
especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vitamin D: The vitamin that mediates intestinal calcium absorption, bone calcium metabolism, and probably muscle activity. It usually acts as a hormone precursor, requiring 2 stages of metabolism before reaching actual hormonal form. It is isolated from fish liver oils and used in the treatment and prevention of rickets. [NIH] Vitelline Membrane: The plasma membrane of the egg. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xanthine: An urinary calculus. [NIH] Xanthine Oxidase: An iron-molybdenum flavoprotein containing FAD that oxidizes hypoxanthine, some other purines and pterins, and aldehydes. Deficiency of the enzyme, an autosomal recessive trait, causes xanthinuria. EC 1.1.3.22. [NIH] Xanthoma: A tumour composed of lipid-laden foam cells, which are histiocytes containing cytoplasmic lipid material. Called also xanthelasma. [EU] Xanthomatosis: A condition of morphologic change in which there is accumulation of lipids in the large foam cells of tissues. It is the cutaneous manifestation of lipidosis in which plasma fatty acids and lipoproteins are quantitatively changed. The xanthomatous eruptions have several different distinct morphologies dependent upon the specific form taken by the disease. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH]
268
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Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Yolk Sac: An embryonic membrane formed from endoderm and mesoderm. In reptiles and birds it incorporates the yolk into the digestive tract for nourishing the embryo. In placental mammals its nutritional function is vestigial; however, it is the source of most of the intestinal mucosa and the site of formation of the germ cells. It is sometimes called the vitelline sac, which should not be confused with the vitelline membrane of the egg. [NIH] Zalcitabine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication at low concentrations, acting as a chainterminator of viral DNA by binding to reverse transcriptase. Its principal toxic side effect is axonal degeneration resulting in peripheral neuropathy. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
269
INDEX A Abdomen, 193, 201, 202, 214, 217, 230, 232, 235, 245, 246, 259, 260, 267 Abdominal, 12, 35, 154, 193, 221, 232, 234, 244, 246, 254 Abdominal Cramps, 154, 193 Abdominal Pain, 154, 193, 221, 232 Acceptor, 69, 193, 234, 244, 263 Acetylcholine, 193, 206, 242 Actin, 193, 241 Acyl, 70, 193, 218, 237 Adaptability, 193, 204, 205 Adaptation, 14, 37, 193 Adenine, 193, 252 Adenosine, 44, 193, 229, 247 Adenovirus, 9, 26, 27, 98, 193 Adipocytes, 140, 193, 233 Adipose Tissue, 193, 235 Adjustment, 193 Adjuvant, 193, 221 Adrenal Glands, 194, 196, 254 Adrenergic, 194, 214, 218, 261 Adverse Effect, 37, 194, 258 Aerobic, 178, 194 Aerobic Exercise, 178, 194 Afferent, 194, 233 Affinity, 59, 73, 81, 194, 258 Agar, 194, 247 Age of Onset, 194, 264 Ageing, 21, 194 Agonist, 194, 214 Alanine, 37, 194 Albumin, 19, 194, 248 Aldehydes, 195, 267 Algorithms, 195, 201 Alimentary, 118, 195, 213, 244 Alkaline, 142, 195, 202 Alkylating Agents, 155, 195 Alleles, 195, 226, 227, 234 Allogeneic, 195, 224 Allograft, 4, 195 Alopecia, 195, 211 Alpha-Linolenic Acid, 23, 195 Alternative medicine, 162, 195 Amaurosis, 195, 204 Ameliorated, 17, 195 Ameliorating, 9, 195 Amino Acid Sequence, 195, 197, 219, 222
Amino-terminal, 58, 195 Ampulla, 195, 206 Amputation, 41, 195 Amyloid, 15, 61, 100, 105, 196 Amyloidosis, 157, 158, 196 Anaesthesia, 196, 230 Anal, 154, 196, 217, 235 Anal Fissure, 154, 196 Analgesic, 139, 196 Analog, 139, 196, 233 Analogous, 196, 248, 263 Anaphylatoxins, 196, 208 Anastomosis, 68, 196, 249 Anatomical, 196, 199, 205, 213, 230, 257 Androgens, 52, 196, 210 Anemia, 196, 220, 236, 246 Aneuploidy, 157, 196 Aneurysm, 196, 266 Angina, 97, 111, 196 Anginal, 4, 196 Angiogenesis, 21, 35, 54, 55, 128, 196, 237 Angiogram, 106, 196 Angiography, 42, 197 Angiotensinogen, 197, 254 Animal model, 11, 12, 13, 17, 21, 22, 26, 30, 41, 44, 46, 57, 61, 140, 197 Anions, 55, 194, 197, 232, 260 Anode, 197 Anorexia, 197, 221, 265 Antagonism, 122, 197 Antibacterial, 197, 259 Antibiotic, 197, 245, 259 Antibodies, 57, 60, 81, 197, 218, 225, 226, 227, 229, 236, 248 Antibody, 60, 156, 194, 197, 208, 225, 227, 229, 230, 237, 240, 259 Anticoagulant, 197, 212, 251 Antidiabetic, 140, 197 Antidote, 197, 202 Antigen, 26, 194, 197, 208, 218, 227, 228, 229, 230, 231, 237 Antigen-Antibody Complex, 197, 208 Antineoplastic, 195, 197, 198, 210, 211 Antineoplastic Agents, 195, 198 Antioxidant, 7, 19, 22, 28, 30, 42, 45, 64, 92, 110, 128, 130, 198, 199, 221, 244 Antipruritic, 198, 206 Antiviral, 198, 212, 245
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Hypercholesterolemia
Anus, 196, 198, 208, 220, 254 Aorta, 12, 55, 198, 254, 266 Aortic Valve, 39, 40, 198 Apheresis, 74, 89, 93, 95, 96, 97, 98, 99, 104, 105, 198 Apolipoproteins, 52, 138, 157, 198, 221, 234 Apoptosis, 14, 29, 44, 198 Applicability, 44, 198 Aqueous, 51, 146, 198, 211, 227 Arachidonic Acid, 198, 251 Arginine, 12, 19, 102, 196, 198, 227, 242, 264 Arrhythmia, 50, 198 Arterial, 9, 12, 16, 19, 22, 41, 51, 75, 137, 198, 199, 206, 228, 251, 261 Arterioles, 198, 199, 201, 203, 238, 240 Arteriolosclerosis, 198, 199 Arteriosclerosis, 78, 87, 88, 90, 92, 99, 100, 123, 126, 138, 144, 198, 228 Arteriovenous, 19, 199, 238 Ascorbic Acid, 7, 199, 228 Aseptic, 199, 243, 259 Aspartate, 37, 199 Assay, 7, 13, 36, 38, 85, 199 Asymptomatic, 62, 148, 199, 244 Ataxia, 157, 199, 262 Atherogenic, 8, 9, 10, 22, 27, 28, 35, 44, 49, 57, 104, 147, 199, 266 Atrial, 50, 199 Atrium, 199, 266 Atrophy, 199, 234 Attenuated, 57, 199, 265 Autodigestion, 199, 244 Autologous, 21, 199 Autonomic, 50, 193, 199, 242, 245 Autonomic Neuropathy, 50, 199 Axillary, 199, 202 Axillary Artery, 199, 202 B Backcross, 24, 25, 199 Bacteria, 193, 197, 199, 200, 214, 216, 219, 224, 226, 235, 238, 253, 257, 259, 263, 265 Bacterial Physiology, 193, 200 Bactericidal, 200, 218 Bacteriophage, 200, 247, 263 Basal Ganglia, 199, 200 Basal Ganglia Diseases, 199, 200 Basilar Artery, 14, 200 Basophils, 200, 224, 234, 248 Beta-Galactosidase, 27, 200 Beta-pleated, 196, 200
