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

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

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HYPERGLYCEMIA A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

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

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

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Hyperglycemia: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84457-7 1. Hyperglycemia-Popular works. I. Title.

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

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

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on hyperglycemia. 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 HYPERGLYCEMIA ...................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Hyperglycemia ............................................................................ 12 E-Journals: PubMed Central ....................................................................................................... 71 The National Library of Medicine: PubMed ................................................................................ 73 CHAPTER 2. NUTRITION AND HYPERGLYCEMIA ............................................................................ 97 Overview...................................................................................................................................... 97 Finding Nutrition Studies on Hyperglycemia............................................................................. 97 Federal Resources on Nutrition ................................................................................................. 102 Additional Web Resources ......................................................................................................... 103 CHAPTER 3. DISSERTATIONS ON HYPERGLYCEMIA ...................................................................... 105 Overview.................................................................................................................................... 105 Dissertations on Hyperglycemia................................................................................................ 105 Keeping Current ........................................................................................................................ 106 CHAPTER 4. CLINICAL TRIALS AND HYPERGLYCEMIA ................................................................ 107 Overview.................................................................................................................................... 107 Recent Trials on Hyperglycemia................................................................................................ 107 Keeping Current on Clinical Trials ........................................................................................... 108 CHAPTER 5. PATENTS ON HYPERGLYCEMIA................................................................................. 111 Overview.................................................................................................................................... 111 Patents on Hyperglycemia ......................................................................................................... 111 Patent Applications on Hyperglycemia ..................................................................................... 117 Keeping Current ........................................................................................................................ 148 CHAPTER 6. BOOKS ON HYPERGLYCEMIA .................................................................................... 151 Overview.................................................................................................................................... 151 Book Summaries: Federal Agencies............................................................................................ 151 Book Summaries: Online Booksellers......................................................................................... 168 The National Library of Medicine Book Index ........................................................................... 169 Chapters on Hyperglycemia....................................................................................................... 169 CHAPTER 7. MULTIMEDIA ON HYPERGLYCEMIA ......................................................................... 173 Overview.................................................................................................................................... 173 Video Recordings ....................................................................................................................... 173 Audio Recordings....................................................................................................................... 176 CHAPTER 8. PERIODICALS AND NEWS ON HYPERGLYCEMIA ...................................................... 179 Overview.................................................................................................................................... 179 News Services and Press Releases.............................................................................................. 179 Newsletter Articles .................................................................................................................... 182 Academic Periodicals covering Hyperglycemia ......................................................................... 183 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 185 Overview.................................................................................................................................... 185 U.S. Pharmacopeia..................................................................................................................... 185 Commercial Databases ............................................................................................................... 186 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 189 Overview.................................................................................................................................... 189 NIH Guidelines.......................................................................................................................... 189 NIH Databases........................................................................................................................... 191 Other Commercial Databases..................................................................................................... 193 APPENDIX B. PATIENT RESOURCES ............................................................................................... 195 Overview.................................................................................................................................... 195

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Patient Guideline Sources.......................................................................................................... 195 Finding Associations.................................................................................................................. 206 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 209 Overview.................................................................................................................................... 209 Preparation................................................................................................................................. 209 Finding a Local Medical Library................................................................................................ 209 Medical Libraries in the U.S. and Canada ................................................................................. 209 ONLINE GLOSSARIES................................................................................................................ 215 Online Dictionary Directories ................................................................................................... 215 HYPERGLYCEMIA DICTIONARY ........................................................................................... 217 INDEX .............................................................................................................................................. 301

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

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

Oral Antihyperglycemic Therapy for Type 2 Diabetes: Scientific Review Source: JAMA. Journal of the American Medical Association. 287(3): 360-372. January 16, 2002. Summary: Care of patients with type 2 diabetes has been revolutionized throughout the past several years; first, by the realization of the importance of tight glycemic (blood glucose) control in forestalling complications, and second, by the availability of several unique classes of oral antidiabetes agents. Figuring out which agent to use in certain clinical situations is a new problem facing the primary care physician. This article reports on a systematic review of available data from the literature regarding the effectiveness of oral antidiabetes agents, both as monotherapy (alone) and in combination (more than one drug given at a time). Studies (n = 63) were included in the analysis if they had a study period of at least 3 months; if each group contained at least

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10 subjects at the study's conclusion; and if hemoglobin A1c (a measure of blood glucose levels over time) was reported. When multiple dosages of a drug were tested, the results of the highest approved dosage were used. Five distinct oral drug classes are now available for the treatment of type 2 diabetes. Compared with placebo treatment, most of these agents lower hemoglobin A1c levels approximately 1 to 2 percent. Equivalent effectiveness is usually demonstrated when different agents are compared with one another in the same study population. When they are used in combination, there are additional glycemic benefits. Long term vascular risk reduction has been demonstrated only with sulfonylureas and metformin. The mechanisms of action of the various oral antidiabetes agents are different and as a result they appear to have distinct metabolic effects. These are reflected in their adverse effect profiles and their effect on cardiovascular risk, which may influence drug choice. 1 figure. 4 tables. 154 references. •

Nonlinear Effect of Hyperglycemia and Current Cigarette Smoking are Major Determinants of the Onset of Microalbuminuria in Type 1 Diabetes Source: Diabetes. 50(12): 2842-2849. December 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Cigarette smoking and poor glycemic control are risk factors for diabetic nephropathy (kidney disease) in patients with type 1 diabetes. However, the specifics of the relation of these risk factors to the onset of this complication have not been elucidated. This article reports on a study that followed for 4 years 943 Joslin Clinic patients aged 15 to 44 years with type 1 diabetes who had normoalbuminuria (normal levels of protein in the urine) during the 2 year baseline period. Microalbuminuria developed in 109 of the 943 individuals, giving an incidence rate of 3.3 per 100 person years. The risk of onset of microalbuminuria was predicted somewhat more precisely by the measurements during the first and second years preceding onset than by all the measurements during the longer (4 year) interval, suggesting weakening of the impact of past hyperglycemia over time. Point estimates of the incidence rate (per 100 person years) according to smoking status were 7.9 for current smokers, 1.8 for past smokers, and 2.2 for those who had never smoked. In multivariate modeling, the independent effects of HbA1c level and cigarette smoking remained highly significant, but their magnitudes were reduced. The authors also investigated the relationship between HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time) and onset of microalbuminuria. The authors conclude that patients with type 1 diabetes who smoke and have an HbA1c level greater than 8 percent have the highest risk of onset of microalbuminuria. 2 figures. 3 tables. 37 references.

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Hyperglycemic Crises in Patients with Diabetes Mellitus Source: Diabetes Care. 25(Supplement 1): S100-S108. January 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemia (HHS) are the two most serious acute metabolic complications of diabetes, even if managed properly. This article presents the American Diabetes Association position statement on managing hyperglycemic (high blood glucose) crises in patients with diabetes mellitus. The position statement outlines precipitating factors and recommendations for the diagnosis, treatment, and prevention of DKA and HHS. The most common complications of DKA and HHS include hypoglycemia due to overzealous treatment with insulin,

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hypokalemia (low levels of potassium) due to insulin administration and treatment of acidosis with bicarbonate, and hyperglycemia secondary to interruption or discontinuance of intravenous insulin therapy after recovery without subsequent coverage with subcutaneous insulin. Many cases of DKA and HHS can be prevented by better access to medical care, proper education, and effective communication with a health care provider during an intercurrent illness. Because repeated admissions for DKA are estimated to drain approximately one of every two health care dollars spent on adult patients with type 1 diabetes, resources need to be redirected toward prevention by funding better access to care and educational programs tailored to individual needs, including ethnic and personal health care beliefs. 4 figures. 3 tables. 38 references. •

Morning Hyperglycemic Excursions: a Constant Failure in the Metabolic Control of Non-Insulin-Using Patients with Type 2 Diabetes Source: Diabetes Care. 25(4): 737-741. April 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: It has been observed in individuals with diabetes that blood glucose concentrations increased during the morning period and remained elevated over a time interval from breakfast to lunch, whereas progressive improvements in blood glucose were observed in more than two thirds of the patients during the second part of the daytime (diurnal). This article reports on research undertaken to determine if one or several hyperglycemia excursions exist that can contribute to general failures in the glycemic control of patients with type 2 diabetes. In 200 non insulin using patients with type 2 diabetes, daytime plasma glucose and insulin profiles were studied. Plasma glucose (blood sugar) concentrations were measured after an overnight fast (at 8:00 A.M. immediately before breakfast), during the postprandial period (at 11:00 A.M. and 2:00 P.M.), and during the postabsorptive period (at 5:00 P.M., extended postlunch time). In the population considered as a whole, prelunch glucose concentrations were found to be significantly increased when compared with those observed at 8:00 A.M., at 2:00 P.M., and at 5:00 P.M. Similar significant excursions in prelunch glucose were observed within subsets of patients selected from the following criteria: body weight, HbA1c, categories of treatment, and residual beta cell function. The relative contributions of postprandial (after a meal) and fasting glucose to the total glucose increment were found to be similar. The authors conclude that high plasma glucose excursions over morning periods seem to be a permanent failure in non insulin using patients with type 2 diabetes, whatever the clinical, biological, therapeutic, and pathophysiological status. Midmorning glucose testing should be recommended for detecting such abnormalities and for correcting them with appropriate therapies. 1 figure. 1 table. 25 references.

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Postchallenge Hyperglycemia in a National Sample of U.S. Adults with Type 2 Diabetes Source: Diabetes Care. 24(10): 1734-1738. October 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Postchallenge hyperglycemia (PCH, high levels of blood glucose, or sugar) is known to contribute to less than optimal glycemic control in adults with non insulinrequiring type 2 diabetes. This article reports on a study undertaken to estimate the prevalence of PCH among individuals with diabetes. The authors conducted a cross