Bile, 8, 13, 24, 31, 36, 38, 58, 92, 110, 137, 141, 143, 144, 156, 159, 190, 200, 206, 217, 221, 226, 227, 232, 235, 259, 261 Bile Acids, 32, 58, 137, 200, 259, 261 Bile Acids and Salts, 200 Bile duct, 156, 200, 206 Bile Pigments, 200, 233 Biliary, 36, 47, 58, 73, 156, 158, 200, 202, 206, 226, 244 Biliary Tract, 200, 202, 244 Bilirubin, 194, 200, 228 Binding Sites, 46, 200 Bioavailability, 34, 45, 64, 142, 146, 200 Bioavailable, 142, 200 Biochemical, 9, 23, 24, 28, 44, 46, 61, 73, 74, 79, 122, 195, 201, 222, 224, 257 Biological therapy, 201, 224 Biopsy, 155, 201 Biosynthesis, 13, 32, 55, 58, 136, 145, 198, 201, 211, 227, 235, 251, 257, 258, 265 Biotechnology, 65, 68, 88, 126, 162, 173, 201 Biphasic, 37, 201 Bladder, 154, 199, 201, 208, 265 Blastocyst, 201, 209, 247 Bloating, 201, 230, 232 Blood Coagulation, 128, 201, 202, 262 Blood Glucose, 157, 201, 225, 228, 231 Blood Platelets, 201, 257, 262 Blood pressure, 4, 6, 19, 43, 63, 102, 109, 155, 201, 203, 228, 239, 246, 249, 258 Body Composition, 35, 37, 39, 201 Body Fluids, 201, 202, 214, 258 Body Mass Index, 201, 243 Bone Marrow, 20, 57, 68, 201, 211, 222, 229, 236, 258 Bone Marrow Transplantation, 68, 201 Boron, 202, 211 Bowel, 58, 154, 193, 196, 202, 217, 232, 246, 259, 260 Brachial, 7, 19, 42, 107, 123, 202 Brachial Artery, 7, 19, 42, 202 Bradycardia, 88, 202 Bradykinin, 7, 202, 233, 242, 248 Brain Stem, 202, 241 Bronchoconstriction, 202, 248 Bursitis, 71, 202 Bypass, 12, 86, 103, 158, 202 C Calcification, 39, 40, 42, 91, 198, 202 Calcium, 40, 97, 120, 136, 145, 146, 155, 202, 208, 228, 237, 238, 251, 252, 267
271
Calcium channel blocker, 155, 202 Calcium Channel Blockers, 155, 202 Calcium Chloride, 146, 202 Calculi, 202, 224 Capillary, 59, 202, 203, 204, 222, 235, 256, 266 Capillary Fragility, 203, 204, 256 Capillary Permeability, 202, 203 Capsules, 39, 51, 76, 145, 203, 214, 221, 222 Carbohydrate, 35, 52, 130, 158, 203, 210, 223, 224, 249 Carbon Dioxide, 203, 228, 247, 255 Carcinogenic, 195, 203, 231, 243, 251, 259 Carcinogens, 203, 242, 244, 246 Carcinoma, 53, 203 Cardiac, 30, 45, 50, 139, 203, 210, 218, 224, 240, 259, 260 Cardiomyopathy, 44, 203 Cardiorespiratory, 194, 203 Cardiovascular System, 48, 102, 199, 203 Carotene, 28, 203, 255 Carotenoids, 42, 203 Carotid Artery Thrombosis, 112, 203 Carrier Proteins, 204, 248 Carrier State, 31, 204 Case report, 84, 204, 207 Catabolism, 9, 66, 96, 204 Catechin, 28, 204 Catecholamine, 204, 214, 246 Catheter, 41, 204 Causal, 22, 137, 144, 204, 217, 226, 257 Cause of Death, 11, 18, 24, 26, 34, 55, 204 Caveolae, 36, 204 Caveolins, 204, 207 Cell Adhesion, 45, 59, 204, 231 Cell Adhesion Molecules, 45, 204 Cell Death, 29, 198, 204, 240 Cell Division, 199, 204, 205, 224, 239, 247, 251, 257 Cell membrane, 202, 204, 237, 247, 250 Cell Membrane Structures, 204 Cell motility, 204, 226 Cell proliferation, 28, 51, 55, 199, 205, 231 Cell Survival, 205, 224 Cellobiose, 205 Cellulose, 6, 93, 146, 205, 247 Central Nervous System, 193, 194, 205, 221, 223, 225, 241, 243, 249, 257 Ceramide, 32, 205 Cerebellar, 199, 205, 254 Cerebral, 11, 14, 15, 32, 84, 107, 199, 200, 202, 204, 205, 218, 236, 239, 240, 259
Cerebral Arteries, 14, 200, 205, 239 Cerebral Cortex, 199, 205, 218, 240 Cerebrospinal, 205, 258 Cerebrospinal fluid, 205, 258 Cerebrovascular, 11, 200, 202, 203, 205, 262 Cerebrum, 205 Character, 205, 212 Chemokines, 28, 29, 205 Chemokines, C, 28, 205 Chemotactic Factors, 205, 208 Chest Pain, 111, 205 Chin, 86, 205, 238 Cholangitis, 156, 206 Cholelithiasis, 36, 58, 154, 206 Cholera, 206, 257 Cholestasis, 32, 36, 37, 38, 124, 156, 206 Cholesterol, 3, 4, 5, 8, 9, 13, 15, 18, 22, 23, 24, 25, 29, 30, 31, 32, 35, 36, 38, 39, 42, 46, 47, 50, 51, 52, 53, 54, 57, 58, 59, 62, 63, 65, 66, 67, 68, 70, 71, 72, 77, 78, 79, 82, 87, 89, 92, 94, 96, 97, 99, 100, 103, 106, 108, 110, 121, 122, 124, 125, 126, 127, 128, 131, 136, 137, 138, 139, 141, 143, 144, 145, 146, 147, 148, 149, 150, 158, 178, 190, 200, 204, 206, 210, 214, 221, 228, 234, 235, 237, 247, 256, 258, 259, 266 Cholesterol Esters, 206, 234 Cholesterol, Dietary, 47, 206 Cholestyramine, 77, 144, 206 Choline, 206, 247 Choroid, 206, 255 Chromatin, 33, 198, 206, 217, 242 Chromosomal, 23, 196, 206, 222, 227, 255 Chromosome, 24, 79, 87, 97, 112, 196, 206, 225, 233, 234, 240, 257, 264 Chronic, 4, 7, 16, 23, 27, 28, 34, 44, 47, 55, 60, 61, 62, 90, 94, 122, 128, 130, 144, 150, 155, 156, 179, 206, 216, 220, 221, 230, 233, 244, 260, 261, 265, 267 Chronic Disease, 28, 61, 130, 144, 206 Chronic renal, 179, 206, 221, 265 Chronotropic, 50, 206 Chylomicrons, 206, 234, 235 Circadian, 7, 206 Circulatory system, 144, 206, 215 Cirrhosis, 156, 158, 206, 249 CIS, 206, 255 Clamp, 35, 207 Clathrin, 17, 45, 68, 109, 207 Claudication, 137, 207
272
Hypercholesterolemia