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sectional analysis of data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988 to 1994) in adults aged 40 to 74 years with diabetes who were not using insulin (i.e., they used oral hypoglycemic drugs or received no drug therapy). Each respondent underwent a standard 75 gram oral glucose tolerance test. PCH was defined as a 2 hour glucose level greater than 200 milligrams per deciliter. Overall, PCD was present in 74 percent of those with diagnosed diabetes. Although it was present in virtually all (99 percent) of the adults with diabetes that was not under optimal control, PCD was also common (39 percent) in those patients whose diabetes was under optimal control. Likewise, in those patients receiving sulfonylurea drugs, PCH was present in 99 percent of those under suboptimal control and in 63 percent of those under good control. Similar patterns were observed in those with undiagnosed diabetes. The authors conclude that their data suggest PCH is common among adults with diabetes in the United States, even in the setting of 'optimal' glycemic control and sulfonylurea use. Interventions designed to lower postprandial (after a meal) glucose excursions may help improve overall glycemic control in the general population of U.S. adults with diabetes. 2 figures. 2 tables. 27 references. •

Pharmacy Update: Clinical Importance of Postprandial Hyperglycemia Source: Diabetes Educator. 27(5): 624-637. September-October, 2001. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: The role of elevated postprandial (after a meal) blood glucose levels in the etiology (cause) of diabetes related complications is of great concern. Interventions to manage both fasting and postprandial glucose levels are needed to reduce diabetes complications. This article helps diabetes educators understand these issues and the pharmaceuticals (drugs) available to help patients control hyperglycemia (high levels of blood glucose). One table summarizes the harmful effects of sustained hyperglycemia. Glycosylated hemoglobin (HbA1c, a measure of average blood glucose levels) measurements can be used to monitor both postprandial hyperglycemia (PPHG) as well as fasting plasma glucose (FPG) levels. Drugs discussed include insulin lispro (Humalog), insulin aspart (Novolog), acarbose (Precose), miglitol (Glyset), repaglinide (Prandin), natiglinide (Starlix), and tolbutamide (Orinase). The authors stress that the most efficient way to manage PPHG is to prevent it rather than to try to improve glucose disposal. Health care providers now have the medications that, when used in combination with self monitoring (SMBG), diet, and exercise, can near normalize blood glucose values, both fasting and after meals. Treatment programs for all appropriate diabetes patients should be intensified to bring HbA1c levels to less than 7 percent. 2 tables. 26 references.

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Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome Source: Diabetes Spectrum. 15(1): 28-36. 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article considers diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS), two acute complications of diabetes that can result in increased morbidity and mortality if not efficiently and effectively treated. Although there are important differences in their pathogenesis, the basic underlying mechanism for both disorders is a reduction in the net effective concentration of circulating insulin coupled with a concomitant elevation of counterregulatory hormones (glucagon,

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catecholomines, cortisol, and growth hormone). Mortality rates are 2 to 5 percent for DKA and 15 percent for HHS, and mortality is usually a consequence of the underlying precipitating cause(s) rather than a result of the metabolic changes of hyperglycemia. The authors discuss the pathogenesis, clinical presentation (symptoms), complications, and recommendations for treatment of DKA and HHS. Effective standardized treatment protocols, as well as prompt identification and treatment of the precipitating cause, are important factors affecting outcome. 2 figure. 2 tables. 48 references. •

Targeting Postprandial Hyperglycemia in Type 2 Diabetes with Acarbose Source: Practical Diabetology. 18(2): 45-48. June 1999. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Summary: This article discusses the treatment of postprandial hyperglycemia in people who have diabetes with acarbose. The clinician must understand the natural progression of diabetes to be able to select appropriate therapies. Most patients benefit initially from lifestyle interventions. Any oral agent that is selected as treatment should be targeted at both postprandial and fasting hyperglycemia. Alpha glucosidase inhibitors are therapeutic agents that lower postprandial blood glucose levels. These inhibitors include acarbose, miglitol, and voglibose. Acarbose, a nitrogen-containing pseudotetrasaccharide, was the first alpha-glucosidase inhibitor on the United States market. This agent reversibly inhibits the intestinal alpha-glucosidase enzymes responsible for digestion of complex carbohydrates and conversion of disaccharides to absorbable monosaccharides. Its overall effect is a delay in gastric emptying. Acarbose can be used in lean or obese patients, and it is beneficial for patients with high postprandial blood glucose and normal to slightly elevated fasting blood glucose levels. The agent is compatible with dietary goals, and it can be used with diet as a monotherapy or combined with other agents. Many patients eventually require combination insulin plus an oral antidiabetic agent. The article presents two cases that demonstrate the effectiveness of combining acarbose with multiple, daily insulin injections. In both patients, the addition of acarbose improved their glycemic control. In addition, the article discusses the practical implications of these cases. 2 figures. 15 references.

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Hyperglycemia and Cardiovascular Disease in Type 2 Diabetes Source: Diabetes. 48(5): 937-942. May 1999. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Fax (703) 683-2890. Summary: This article focuses on hyperglycemia and cardiovascular disease in type 2 diabetes. Cardiovascular disease is the most important cause of mortality and morbidity among patients who have type 2 diabetes. Conventional risk factors contribute similarly to macrovascular complications in patients who have type 2 diabetes and those who do not, so other explanations have been sought for enhanced atherothrombosis in type 2 diabetes. Among the characteristics specific to type 2 diabetes, hyperglycemia has recently been a focus of research. A recent meta analysis of 20 studies of nondiabetic subjects has demonstrated that in the nondiabetic range of glycemia, increased glucose is already associated with an increased risk for cardiovascular disease. Similarly, 12 recent prospective studies have convincingly indicated that hyperglycemia contributes to cardiovascular complications in patients who have type 2 diabetes. The recently published United Kingdom Prospective Diabetes Study (UKPDS) has shown that

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intensive glucose control effectively reduces microvascular complications among patients who have type 2 diabetes, but that its effect on preventing cardiovascular complications is limited. Given the fact that none of the treatment modalities in the UKPDS was particularly effective in reducing glucose, this underestimates the true potential of the correction of hyperglycemia in the prevention of cardiovascular disease in people with type 2 diabetes. However, in addition to intensive treatment for hyperglycemia, other conventional risk factors should also be normalized to prevent cardiovascular disease in patients with type 2 diabetes. 1 figure. 3 tables. 50 references. (AA-M). •

Hyperglycemic Crises: What They are and How to Avoid Them Source: Diabetes Self-Management. 18(4): 112-117. July-August 2001. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Website: www.diabetes-self-mgmt.com. Summary: This article focuses on the cause, prevention, and treatment of severe hyperglycemic conditions. The body constantly balances glucose extracted from foods and produced by the liver with glucose utilization by the body's tissues. Insulin lowers blood glucose levels both by slowing down the liver's glucose production and by helping the body's tissues to use glucose for its energy needs. Other hormones work against the action of insulin to raise blood glucose if the blood glucose level falls too low. In people who have diabetes, this balance is disrupted because they either do not make any insulin (type 1 diabetes) or because they do not produce enough insulin or do not properly respond to insulin (type 2 diabetes). High blood glucose and lack of insulin set the stage for the complication of diabetic ketoacidosis (DKA). Another complication, hyperosmolar hyperglycemic state (HHS), also starts with hyperglycemia and insulin insufficiency. Although either of these conditions can occur in anyone with diabetes, DKA more commonly affects people with type 1 diabetes and HHS more commonly affects those with type 2 diabetes. The most common trigger for a hyperglycemic crisis is an infection. DKA and HHS can be prevented by keeping hyperglycemia from occurring through monitoring blood glucose regularly and learning to adjust insulin dose properly. DKA is the most common diabetes related cause of hospitalization and death in children who have diabetes, so parents need to find a balance between giving children responsibility for their diabetes care and taking a supportive and active role in helping them maintain good self care habits. Skipping insulin to control weight can lead to DKA, so people should not do this. Alcohol use can cause dehydration, leading to DKA and HHS, so alcohol should be consumed in moderation. Both DKA and HHS usually require treatment in an emergency room. Hyperglycemic crises are treated with intravenous saline solution, insulin, and potassium. The article includes guidelines people should follow when they are sick to avoid DKA or HHS.

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Glucose Monitoring of the Arm: Risky Delays of Hypoglycemia and Hyperglycemia Detection Source: Diabetes Care. 25(6): 956-960. June 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study that examined whether rapid changes in blood glucose (BG) result in clinically relevant differences between capillary BG values measured at the forearm and the fingertip and whether local rubbing of the skin before blood sampling can diminish such differences. In the fasting state, the BG values at the

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fingertip and at the forearm were similar. However, during rapid increase in glucose, BG values at the fingertip were consistently higher than at the forearm. During rapid decrease in glucose, lower BG values were recorded at the fingertip. At the forearm, BG was delayed by a median of 35 minutes in relation to the fingertip. Rubbing of forearm skin decreased the observed differences but with a large intraindividual and interindividual variability. There were no obvious device-specific differences (three different meters were tested). The authors conclude that to avoid risky delays of hyperglycemia (high blood glucose) and hypoglycemia (low blood glucose) detection, BG monitoring at the arm should be limited to situations in which ongoing rapid changes in BG can be excluded. 2 figures. 1 table. 21 references. •

Relationship between Gastric Emptying and an Alpha-Glucosidase Inhibitor Effect on Postprandial Hyperglycemia in NIDDM Patients Source: Diabetes Care. 20(10): 1529-1532. October 1997. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 342-2383. Website: www.diabetes.org. Summary: This article reports on a study undertaken to examine the relationship between gastric emptying and the efficacy of an alpha glucosidase inhibitor in patients with type 2 diabetes (noninsulin dependent diabetes mellitus). Sixteen patients with type 2 diabetes (4 patients treated with diet therapy alone and 12 receiving a sulfonylurea) were given 0.6 mg of voglibose daily for 4 weeks. The efficacy of voglibose was assessed by measurement of HbA1c, fasting plasma glucose, and 45 and 120 minute postprandial plasma glucose (PPG) and serum insulin concentrations before and after the 4 weeks of voglibose therapy. Gastric emptying was evaluated measuring the plasma acetaminophen concentration at 60 minutes after ingestion of a liquid test meal containing 20 mg per kg of acetaminophen. These measurements were also taken before and after the therapy. The mean 45 minute and 2 hour PPG levels were reduced significantly after 4 weeks of voglibose. Two-hour postprandial serum insulin concentrations were also significantly reduced at the end of the treatment period. There was no significant difference in the plasma acetaminophen concentrations between pretreatment and posttreatment periods. The authors conclude that the rate of gastric emptying affects the efficacy of voglibose therapy in patients with type 2 diabetes. Voglibose did not, however, alter the rate of gastric emptying. 4 figures. 1 table. 17 references. (AA-M).