Clinical Medicine, 124, 207, 250 Clinical study, 207, 209 Clinical trial, 6, 12, 34, 43, 86, 150, 173, 207, 209, 211, 214, 252, 253 Clone, 24, 25, 207 Cloning, 40, 201, 207 Coated Vesicles, 17, 207 Coenzyme, 63, 70, 136, 141, 146, 148, 159, 199, 207, 235, 258 Cofactor, 12, 55, 207, 251, 262 Cohort Studies, 207, 217 Colestipol, 67, 144, 166, 207 Colitis, 154, 207, 232 Collagen, 51, 195, 204, 207, 219, 220, 221, 237, 248, 251 Colloidal, 194, 207, 215 Colon, 118, 157, 207, 214, 232, 233 Complement, 61, 196, 208, 222, 231, 233, 236, 248 Complementary and alternative medicine, 121, 133, 208 Complementary medicine, 121, 208 Compliance, 77, 97, 208 Computational Biology, 173, 208 Computed tomography, 35, 78, 208, 209 Computer Simulation, 19, 208 Computerized axial tomography, 208, 209 Computerized tomography, 208, 209 Conception, 209, 219, 259 Cones, 209, 255 Confidence Intervals, 21, 24, 209 Confusion, 209, 265 Conjugated, 200, 209, 211 Conjunctiva, 209, 230 Connective Tissue, 199, 201, 207, 209, 220, 221, 236, 238, 255, 261 Consciousness, 196, 209, 212, 214, 252 Constipation, 154, 157, 209, 232 Constitutional, 157, 209 Constriction, 209, 232 Contraindications, ii, 154, 209 Contrast medium, 197, 209 Control group, 39, 209, 250, 253 Controlled clinical trial, 7, 18, 23, 209 Controlled study, 82, 209 Coordination, 58, 209 Cornea, 209, 224 Coronary, 4, 5, 7, 8, 10, 11, 16, 18, 24, 26, 28, 31, 32, 33, 41, 44, 47, 48, 51, 54, 61, 65, 71, 72, 75, 76, 80, 81, 89, 95, 96, 99, 102, 103, 106, 111, 122, 136, 137, 138,
143, 144, 147, 150, 154, 203, 209, 210, 228, 238, 240 Coronary Arteriosclerosis, 138, 209, 240 Coronary Disease, 4, 144, 210 Coronary heart disease, 4, 5, 11, 18, 44, 47, 65, 89, 96, 102, 137, 143, 144, 147, 203, 210 Coronary Thrombosis, 7, 210, 238, 240 Coronary Vessels, 210 Corpuscle, 210, 218 Cortex, 210, 218, 226, 239, 250, 254 Corticosteroid, 210, 260 Cortisol, 194, 210 Cranial, 11, 210, 225, 243, 245 Creatine, 148, 210 Creatine Kinase, 148, 210 Creatinine, 210, 265 Crossing-over, 210, 254 Cross-Sectional Studies, 210, 217 Cultured cells, 46, 211 Curative, 211, 242, 256, 262 Curcumin, 124, 211 Cutaneous, 17, 211, 232, 236, 247, 267 Cyclic, 30, 211, 225, 242, 249 Cyclophosphamide, 155, 211 Cyclosporine, 124, 155, 211 Cystathionine beta-Synthase, 211, 228 Cysteine, 54, 205, 211, 216, 260 Cystine, 211 Cytochrome, 53, 211 Cytokine, 26, 27, 38, 59, 211 Cytoplasm, 198, 200, 204, 211, 216, 217, 224, 241, 242, 256 Cytoskeletal Proteins, 207, 211 Cytoskeleton, 20, 211, 231, 239 Cytotoxins, 30, 212 D Dairy Products, 212, 256 Data Collection, 22, 212, 220 De novo, 32, 35, 53, 212 Decidua, 212, 247 Degenerative, 28, 212, 226, 236 Dehydration, 154, 206, 212 Deletion, 9, 70, 107, 198, 212, 221 Dementia, 63, 212, 241 Deoxyguanosine, 19, 212 Dermal, 17, 41, 212 Desensitization, 212, 229 Detoxification, 53, 212 Dextran Sulfate, 93, 212 Diabetes Mellitus, 7, 10, 50, 75, 94, 118, 131, 156, 157, 158, 159, 212, 223, 225
273
Diagnostic procedure, 135, 162, 212 Dialyzer, 212, 225 Diarrhea, 36, 154, 206, 212, 232 Diarrhoea, 212, 221 Diastolic, 212, 228 Dichloroacetate, 168, 213 Diencephalon, 213, 228, 241 Dietary Fats, 213, 234 Dietary Fiber, 5, 213 Dietary Proteins, 213, 266 Dietetics, 157, 213 Diffusion, 203, 213, 230 Digestion, 195, 200, 202, 213, 215, 230, 232, 234, 235, 260, 265 Digestive tract, 139, 199, 213, 258, 268 Dihydrotestosterone, 213, 254 Dihydroxy, 150, 213, 256 Dilatation, Pathologic, 213, 266 Dilation, 8, 42, 67, 108, 202, 213, 266 Diploid, 196, 213, 240, 247, 264 Direct, iii, 9, 12, 19, 22, 38, 39, 53, 56, 60, 138, 165, 207, 213, 214, 254 Disaccharides, 146, 213 Discrete, 213, 261 Disease Susceptibility, 25, 213 Disinfectant, 213, 218 Dissection, 62, 213 Dissociation, 194, 213 Distal, 16, 79, 214 Diuretic, 202, 214, 220 Diurnal, 109, 214 Dopamine, 139, 214, 242, 247 Dosage Forms, 136, 214 Double-blind, 4, 7, 12, 23, 69, 82, 83, 127, 214 Drive, ii, vi, 10, 17, 117, 156, 214, 234 Drug Interactions, 167, 168, 214 Drug Tolerance, 214, 263 Duct, 195, 214, 218, 236, 259 Duodenum, 200, 214, 241, 260 Dyes, 196, 200, 214, 242 Dysentery, 154, 214 Dyskinesia, 72, 214 Dyslipidemia, 4, 23, 80, 101, 140, 214 Dyspepsia, 215, 230 Dystrophic, 158, 215 E Echocardiography, 106, 215 Edema, 155, 159, 215, 221, 233, 241, 265 Effector, 193, 208, 215 Efficacy, 4, 7, 12, 17, 20, 23, 26, 30, 46, 76, 77, 80, 82, 83, 85, 86, 98, 146, 155, 215
Elastic, 215, 261 Elasticity, 198, 209, 215 Elastin, 207, 215, 219 Elective, 108, 215 Electrolysis, 197, 215 Electrolyte, 210, 215, 249, 258, 265 Electrons, 198, 215, 232, 243, 244, 253 Electrophoresis, 141, 215 Embryo, 54, 201, 215, 219, 230, 238, 248, 268 Emollient, 215, 223, 242 Endemic, 206, 215, 236, 259 Endocrine Glands, 215, 227 Endocrine System, 215 Endocrinology, 31, 75, 87, 94, 215 Endocytosis, 17, 45, 204, 215 Endoderm, 215, 268 Endogenous, 6, 45, 47, 55, 58, 214, 215, 216, 217, 244, 251, 263 Endometrial, 157, 216 Endometrium, 212, 216 Endopeptidases, 216, 251 Endorphins, 216, 242 Endothelial cell, 7, 11, 12, 16, 20, 48, 59, 60, 64, 216, 262 Endothelins, 50, 216 Endothelium, 7, 14, 16, 34, 45, 48, 55, 64, 67, 72, 106, 112, 124, 216, 242, 248 Endothelium, Lymphatic, 216 Endothelium, Vascular, 14, 216 Endothelium-derived, 34, 216, 242 Endotoxemia, 37, 216 Endotoxic, 216, 234 Endotoxins, 38, 208, 216 End-stage renal, 49, 93, 206, 216 Energy balance, 216, 233 Enkephalins, 217, 242 Enteritis, 154, 217 Enterocolitis, 217 Enterocytes, 37, 217 Enterohepatic, 137, 217 Enterohepatic Circulation, 137, 217 Enteropeptidase, 217, 264 Environmental Health, 172, 174, 217 Environmental Pollutants, 60, 217 Enzymatic, 14, 15, 44, 55, 195, 202, 203, 208, 217, 218, 220, 237, 255 Enzyme Inhibitors, 217, 248 Eosinophils, 217, 224, 234 Epidemic, 37, 217, 259 Epidemiologic Studies, 40, 217
274
Hypercholesterolemia
Epidemiological, 11, 15, 63, 105, 137, 144, 217 Epidermal, 17, 54, 88, 217, 233 Epidermal Growth Factor, 54, 88, 217 Epidermis, 217, 233, 250 Epigastric, 217, 244 Epinephrine, 194, 214, 218, 242, 265 Epithelial, 212, 217, 218, 224, 226, 245 Epithelial Cells, 217, 218, 226 Epithelium, 216, 217, 218 Epitopes, 57, 218 Erectile, 139, 218 Erection, 218 Erythrocyte Membrane, 109, 218 Erythrocytes, 196, 201, 218, 226, 254 Esophagus, 213, 218, 225, 246, 260 Esterification, 8, 218 Estradiol, 48, 218 Estrogen, 23, 47, 48, 50, 118, 218 Estrogen receptor, 23, 218 Ethanol, 125, 136, 218, 219 Ethnic Groups, 22, 43, 218 Eukaryotic Cells, 211, 218, 230, 243, 265 Evacuation, 209, 218 Evoke, 218, 260 Excitation, 218, 241 Exhaustion, 197, 218, 236 Exocrine, 218, 244 Exogenous, 26, 45, 46, 53, 55, 215, 218, 251, 264 Exon, 68, 70, 78, 92, 219 Extracellular, 196, 209, 215, 219, 220, 231, 237, 239, 243, 258 Extracellular Matrix, 209, 219, 220, 231, 237, 243 Extracellular Matrix Proteins, 219, 237 Extracorporeal, 113, 219 Extrapyramidal, 214, 219 Eye Infections, 193, 219 F Family Planning, 173, 219 Family Practice, 110, 219 Fatigue, 219, 225 Fatty Liver, 37, 158, 219 Feces, 209, 219, 260 Femoral, 19, 107, 113, 219 Femur, 111, 219 Fermentation, 149, 219 Fetal Development, 22, 53, 219 Fetus, 53, 219, 247, 250, 265 Fibrinogen, 85, 219, 248, 262 Fibrinolysis, 7, 128, 220
Fibrinolytic, 7, 220 Fibroblasts, 17, 66, 67, 220, 231 Fibronectin, 57, 220 Fibrosis, 14, 49, 158, 220, 257 Filtration, 83, 146, 220 Flatulence, 154, 220 Flatus, 220, 221 Fluorescence, 7, 25, 32, 36, 40, 45, 59, 220 Foam Cells, 33, 220, 267 Focus Groups, 62, 220 Folate, 11, 28, 128, 220 Fold, 22, 41, 46, 220 Folic Acid, 11, 19, 83, 220 Forearm, 74, 76, 90, 112, 201, 220 Free Radicals, 45, 64, 198, 213, 220 Fructose Intolerance, 158, 220 Furosemide, 155, 220 G Galactosemia, 158, 221 Galactosides, 200, 221 Gallate, 148, 221 Gallbladder, 193, 200, 221 Ganglia, 193, 200, 221, 241, 245 Gangrenous, 221, 257 Gas, 154, 203, 213, 220, 221, 227, 230, 232, 242, 260 Gasoline, 60, 221 Gastric, 86, 199, 214, 217, 221, 225, 232 Gastrin, 221, 227 Gastritis, 154, 221 Gastroenteritis, 154, 221 Gastrointestinal, 58, 154, 156, 157, 202, 218, 220, 221, 236, 257, 259, 260 Gastrointestinal tract, 58, 156, 218, 220, 221, 257, 259 Gelatin, 147, 221, 223, 260, 262 Gemfibrozil, 4, 76, 118, 221 Gene Deletion, 78, 221 Gene Expression, 9, 17, 22, 28, 37, 40, 46, 51, 61, 221, 222 Gene Expression Profiling, 9, 222 Gene Therapy, 12, 17, 46, 156, 193, 222 General practitioner, 155, 222 Genetic Code, 222, 242 Genetic Engineering, 201, 207, 222 Genetic Screening, 97, 107, 222 Genetic Techniques, 31, 222 Genital, 131, 199, 222, 265 Genomics, 43, 80, 222 Genotype, 21, 25, 81, 222, 246 Geriatric, 63, 157, 222 Germ Cells, 222, 243, 258, 261, 268
275
Gestation, 222, 247 Gestational, 159, 222 Gland, 210, 222, 236, 237, 244, 257, 260, 262 Glomerular, 122, 155, 222, 223, 232, 254 Glomerular Filtration Rate, 122, 222 Glomeruli, 223 Glomerulonephritis, 155, 223 Glomerulosclerosis, 155, 223 Glomerulus, 155, 222, 223 Gluconeogenesis, 35, 220, 223 Glucose Intolerance, 5, 158, 212, 223 Glucose tolerance, 35, 139, 159, 223 Glucose Tolerance Test, 35, 159, 223 Glucuronic Acid, 223, 226 Glutamic Acid, 220, 223, 242, 250 Glycerol, 57, 223, 247 Glycerophospholipids, 223, 247 Glycine, 195, 200, 223, 242, 257 Glycogen, 158, 223 Glycogen Storage Disease, 158, 223 Glycoprotein, 85, 219, 220, 224, 232, 262 Glycosaminoglycan, 64, 224 Glycoside, 213, 224, 256 Glycosylation, 14, 224 Goblet Cells, 217, 224 Gonad, 224 Gonadal, 35, 71, 224, 259 Gout, 88, 154, 224 Governing Board, 224, 250 Gp120, 224, 245 Graft, 20, 27, 94, 224 Graft Rejection, 94, 224 Graft Survival, 94, 224 Grafting, 103, 224, 230 Gram-negative, 216, 224 Granulocytes, 224, 267 Grasses, 220, 224 Growth factors, 21, 54, 224 Guanine, 212, 224, 252 Guanylate Cyclase, 225, 242 H Hair follicles, 225, 267 Haploid, 225, 247 Haplotypes, 43, 225 Haptens, 194, 225 Headache, 225, 230 Health Behavior, 42, 225 Health Services, 31, 225 Health Status, 42, 225 Heart attack, 137, 138, 203, 225 Heart failure, 122, 225
Heart Transplantation, 76, 82, 91, 225 Heartbeat, 225, 260 Heartburn, 225, 230 Helminthiasis, 154, 225 Heme, 200, 211, 225, 249, 265 Hemodialysis, 93, 158, 212, 225, 233 Hemodynamics, 19, 225 Hemoglobin, 62, 196, 218, 225, 226, 249 Hemoglobin A, 62, 226, 249 Hemoglobinopathies, 222, 226 Hemolysis, 218, 226 Hemorrhage, 154, 225, 226, 260 Hemorrhoids, 154, 226 Hemostasis, 226, 231, 257 Heparin, 113, 226 Hepatitis, 154, 226 Hepatobiliary, 158, 226 Hepatocellular, 36, 59, 158, 226 Hepatocyte, 33, 36, 206, 226 Hepatocyte Growth Factor, 33, 226 Hepatoma, 9, 36, 226 Hereditary, 157, 158, 224, 226 Heredity, 138, 157, 221, 222, 226 Heterodimers, 140, 226, 231, 264 Heterogeneity, 194, 226 Heterozygotes, 67, 96, 112, 226 Hippocampus, 226, 241 Histology, 158, 227, 241 Histones, 206, 227 Homeostasis, 6, 13, 15, 33, 37, 46, 58, 64, 140, 227 Homodimer, 227, 264 Homogeneous, 22, 198, 227, 246 Homologous, 61, 195, 210, 222, 226, 227, 257, 261, 264 Homozygote, 67, 227 Hormonal, 23, 48, 52, 56, 199, 210, 227, 245, 267 Hormone Antagonists, 59, 227 Hormone Replacement Therapy, 47, 227 Human Development, 25, 172, 227 Humoral, 33, 224, 227 Humour, 227 Hybrid, 33, 199, 207, 227 Hybridomas, 227, 231 Hydrogen, 193, 203, 219, 227, 234, 239, 244, 260, 268 Hydrogen Peroxide, 227, 234, 260 Hydrolysis, 200, 205, 227, 234, 247, 249, 252, 264 Hydrophobic, 138, 223, 228, 234 Hydroxy Acids, 150, 228
276
Hypercholesterolemia