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Cochlear Dysfunction in Type 2 Diabetes: A Complication Independent of Neuropathy and Acute Hyperglycemia Source: Metabolism. 48(11): 1346-1350. November 1999. Contact: Available from W.B. Saunders Company. Metabolism, Periodicals Department, P.O. Box 628239, Orlando, FL 32862-8239. (800) 654-2452. Summary: This article reports on a study which investigated the effects of type 2 diabetes mellitus on evoked otoacoustic emissions (eOAEs) elicited by clicks in subjects with normal hearing; the involvement of the central (CNS) and peripheral nervous system and acute hyperglycemia were also investigated. In Study I, 110 patients with type 2 diabetes and 106 controls were investigated by eOAEs; central and peripheral neuropathy were evaluated respectively by auditory brainstem responses (ABR) and according to San Antonio Consensus Conference criteria. In Study II, 10 healthy men and 10 men with type 2 diabetes, all with normal eOAEs, underwent a 5 hour hyperglycemic clamp study (eOAEs were performed before and during the

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hyperglycemic clamp). In Study I, eOAEs were impaired in 51.8 percent of the subjects with diabetes, compared to 4.7 percent of the controls. People with diabetes and impaired eOAEs, in comparison to those with normal eOAEs, were older, had diabetes longer, achieved poorer metabolic control, and had more peripheral neuropathy. In Study II, there were no significant changes in eOAE intensities compared with basal values during the entire hyperglycemic clamp in either diabetic or control subjects. The eOAE dysfunction does not associate with either an injury to the auditory nervous pathway or diabetic microvasculopathy. The apparent interference of peripheral neuropathy in eOAEs loses significance when corrected for the duration of diabetes. 1 figure. 5 tables. 30 references. •

UKPDS 59: Hyperglycemia and Other Potentially Modifiable Risk Factors for Peripheral Vascular Disease in Type 2 Diabetes Source: Diabetes Care. 25(5): 894-899. May 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a subset study undertaken to determine the role of hyperglycemia (high blood glucose levels) in prospective analyses of peripheral vascular disease (PVD) in type 2 diabetes, taking into account other potential risk factors. Potential risk factors for the development of PVD were examined in 3,834 of 5,102 individuals enrolled in the United Kingdom Prospective Diabetes Study (UKPDS) without PVD at diagnosis of diabetes, followed for 6 years, and for whom relevant data were available. Hyperglycemia, assessed as HbA1c (a measure of blood glucose levels over time), was associated with an increased risk for incident PVD, independent of other risk factors including age, increased systolic blood pressure, reduced HDL cholesterol, smoking, prior cardiovascular disease, peripheral sensory neuropathy, and retinopathy. Each 1 percent increase in HbA1c was associated with a 28 percent increased risk of PVD and each 10 mmHg increase in systolic blood pressure with a 25 percent increase in risk. The authors conclude that hyperglycemia, as well as smoking, dyslipidemia, and blood pressure, are potentially modifiable risk factors for the development of PVD. 3 figures. 2 tables. 37 references.

•

Controlling Hyperglycemia in the Hospital: A Matter of Life and Death Source: Clinical Diabetes. 18(1): 17-24. 2000. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article uses a question and answer format to provide health professionals with information on the importance of controlling hyperglycemia in hospitalized patients. The hospital setting provides a unique opportunity to identify patients who may have unrecognized diabetes, thus hyperglycemia should be aggressively controlled from the time of admission regardless of the primary medical problem or the previous diabetes status of the patient. The article explains why the hospital is the best place to find unrecognized diabetes and why hyperglycemia is so easy to overlook when a hospitalized patient is acutely ill or is facing a life threatening illness, presents evidence on the beneficial effects of treating hyperglycemia in hospitalized patients, and discusses the treatment of hyperglycemia caused by medications. Other topics include the diagnostic role for hemoglobin A1c, the effect of diabetes on a primary medical condition, and the deleterious short term effects of hyperglycemia. In addition, the article reviews data from inpatient studies evaluating

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the impact of potentially correcting the pathophysiological changes that accompany hyperglycemia among patients with myocardial infarct and stroke and those undergoing coronary artery bypass surgery. These studies suggest that treatment of hyperglycemia can potentially affect morbidity and mortality. The article concludes with a discussion on the need for a new hospital paradigm for glycemic control. Although the subcutaneous sliding scale regimens have been a hospital standard, there is no evidence demonstrating their efficacy, and some literature suggests that subcutaneous coverage alone may be detrimental to glycemic control. However, newer technology may improve the monitoring of glucose and treatment of hyperglycemia. 3 figures. 1 table. 81 references. •