Hydroxylysine, 207, 228 Hydroxyproline, 195, 207, 228 Hyperbilirubinemia, 228, 232 Hypercalcemia, 108, 228 Hypercapnia, 11, 228 Hyperglycemia, 14, 35, 127, 130, 158, 228 Hyperhomocysteinemia, 16, 21, 34, 88, 211, 228 Hyperlipoproteinemia, 17, 66, 94, 228, 235 Hyperplasia, 9, 12, 228 Hypersensitivity, 212, 228, 255 Hypertension, 4, 16, 22, 34, 44, 46, 48, 63, 77, 95, 103, 105, 109, 110, 130, 159, 162, 179, 198, 202, 203, 225, 228, 249, 265 Hyperthyroidism, 59, 228 Hypertriglyceridemia, 35, 37, 61, 72, 77, 79, 128, 146, 147, 155, 159, 214, 228 Hypertrophy, 89, 228 Hyperuricemia, 224, 228 Hypoglycemia, 158, 220, 228 Hypoglycemic, 4, 228 Hypoglycemic Agents, 4, 228 Hypolipidemic, 92, 126, 129, 228 Hypotension, 228, 241, 248 Hypothalamus, 213, 228, 241 Hypothyroidism, 66, 189, 229 Hypoxanthine, 229, 267 Hypoxia, 59, 90, 229, 262 I Idiopathic, 155, 229 Ileal, 37, 86, 137, 158, 229 Ileitis, 37, 229 Ileum, 13, 37, 229, 241 Immune function, 19, 229, 264 Immune response, 26, 194, 197, 210, 224, 225, 229, 236, 260, 266 Immune system, 201, 229, 236, 246, 267 Immunization, 229, 250 Immunochemistry, 31, 229 Immunogenic, 229, 234 Immunoglobulin, 197, 229, 240 Immunohistochemistry, 28, 229 Immunology, 31, 32, 193, 194, 229 Immunosuppressant, 195, 229 Immunosuppression, 26, 99, 229, 236 Immunosuppressive, 211, 229, 261 Immunosuppressive Agents, 229 Impairment, 56, 67, 128, 199, 206, 214, 219, 230, 238 Implantation, 55, 209, 230 Impotence, 218, 230 In situ, 25, 40, 48, 230
In Situ Hybridization, 25, 40, 230 In vitro, 7, 14, 15, 17, 20, 21, 25, 27, 29, 32, 34, 36, 46, 55, 57, 122, 123, 126, 140, 222, 230, 261 Incision, 230, 232 Incubation, 230, 233 Incubation period, 230, 233 Indigestion, 154, 230 Induction, 17, 33, 55, 61, 100, 196, 230, 258 Infantile, 230, 234 Infarction, 83, 204, 230, 255 Infection, 18, 199, 201, 204, 205, 219, 221, 229, 230, 233, 236, 241, 245, 255, 257, 260, 267 Inferior vena cava, 27, 230 Infertility, 230, 265 Infiltration, 27, 59, 223, 230 Influenza, 45, 230 Information Centers, 154, 231 Infuse, 57, 231 Infusion, 57, 154, 231 Ingestion, 23, 127, 145, 220, 223, 231, 248 Initiation, 16, 35, 40, 55, 231, 263 Inorganic, 142, 231, 240 Inotropic, 214, 231 Inpatients, 35, 231 Insight, 14, 15, 16, 19, 30, 41, 46, 62, 65, 140, 231 Insulin, 4, 10, 35, 38, 47, 50, 56, 69, 91, 102, 139, 140, 144, 156, 158, 159, 223, 231, 264 Insulin-dependent diabetes mellitus, 69, 140, 231 Integrins, 57, 231 Interindividual, 43, 231 Interleukin-1, 33, 231 Interleukin-2, 231 Interleukin-6, 106, 231 Interleukins, 50, 229, 231 Intermediate Filaments, 232, 241 Intermittent, 158, 232, 249 Interstitial, 64, 232, 254 Intestinal, 36, 47, 51, 58, 79, 137, 154, 203, 217, 223, 232, 267, 268 Intestinal Mucosa, 217, 232, 268 Intestine, 37, 200, 202, 217, 232, 233, 246, 252 Intoxication, 232, 267 Intracellular, 7, 32, 34, 45, 64, 67, 202, 207, 222, 230, 231, 232, 236, 237, 242, 249, 253 Intramuscular, 232, 244 Intravascular, 6, 10, 31, 95, 232 Intravenous, 35, 155, 231, 232, 244
277
Intrinsic, 54, 63, 194, 232 Intrinsic Factor, 63, 232 Inulin, 222, 232 Invasive, 42, 232 Ions, 206, 213, 215, 227, 232, 250, 252 Irritable Bowel Syndrome, 157, 232 Irritants, 214, 232 Ischemia, 11, 21, 41, 48, 55, 59, 199, 203, 232, 255 Isoenzyme, 210, 232 Isopropyl, 145, 146, 150, 232 Isozymes, 34, 232 J Jaundice, 95, 154, 228, 232 K Kallidin, 202, 233 Karyotypes, 222, 233 Kb, 107, 172, 233 Keratin, 233 Keratinocytes, 17, 233 Kidney Disease, 155, 158, 172, 233 Kidney Failure, 216, 223, 233 Kidney stone, 233, 265 Kidney Transplantation, 112, 233 Kinetic, 45, 46, 233 L Labile, 208, 233 Lamivudine, 35, 233 Large Intestine, 213, 232, 233, 254, 258 Lentivirus, 17, 233 Leptin, 24, 233 Lesion, 9, 10, 22, 26, 27, 28, 57, 63, 97, 155, 234, 235 Lethargy, 229, 234 Leukapheresis, 198, 234 Leukemia, 222, 234 Leukocytes, 57, 59, 200, 201, 205, 217, 224, 231, 234, 242 Libido, 196, 234 Life cycle, 201, 234 Ligaments, 209, 234 Ligands, 45, 54, 57, 58, 140, 204, 231, 234 Linear Models, 43, 234 Linkage, 21, 25, 37, 205, 234, 235, 247 Linkage Disequilibrium, 21, 234 Lipase, 24, 234 Lipid A, 6, 32, 33, 53, 138, 150, 157, 234 Lipid Peroxidation, 7, 38, 234, 244 Lipodystrophy, 38, 234 Lipolysis, 35, 234 Lipopolysaccharide, 58, 224, 234 Lipoprotein Lipase, 104, 234
Lipoprotein(a), 67, 235 Liver Transplantation, 64, 90, 97, 98, 114, 156, 178, 235 Localization, 13, 19, 26, 44, 46, 67, 87, 229, 235 Localized, 14, 41, 196, 230, 234, 235, 247 Locomotion, 235, 247 Lod, 21, 235 Lod Score, 21, 235 Longitudinal study, 13, 42, 235 Lovastatin, 66, 69, 72, 74, 75, 76, 80, 83, 101, 109, 120, 149, 235, 258 Lubricants, 149, 235, 246 Luciferase, 37, 235 Lupus, 236, 261 Lymph, 199, 206, 210, 216, 227, 236, 260 Lymph node, 199, 236 Lymphatic, 17, 216, 230, 236, 238, 258, 259, 262 Lymphocyte, 27, 60, 197, 229, 236, 237 Lymphocyte Depletion, 229, 236 Lymphoid, 197, 236 Lysine, 132, 227, 228, 236, 264 Lysosomal Storage Diseases, 236, 240 M Macrophage, 27, 49, 50, 57, 61, 78, 231, 236 Macula, 236 Macula Lutea, 236 Macular Degeneration, 30, 236 Major Histocompatibility Complex, 225, 236 Malaria, 154, 236 Malaria, Falciparum, 236, 237 Malaria, Vivax, 236 Malignant, 197, 198, 237, 241, 261 Malnutrition, 158, 195, 199, 237 Mammary, 235, 237 Mammogram, 202, 237, 238 Mastitis, 237, 257 Matrix metalloproteinase, 29, 237 Meat, 213, 237, 256 Medial, 41, 50, 198, 237 Mediate, 14, 15, 20, 34, 40, 50, 57, 58, 140, 204, 214, 237 Mediator, 11, 55, 231, 237, 257 MEDLINE, 173, 237 Megaloblastic, 220, 237 Melanin, 237, 247, 265 Membrane Fluidity, 20, 237 Membrane Lipids, 237, 247 Membrane Microdomains, 36, 237 Membrane Proteins, 204, 237
278
Hypercholesterolemia
Memory, 29, 61, 197, 212, 237 Menopause, 48, 238, 249, 250 Menstruation, 212, 238 Mental, iv, 6, 139, 172, 174, 205, 209, 212, 213, 219, 229, 237, 238, 250, 252, 256, 265 Mental Disorders, 238, 250, 252 Mental Health, iv, 6, 139, 172, 174, 238, 250, 252 Mentors, 39, 238 Mesenchymal, 40, 140, 217, 238 Mesoderm, 238, 268 Meta-Analysis, 122, 125, 238 Metabolic disorder, 56, 223, 224, 238 Metabolite, 147, 235, 238, 250, 253 Metastasis, 204, 237, 238, 241 MI, 30, 112, 148, 191, 238 Microbe, 238, 263 Microbiology, 31, 32, 193, 238 Microcalcifications, 202, 238 Microcirculation, 14, 238, 248 Micronutrients, 28, 238 Microorganism, 207, 238, 267 Microtubule-Associated Proteins, 238, 241 Microtubules, 36, 232, 239, 241 Middle Cerebral Artery, 11, 239 Migration, 20, 57, 103, 239, 245 Mineralization, 40, 239 Miscible, 138, 239, 246 Mitochondrial Swelling, 239, 240 Mitogen-Activated Protein Kinase Kinases, 239 Mitogen-Activated Protein Kinases, 44, 239 Mitosis, 198, 239 Mobilization, 21, 239 Modeling, 43, 62, 239 Modification, 19, 31, 33, 64, 130, 195, 222, 239, 253, 268 Modulator, 139, 239 Monitor, 10, 59, 210, 239, 242 Monoclonal, 60, 227, 240 Monocyte, 57, 240 Monosomy, 196, 240 Monotherapy, 99, 240 Morphological, 194, 215, 240 Motility, 36, 58, 240, 257 Motion Sickness, 240 Mucins, 217, 224, 240 Mucopolysaccharidoses, 158, 240 Mucosa, 236, 240 Mucus, 214, 240 Mutagenic, 195, 240
Myalgia, 231, 240 Mydriatic, 213, 240 Myocardial infarction, 4, 44, 46, 83, 210, 238, 240 Myocardial Ischemia, 55, 210, 240 Myocardium, 238, 240 Myopathy, 147, 148, 240 N Nasal Mucosa, 230, 240 Nausea, 154, 214, 221, 230, 240, 265 Necrosis, 27, 29, 59, 198, 230, 238, 240, 255 Neocortex, 240, 241 Neoplasms, 197, 198, 203, 241, 246, 262 Nephrology, 95, 128, 155, 159, 241 Nephropathy, 94, 233, 241 Nephrosis, 241 Nephrotic, 155, 159, 189, 241 Nephrotic Syndrome, 155, 159, 241 Nerve, 194, 199, 205, 210, 237, 241, 243, 256, 257, 260, 264 Nervous System, 74, 139, 194, 205, 237, 241, 245, 261 Neural, 194, 196, 227, 241, 245 Neurofibrillary Tangles, 61, 241 Neurofilaments, 241 Neuronal, 15, 29, 61, 241 Neurons, 221, 240, 241, 261 Neuropathy, 199, 241, 268 Neurotensin, 139, 241 Neurotic, 241, 265 Neurotoxic, 29, 241 Neurotoxicity, 29, 241 Neurotransmitter, 58, 139, 193, 195, 202, 214, 223, 241, 242, 260 Neutropenia, 242, 248 Neutrophils, 224, 234, 242, 248 Niacin, 75, 83, 85, 86, 101, 120, 190, 242, 264 Nitric Oxide, 7, 12, 15, 34, 41, 45, 54, 55, 58, 64, 91, 125, 242 Nitrogen, 28, 196, 211, 219, 242, 264 Norepinephrine, 194, 214, 242 Nuclear, 28, 33, 38, 44, 58, 98, 200, 215, 218, 240, 242 Nuclei, 215, 222, 227, 239, 242, 243 Nucleic acid, 141, 222, 229, 230, 242, 252, 253, 268 Nucleus, 198, 200, 206, 211, 217, 218, 232, 242, 251, 260, 262 Nursing Care, 242, 245 O Ointments, 214, 242
279
Omega-3 fatty acid, 123, 242 Oncogene, 226, 242 Oncogenic, 231, 233, 243 Oocytes, 114, 243 Opacity, 212, 243 Open Reading Frames, 233, 243 Ophthalmic, 30, 243 Opsin, 243, 255, 256 Optic Nerve, 243, 255 Oral Health, 243 Oral Hygiene, 4, 243 Organ Culture, 53, 243 Organelles, 207, 211, 243 Osmotic, 194, 239, 243 Osteoblasts, 40, 243 Outpatient, 6, 243 Ovariectomy, 49, 127, 243 Ovaries, 243, 257 Ovary, 32, 218, 224, 243, 248 Overdosage, 154, 243 Overweight, 103, 119, 243 Oxidants, 60, 64, 243 Oxidation, 19, 20, 31, 41, 44, 49, 56, 57, 59, 75, 93, 138, 193, 198, 211, 234, 243, 244 Oxidation-Reduction, 243, 244 Oxidative Stress, 18, 22, 23, 28, 29, 38, 44, 45, 50, 55, 59, 244 P Palliative, 244, 262 Pancreas, 156, 193, 231, 234, 244, 264 Pancreatic, 156, 244 Pancreatitis, 138, 244 Parasitic, 214, 225, 244 Parenteral, 158, 244 Parenteral Nutrition, 158, 244 Partial remission, 244, 254 Particle, 8, 61, 73, 126, 136, 244, 263 Pathogenesis, 15, 18, 26, 28, 29, 31, 32, 39, 43, 49, 56, 61, 64, 127, 155, 156, 244 Pathologic, 21, 33, 36, 155, 198, 201, 209, 228, 244, 245 Pathologic Processes, 198, 245 Pathophysiology, 16, 20, 31, 155, 156, 245 Patient Care Management, 158, 245 Patient Education, 178, 184, 186, 191, 245 Patient Satisfaction, 99, 245 Pedigree, 25, 66, 69, 245 Pelvis, 193, 230, 233, 243, 245, 265 Penicillin, 197, 245 Peptide, 59, 139, 195, 216, 217, 233, 245, 249, 251, 252, 262 Peptide T, 139, 245
Perception, 107, 245, 256 Perfusion, 16, 41, 55, 229, 245, 263 Periodicity, 109, 245 Periodontal disease, 4, 103, 245 Periodontal Index, 4, 245 Periodontal Pocket, 245 Peripheral blood, 57, 245 Peripheral Nervous System, 217, 241, 245, 260 Peripheral Vascular Disease, 143, 246 Peristalsis, 58, 246 Peritoneal, 156, 246 Peritoneum, 246 Pernicious anemia, 232, 246 Peroral, 145, 246 Peroxisome Proliferators, 140, 246 Personality Assessment, 42, 246 Petroleum, 221, 246 Phagocyte, 243, 246 Pharmaceutical Preparations, 205, 218, 221, 246 Pharmaceutical Solutions, 214, 246 Pharmacologic, 11, 33, 65, 246, 263 Pharmacotherapy, 4, 40, 77, 84, 92, 101, 122, 125, 246 Pharynx, 230, 246 Phenotype, 5, 8, 39, 51, 57, 62, 67, 88, 89, 108, 110, 157, 221, 246 Phenylalanine, 246, 264 Phosphatidic Acids, 247 Phosphatidylcholines, 36, 247 Phospholipids, 8, 44, 138, 143, 219, 234, 237, 247, 251 Phosphorus, 202, 247 Phosphorylated, 207, 239, 247 Phosphorylation, 50, 239, 247, 251 Photosensitivity, 247, 249 Physical Fitness, 42, 247 Physicochemical, 229, 247 Physiologic, 25, 61, 194, 201, 219, 232, 238, 247, 253 Physiology, 11, 25, 29, 31, 37, 126, 137, 203, 215, 241, 247 Pigments, 200, 203, 247, 255 Placenta, 53, 218, 247, 250 Plant Proteins, 247, 266 Plant sterols, 24, 47, 51, 121, 128, 129, 247 Plants, 154, 195, 203, 204, 206, 212, 223, 224, 232, 242, 247, 248, 249, 256, 263, 266 Plaque, 57, 95, 138, 199, 247 Plasma cells, 197, 248 Plasma protein, 93, 194, 216, 248, 252