Management of Hyperglycemic Crises in Patients with Diabetes Source: Diabetes Care. 24(1): 131-153. January 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This review article presents updated recommendations for management of patients with hyperglycemic crises based on the pathophysiological basis of these conditions. Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are two of the most serious acute metabolic complications of diabetes. A common precipitating factor in the development of these hyperglycemic crises is infection. Other factors include omission of insulin or undertreatment with insulin, alcohol abuse, trauma, pulmonary embolism, and myocardial infarction. Various drugs that alter carbohydrate metabolism and excessive use of diuretics in the elderly may also precipitate the development of DKA and HHS. Psychological factors and poor compliance are important precipitating factors for recurring ketoacidosis. The basic underlying mechanism for DKA and HHS is a reduction in the net effective action of circulating insulin coupled with a concomitant elevation of counterregulatory hormones. Diagnosis involves obtaining a medical history, performing a physical examination, and conducting laboratory tests. Successful treatment of DKA and HHS requires correcting dehydration, hyperglycemia, and electrolyte imbalances; identifying comorbid precipitating events; and monitoring the patient frequently. The article presents guidelines for fluid therapy; insulin therapy; and potassium, bicarbonate, and phosphate therapy. In addition, the article identifies the most common complications of DKA and HHS, including hypoglycemia, hypokalemia, cerebral edema, adult respiratory distress syndrome, and hyperchloremic metabolic acidosis. Measures to prevent DKA and HHS include better access to medical care, proper education, and effective communication with a health care provider during an intercurrent illness. 7 figures. 7 tables. 220 references.

•

Control of Postprandial Hyperglycemia: Optimal Use of Short-Acting Insulin Secretagogues Source: Diabetes Care. 25(12): 2147-2152. December 2002. Contact: Available from American Diabetes Association (ADA). 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This study was designed to compare the efficacy of acute premeal administration of glipizide versus nateglinide in controlling postprandial (after a meal) hyperglycemia in subjects with non-insulin- requiring type 2 diabetes. A total of 20 subjects (10 female, 10 male) with non-insulin-requiring type 2 diabetes were admitted overnight to the General Clinical Research Center on four occasions. The subjects were

12

Hyperglycemia

aged 56 years, plus or minus 2 years, and were moderately obese, with a mean HbA1c of 7.4 percent. Peak and integrated glucose excursions did not differ significantly between glipizide and nateglinide. However, by 4 hours postmeal, plasma glucose levels were significantly higher with nateglinide compared with the premeal baseline and compared with the 4 hour postprandial glucose level after administration of glipizide. Early insulin secretion, as measured by insulin levels at 30 minutes postmeal, did not differ between glipizide and nateglinide. The authors conclude that the clinical decision to use glipizide versus nateglinide should be based on factors other than the control of postprandial hyperglycemia in type 2 diabetes. 3 figures. 1 table. 25 references.

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

Project Title: AMADORI-MODIFIED ALBUMIN IN DIABETIC NEPHROPATHY Principal Investigator & Institution: Ziyadeh, Fuad N.; Associate Professor; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 14-AUG-1998; Project End 31-JUL-2004 Summary: The mechanisms mediating kidney damage in diabetes mellitus undoubtedly stem from chronic hyperglycemia, but the intermediary steps are not completely understood. Evidence is accumulating that increased nonenzymatic glycation of proteins represents a mechanistic link between hyperglycemia and renal pathobiology. Glucose-derived modifications of proteins alter their functional and structural properties. In vivo, circulating glycated proteins principally exist as Amadori products (as opposed to advanced glycation products), and their concentration is significantly increased in diabetes with exposure to a hyperglycemic milieu. Recent focus on pathophysiologic events induced by advanced glycation has shifted attention from the possible role of Amadori- modified proteins in the development of diabetic complications. However, our published data with mesangial cells in culture and in the db/db diabetic mice have show that: Amadori-modified glucose adducts in albumin (GA) induce significant alterations in glomerular cell biology that resemble those of transforming growth factor-beta (TGF-b), a multi- functional cytokine with potent anti-