280
Hypercholesterolemia
Plasmapheresis, 83, 198, 248 Plasmin, 248 Plasminogen, 6, 248 Plasminogen Activators, 248 Platelet Activating Factor, 19, 248 Platelet Aggregation, 55, 102, 196, 242, 248 Plateletpheresis, 198, 248 Platelets, 59, 73, 85, 242, 248, 262 Pneumonia, 209, 248 Point Mutation, 67, 107, 157, 248 Poison Control Centers, 154, 248 Poisoning, 202, 221, 232, 240, 248 Pollen, 248, 253 Polymorphic, 25, 136, 248 Polymorphism, 70, 93, 122, 249 Polypeptide, 195, 207, 217, 219, 248, 249, 268 Polysaccharide, 197, 205, 224, 249 Polyunsaturated fat, 39, 249 Pons, 200, 202, 249 Porphyria, 158, 249 Porphyria Cutanea Tarda, 158, 249 Porphyria, Hepatic, 249 Porphyrins, 249 Portacaval, 68, 249 Portal Hypertension, 156, 249 Posterior, 196, 199, 200, 206, 244, 249 Postmenopausal, 48, 76, 94, 118, 124, 125, 130, 249 Postnatal, 21, 110, 249, 259 Postprandial, 5, 126, 144, 157, 249 Postprandial Blood Glucose, 144, 249 Potassium, 16, 249, 250 Potassium Channels, 16, 250 Potentiate, 179, 250 Practice Guidelines, 174, 250 Pravastatin, 69, 74, 82, 91, 98, 106, 108, 120, 149, 250 Precipitation, 113, 250 Premenopausal, 47, 76, 250 Prenatal, 105, 215, 222, 250 Presynaptic, 241, 250 Prevalence, 5, 15, 56, 92, 93, 105, 245, 250 Prickle, 233, 250 Primary endpoint, 23, 250 Primary Prevention, 11, 31, 250 Probe, 17, 245, 250 Prodrug, 250, 253 Progesterone, 250, 259 Progression, 10, 11, 22, 26, 28, 31, 40, 41, 48, 55, 57, 62, 64, 98, 139, 144, 179, 197, 250
Progressive, 10, 49, 56, 198, 206, 212, 214, 240, 250, 254, 264 Proline, 8, 207, 228, 250 Promoter, 9, 15, 33, 37, 70, 85, 94, 251 Prophase, 243, 251, 261 Prophylaxis, 137, 139, 143, 147, 251 Prospective Studies, 34, 251 Prospective study, 235, 251 Prostaglandins, 58, 195, 198, 251 Protease, 35, 251 Protease Inhibitors, 35, 251 Protective Agents, 202, 251 Protein Binding, 251, 263 Protein C, 104, 114, 194, 195, 198, 200, 207, 233, 234, 235, 251, 265 Protein Kinase C, 239, 251 Protein S, 14, 52, 201, 222, 251, 256 Protein-Serine-Threonine Kinases, 239, 251 Proteinuria, 155, 159, 179, 223, 241, 251 Proteolytic, 208, 217, 219, 248, 251 Prothrombin, 252, 262 Protocol, 26, 48, 252 Protozoa, 214, 238, 252, 265 Protozoan, 236, 252 Pruritus, 156, 252, 265 Psychiatric, 91, 238, 252 Psychiatry, 63, 252 Psychic, 234, 238, 252 Psychoactive, 252, 267 Psyllium, 5, 122, 124, 127, 132, 133, 252 Public Health, 52, 110, 174, 252 Public Policy, 173, 252 Publishing, 66, 153, 179, 252 Pulmonary, 201, 233, 252, 261, 266 Pulmonary Artery, 201, 252, 266 Pulse, 239, 252 Pupil, 209, 213, 240, 252 Purines, 252, 257, 267 Pylorus, 73, 252 Pyrimidines, 253, 257 Q Quality of Life, 31, 99, 253 Quercetin, 28, 253 R Race, 159, 233, 239, 253 Radiation, 220, 229, 253, 267 Radioactive, 227, 230, 242, 243, 253 Ramipril, 43, 253 Random Allocation, 253 Randomization, 23, 253
281
Randomized, 4, 12, 18, 23, 30, 39, 47, 69, 77, 82, 83, 102, 125, 127, 215, 253 Randomized clinical trial, 30, 102, 125, 253 Reabsorption, 217, 253 Reactive Oxygen Species, 20, 34, 44, 253 Reagent, 212, 235, 253 Receptors, Serotonin, 253, 257 Recombinant, 12, 27, 254, 266 Recombination, 22, 24, 25, 222, 254 Rectal, 154, 254 Rectum, 198, 207, 213, 220, 221, 233, 254, 260 Recur, 245, 254 Recurrence, 245, 254 Red blood cells, 218, 249, 254, 256 Red Nucleus, 199, 254 Refer, 1, 208, 216, 235, 236, 254, 263 Reference Values, 31, 254 Refraction, 254, 259 Refractory, 96, 254 Regimen, 25, 35, 51, 144, 215, 246, 254 Remission, 155, 254 Renal Artery, 16, 254 Renal failure, 157, 254 Renin, 6, 197, 254 Renin-Angiotensin System, 6, 254 Reperfusion, 59, 255 Reperfusion Injury, 255 Research Support, 56, 255 Resection, 37, 255 Respiration, 203, 239, 255 Retina, 29, 206, 209, 236, 243, 255, 256, 267 Retinal, 30, 243, 255, 256 Retinoid, 59, 140, 255 Retinol, 255, 256 Retrospective, 34, 255 Retroviral vector, 17, 222, 255 Retrovirus, 17, 255 Rheology, 4, 255 Rheumatism, 255 Rheumatoid, 140, 244, 255 Rheumatoid arthritis, 140, 255 Rhinitis, 256, 257 Rhodopsin, 243, 255, 256 Riboflavin, 28, 256 Ribose, 193, 256 Ribosome, 256, 264 Rickets, 256, 267 Rod, 207, 216, 256 Rutin, 253, 256 S Saponins, 256, 259
Saturated fat, 39, 144, 256 Schizoid, 256, 267 Schizophrenia, 256, 267 Schizotypal Personality Disorder, 256, 267 Sclerosis, 155, 198, 257 Screening, 38, 65, 107, 109, 148, 158, 162, 207, 222, 257 Sebaceous, 232, 257, 267 Secretion, 8, 10, 23, 36, 53, 58, 139, 210, 217, 227, 229, 231, 232, 240, 257, 264, 265 Secretory, 17, 257 Sedative, 257, 265 Sediment, 257 Sedimentation, 94, 257, 264 Segmental, 155, 157, 223, 257 Segmentation, 257 Segregation, 254, 257 Sepsis, 64, 257 Septicaemia, 257 Sequence Homology, 245, 257 Serine, 21, 70, 211, 216, 239, 251, 257, 264 Serotonin, 128, 242, 246, 253, 257, 264 Serotypes, 26, 257 Serous, 216, 257 Sex Characteristics, 196, 257, 261 Shock, 45, 216, 257, 264 Shunt, 19, 258 Side effect, 65, 144, 145, 148, 149, 154, 165, 168, 194, 201, 211, 228, 258, 263, 268 Signs and Symptoms, 254, 258, 265 Skeletal, 40, 196, 207, 210, 258 Skeleton, 193, 219, 258 Skull, 258, 261 Small intestine, 206, 214, 217, 227, 229, 232, 258, 264 Smooth muscle, 9, 12, 14, 16, 27, 28, 40, 46, 50, 55, 196, 202, 220, 254, 258, 260 Social Environment, 62, 253, 258 Sodium, 36, 141, 142, 146, 168, 224, 253, 258 Soft tissue, 144, 201, 258 Solid tumor, 196, 258 Solvent, 218, 223, 243, 246, 258 Soma, 72, 258 Somatic, 156, 227, 239, 245, 258, 261 Soybean Oil, 249, 258 Spasmodic, 193, 258 Spastic, 232, 258 Specialist, 180, 213, 259 Species, 25, 28, 29, 37, 63, 65, 149, 195, 218, 221, 227, 233, 236, 239, 240, 244, 253, 257, 259, 260, 264, 266, 267
282
Hypercholesterolemia
Specificity, 37, 194, 216, 259, 263 Spectrum, 28, 48, 101, 211, 240, 259 Sperm, 196, 206, 248, 259, 264 Sphincter, 72, 259 Spinal cord, 202, 205, 206, 241, 245, 259 Spinous, 217, 233, 259 Spleen, 196, 236, 259 Sporadic, 249, 259 Stabilization, 5, 259 Steatorrhea, 156, 259 Steatosis, 158, 219, 259 Steel, 207, 259 Stem Cells, 17, 140, 259 Stenosis, 39, 111, 203, 259, 260 Stent, 9, 16, 259 Sterility, 211, 230, 259 Steroid, 38, 58, 140, 155, 200, 210, 256, 258, 259, 260 Steroid therapy, 155, 260 Stimulus, 40, 44, 214, 218, 260, 262 Stomach, 73, 145, 154, 193, 199, 213, 218, 221, 223, 227, 240, 246, 252, 258, 259, 260 Stool, 166, 207, 232, 233, 259, 260, 261 Strand, 93, 260 Stricture, 259, 260 Stroke, 11, 13, 16, 34, 44, 63, 84, 95, 107, 137, 143, 172, 178, 203, 260 Subacute, 230, 260 Subclinical, 11, 230, 260 Subcutaneous, 193, 215, 221, 234, 244, 260 Submaxillary, 217, 260 Subspecies, 104, 259, 260 Substance P, 238, 257, 260 Substrate, 45, 217, 260 Suction, 220, 260 Sudden death, 50, 260 Sulfur, 212, 219, 233, 260 Superoxide, 11, 14, 15, 20, 45, 55, 64, 91, 260 Superoxide Dismutase, 14, 15, 20, 56, 260 Supplementation, 12, 23, 45, 46, 123, 126, 128, 129, 130, 260 Suppositories, 221, 260 Suppression, 33, 35, 68, 210, 260 Surfactant, 142, 146, 261 Sympathomimetic, 214, 218, 242, 261 Symptomatic, 148, 244, 261 Synaptic, 242, 261 Synergistic, 7, 60, 261 Systemic, 17, 20, 29, 37, 90, 93, 101, 123, 166, 167, 196, 198, 201, 218, 225, 230, 241, 248, 261
Systemic lupus erythematosus, 101, 261 Systolic, 228, 261 T Tacrolimus, 99, 261 Taurine, 126, 200, 261 Telangiectasia, 157, 261 Telomerase, 21, 261 Temporal, 9, 11, 57, 226, 236, 261 Tendon, 24, 202, 261 Tenesmus, 214, 261 Teratogenic, 195, 261 Testicular, 118, 261 Testis, 218, 261 Testosterone, 49, 254, 261 Thalamic, 199, 262 Thalamic Diseases, 199, 262 Therapeutics, 76, 98, 104, 113, 114, 136, 168, 262 Thigh, 219, 262 Threonine, 21, 239, 245, 251, 257, 262 Threshold, 228, 262 Thrombin, 29, 219, 248, 251, 252, 262 Thrombocytes, 248, 262 Thrombocytopenia, 248, 262 Thrombolytic, 248, 262 Thrombomodulin, 251, 262 Thrombosis, 6, 78, 87, 88, 90, 92, 99, 100, 123, 126, 128, 136, 204, 231, 251, 260, 262 Thrombus, 210, 230, 240, 248, 262 Thymus, 229, 236, 262 Thyroid, 52, 58, 140, 158, 228, 229, 262, 265 Thyroid Gland, 228, 262 Thyrotoxicosis, 158, 262 Thyrotropin, 229, 262 Thyroxine, 194, 247, 262 Tissue Distribution, 65, 263 Tolerance, 35, 86, 159, 193, 223, 263 Tomography, 263 Tone, 6, 55, 243, 263 Tonus, 263 Tooth Preparation, 193, 263 Topical, 17, 166, 218, 227, 263 Toxic, iv, 148, 195, 212, 215, 224, 241, 263, 268 Toxicity, 7, 60, 108, 126, 148, 214, 263 Toxicology, 42, 174, 263 Toxin, 216, 263 Trachea, 246, 262, 263 Traction, 207, 263 Transcriptase, 21, 233, 255, 261, 263, 268 Transcription Factors, 28, 40, 44, 140, 263 Transduction, 17, 28, 54, 204, 263
283
Transfection, 40, 201, 222, 263 Transferases, 224, 263 Transforming Growth Factor beta, 155, 264 Translation, 8, 21, 65, 195, 264 Translational, 35, 39, 264 Translocate, 138, 264 Translocation, 8, 264 Transmitter, 193, 214, 237, 242, 264 Transplantation, 3, 21, 49, 88, 90, 91, 94, 97, 98, 99, 112, 114, 158, 179, 206, 229, 236, 264 Transport Vesicles, 18, 264 Trauma, 200, 225, 240, 244, 262, 264 Triglyceride, 5, 8, 35, 52, 53, 61, 65, 108, 138, 140, 146, 150, 207, 228, 264 Trisomy, 196, 264 Trypsin, 90, 217, 264, 268 Tryptophan, 207, 257, 264 Tubulin, 239, 264 Tumour, 264, 267 Type 2 diabetes, 4, 5, 71, 124, 264 Tyrosine, 44, 54, 214, 264 U Ubiquitin, 8, 241, 265 Uraemia, 244, 265 Urea, 265 Uremia, 157, 233, 254, 265 Ureters, 233, 254, 265 Urethra, 265 Uric, 65, 224, 228, 252, 265 Urinary, 7, 23, 202, 265, 267 Urinary tract, 265 Urine, 52, 148, 155, 201, 210, 214, 217, 233, 251, 256, 265 Urology, 118, 179, 265 Uroporphyrinogen Decarboxylase, 249, 265 Uterus, 212, 216, 238, 241, 243, 250, 265 V Vaccines, 265, 266 Vacuoles, 215, 243, 265 Valerian, 153, 265 Valves, 40, 265 Vasa Vasorum, 16, 265 Vasculitis, 244, 266 Vasodilatation, 107, 124, 233, 266 Vasodilation, 12, 48, 72, 112, 266 Vasodilator, 58, 202, 214, 266 Vasomotor, 14, 266 Vector, 26, 46, 263, 266
Vegetable Proteins, 121, 247, 266 Vein, 27, 196, 199, 230, 232, 242, 249, 266 Vena, 266 Venoms, 212, 266 Venous, 199, 226, 251, 266 Ventricle, 198, 226, 228, 252, 261, 266 Ventricular, 89, 266 Venules, 59, 201, 203, 216, 238, 266 Vertebral, 200, 266 Very low-density lipoprotein, 18, 266 Vesicular, 36, 266 Veterinary Medicine, 173, 266 Viral, 12, 16, 35, 46, 230, 243, 255, 263, 266, 268 Virulence, 199, 263, 266 Virus, 12, 18, 45, 200, 222, 224, 247, 255, 263, 266 Viscera, 258, 266 Visceral, 199, 246, 267 Viscosity, 255, 267 Vitamin D, 11, 156, 256, 267 Vitelline Membrane, 267, 268 Vitreous, 255, 267 Vitreous Body, 255, 267 Vitro, 7, 20, 21, 35, 57, 137, 226, 267 Vivo, 7, 9, 10, 11, 13, 14, 17, 20, 21, 23, 26, 27, 31, 32, 33, 34, 39, 40, 49, 55, 57, 60, 62, 65, 66, 73, 123, 140, 222, 226, 230, 236, 243, 261, 267 Vulgaris, 118, 267 W White blood cell, 55, 197, 234, 236, 240, 242, 248, 267 Windpipe, 246, 262, 267 Withdrawal, 48, 148, 155, 267 Wound Healing, 204, 231, 237, 267 X Xanthine, 64, 267 Xanthine Oxidase, 64, 267 Xanthoma, 111, 267 Xanthomatosis, 138, 144, 267 Xenograft, 197, 267 X-ray, 18, 35, 59, 196, 208, 209, 220, 237, 242, 267 Y Yeasts, 246, 268 Yolk Sac, 53, 268 Z Zalcitabine, 233, 268 Zymogen, 251, 268
284
Hypercholesterolemia