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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proliferative and pro-fibrogenic activity; increased GA in diabetes is linked to increased bioactivity of the TGF-b/TGF-b receptor system; and neutralization of biologically active epitopes in GA ameliorates the structural and functional abnormalities characteristic of diabetic renal disease in db/db mice. The general plan of this project is to further investigate the role of GA and its molecular mediators in the increased accumulation of extracellular matrix (ECM) and the decrement in renal function characteristic of diabetic nephropathy. The Specific Aims are 1) to establish that increased expression of TGF-b1 is required for GA- stimulated ECM production; 2) to investigate that mechanism(s) underlying the increased expression of the TGF-b signaling receptors in mesangial cells grown with GA; 3) to examine the nature of the intracellular signal that mediates the stimulatory effect of GA on the production of TGFb1; and 4) to establish that GA mediates up-regulation of the TGF-b1/TGF-b receptor system in the kidney and promotes long-term renal pathobiology in diabetic mice. A major component of these studies will be interventional arms in which we will administer neutralizing anti-GA and anti-TGF-b murine monoclonal antibodies to diabetic mice to prove that mesangial ECM expansion is caused by up-regulation of the renal TGF-b system. Understanding the mechanisms underlying up- regulation of the renal TGF-b system resulting from increased concentrations of GA may lead to the conceptual design of novel therapeutic interventions that could prevent the deleterious effects of diabetes on the kidney. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIOXIDANT & HYPERGLYCEMIA INDUCED PROCOAGULANT STATE Principal Investigator & Institution: Boden, Guenther; Professor; Medicine; Temple University 406 Usb, 083-45 Philadelphia, Pa 19122 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): Diabetes is associated with an increased incidence and prevalence of premature atherosclerotic vascular disease and mortality. The reason for this is not well understood, but is likely to be related, at least in part, to a procoagulant state existing in diabetes. We have recently shown that prolonged hyperglycemia/hyperinsulinemia (about 200 mg/dl x 18-72 h) but not euglycemiahyperglycemia activated the tissue factor (TF) pathway of blood coagulation in healthy young men as evidenced by a rise in plasma factor VIla and factor VII coagulant activity and by elevated TF pathway inhibitor and FVHL This suggested an enhanced potential for acute thrombosis during hyperglycemia when coagulation mechanisms are triggered by intense exposure to tissue factor, such as during plaque rupture. In the proposed project, we plan to test the hypotheses that 1) selective hyperglycemia is as effective as hyperglycemia-hyperinsulinemia in activating the TF pathway; 2) hyperglycemia induces expression of IF in monocytes; 3) in non-diabetic subjects, hyperglycemia mediated activation of the TF pathway of blood coagulation can be prevented or reduced with antioxidants; 4) that the procoagulant state in diabetes is, at least partially, caused by hyperglycemia and can be reduced by either strict glycemic control or with antioxidants (at co-existing hyperglycemia). We will test these hypotheses 1) in obese and non-obese non-diabetic and obese diabetic subjects by determining effects of prolonged (48 h) hyperglycemia (about 200 mg/d1) on IF pathway factor (VIla, VIIc, TF pathway inhibitor) and other coagulation proteins (factor VIII) and markers of thrombin generation (prothrombin fragment 1+2, thrombinantithrombin complex) with and without administration of antioxidants (Vitamin C or Vitamin E) and 2) in patients with Type II diabetes by determining effects of strict

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Hyperglycemia

euglycemic control (for 5 days) on IF pathway activity. We believe that this model of prolonged hyperglycemia (with or without hyperinsulinemia) is uniquely suited to study in vivo effects of therapeutic interventions, including lowering of blood glucose and administration of antioxidant vitamins, on the TF pathway of blood coagulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIRETROVIRAL THERAPY AND LONG-TERM CLINICAL OUTCOMES Principal Investigator & Institution: Kitahata, Mari M.; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (adapted from the application s abstract): Recent advances in antiretroviral therapy have dramatically changed the treatment and clinical outcomes for persons with HIV infection. The goal of therapy has expanded from delaying HIV disease progression and death to suppressing viral replication below the level of quantitation for as long as possible to permit immunologic improvement and clinical stabilization. However, now there is a growing proportion of patients who cannot maintain viral suppression often despite changing and more complex therapeutic regimens. The candidate hypothesis s that in the clinic setting, in contrast to the clinical trials setting, a steadily increasing proportion of patients will not have sustained suppression of viral replication over the long-term. Better definition of the generic relationship between longitudinal urologic and immunologic measures and long-term clinical outcomes across the enormous number of antiretroviral combinations available, will become increasingly essential to clinicians. In addition, there is a need to assess potential survival benefits of early and prolonged potent antiretroviral treatment in relation to the long-term effects of treatment-related events, such as neuropathy and metabolic complications (e.g. hyperlipidemia, hyperglycemia), on health-related quality-of-life and quality-adjusted survival. To complement and extend information available from clinical efficacy trials, the investigator proposes an epidemiological investigation of predictors of AIDS-free survival and quality-adjusted survival among HIV infected individuals receiving potent combination antiretroviral therapies. For this purpose, she has developed a computerized medical information system at the University of Washington that captures real-time clinical practice information for an HIV clinic population in the Northwest. Collection of comprehensive longitudinal information about HIV infected patients in this clinic setting, may enable the candidate to develop sets of measures of virologic, immunologic, and clinical responses to potent antiretroviral treatment that best predict long-term clinical outcomes. The mentoring and additional training provided by the Mentored Patient-Oriented Research Award will provide the candidate with an opportunity to devote significant efforts to research questions using the clinical information system and to develop the skills necessary to pursue a research career that blends epidemiological approaches and health services research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ATHEROSCLEROSIS, DIABETES AND LPL Principal Investigator & Institution: Semenkovich, Clay F.; Professor; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2006 Summary: Diabetes is lethal. Most people with diabetes will die prematurely of vascular disease. Our long term objective is to clarify the mechanisms underlying atherosclerosis

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in diabetes. Type 2 diabetes is an especially important public health problem characterized by abnormal fatty acid metabolism in addition to hyperglycemia. Abnormal fatty acid metabolism precedes hyperglycemia during the progression from insulin resistance to beta cell failure in type 2 patients, suggesting that fatty acids may contribute to the high rate of vascular disease seen in such patients at the time of diagnosis. The experiments in this application will test the hypothesis that fatty acid metabolism in the vessel wall promotes atherosclerosis in part through effects on expression of the alpha-v beta3 integrin. We will pursue four specific aims, all involving apolipoprotein E null mice: 1) To determine if overexpression of lipoprotein lipase enzyme activity in vascular smooth muscle cells affects atherosclerosis and alpha-v beta3 integrin expression. 2) To determine if overexpression of PPARalpha in vascular smooth muscle cells or endothelium affects atherosclerosis and alpha-v beta3 integrin expression. 3) To determine if overexpression of the beta3 integrin subunit in vascular smooth muscle cells or endothelium affects atherosclerosis. 4) To determine if tissuespecific PPARalpha deficiency (achieved with Cre-loxP technology) in the vessel wall affects atherosclerosis and alpha-v beta3 integrin expression. This project has the potential to prove the concept that altering fatty acid metabolism in the native cells of the artery wall affects atherosclerosis. These experiments could lead to innovative strategies for the treatment of vascular disease in diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AUTONOMIC FUNCTION IN INSULIN RESISTANCE AND DIABETES Principal Investigator & Institution: Carnethon, Mercedes R.; Preventive Medicine; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): This proposal describes a 3-year mentored training program during which the candidate will substantially enhance her knowledge in cardiovascular and endocrine function, acquire additional skills in the clinical assessment of cardiovascular autonomic function, and increase her experience designing and conducting a population-based study. While the candidate has formal training in cardiovascular disease epidemiology, she has no training or experience in the above referenced areas that are critical for success in her area of research. Dr. Philip Greenland, a clinician and epidemiologist who Chairs the Department of Preventive Medicine (DPM), will oversee the scientific and career development aspects of the candidate as described in this proposal as the primary mentor. In addition, Dr. Alan Kadish in the Division of Cardiology, will oversee the candidate's training in cardiovascular electrophysiology and in the assessment of autonomic tone, and Dr. Kiang Liu, a biostatistician/epidemiologist will mentor the candidate in the design and recruitment aspects of the proposed population-based study. Research in this proposal will focus on the temporal association between the autonomic nervous system (ANS) and the development of diabetes and cardiovascular complications from diabetes. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in persons with diabetes, and the ANS has been proposed as a mechanism to explain the association between diabetes and CVD. ANS dysfunction was previously thought to be a late-onset complication of diabetes that was the result of hyperglycemia-associated degradation of the microvasculature. However, evidence that the ANS plays a role in the regulation of glucose and fat metabolism, even in the absence of frank diabetes, makes it plausible that ANS dysfunction occurs early in the temporal sequence for disease. This study proposes to extend beyond previous epidemiological research that

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Hyperglycemia

has identified the presence of ANS dysfunction in early diabetes, by assessing the type and extent of impairment using tools that have traditionally been used only at the clinical level. The PI hypothesizes that ANS function, as estimated by autonomic innervations, resting autonomic tone, and the autonomic response to physical and pharmacological provocation, predisposes persons to the development of diabetes and diabetes complications, including CVD, when impaired. Specific aims are to: 1) investigate the temporal sequence between ANS dysfunction and the development of diabetes in two established epidemiology studies using available measurements; 2) learn to implement and compare a comprehensive battery of ANS function tests; and, 3) recruit a population sample to compare the cross-sectional relationship between this battery of ANS function tests among healthy persons, persons who are insulin resistant but not diabetic, and persons who are diabetic. Data from these investigations will be used to modify hypotheses and develop a future prospective examination focused on the type and temporal sequence of autonomic impairment in persons with varying levels of insulin resistance, glucose uptake and metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOCHEMICAL CATARACTOGENESIS

MECHANISM

OF

OXIDATIVE

Principal Investigator & Institution: Ansari, Naseem H.; Associate Professor; Human Biol Chem and Genetics; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-JUL-2003 Summary: Reactive oxygen species (ROS) causing oxidative stress to the ocular lens have been implicated in cataracts of various etiologies. However, the mechanism of how the ROS propagate the injury is not well established. Based upon our demonstration that under oxidative stress, a large amount of lipid-derived aldehydes (LDAs), especially 4hydroxynonenal, is formed in the ocular lens, we hypothesize that LDAs act as toxic messengers that mediate the injurious cataractogenic effects of ROS. We propose that LDAs extend oxidative injury in the lens by causing modifications to membrane proteins (including gap junction and channel proteins), resulting in altered membrane fluidity and calcium homeostasis, leading to apoptosis and cataract. Since LDAs are extremely reactive, exact measurement of their in vivo concentration has been problematic. To quantitate LDAs formed under oxidative stress in rat lens, and assess whether scavenging of LDAs prevents the formation of protein-LDA adducts we will use a cell-permeable tetrapeptide (N-acetyl-Asn-Tyr-Thr-Cys-NH2; NYTC) which readily binds LDAs. The 125I-NYTC-LDA conjugates will be separated by HPLC, quantified by radioactivity determination and characterized by ESI-MS (Aim 1). To understand the mechanism(s) of LDA-mediated injury, we will quantify and identify protein-LDA adducts in cataractous lenses, and will correlate the extent of protein modification to alterations in membrane fluidity, calcium homeostasis and induction of apoptosis and assess whether scavenging of LDAs by NYTC prevents the injury (Aim 2). We have recently shown that LDAs are cataractogenic. However, the metabolic pathways through which the lens detoxifies LDAs, and how these toxicants cause cataract, are not known. Therefore, we will identify the major metabolites of LDAs and assess the relative significance of individual metabolic pathways for LDAs in the ocular lens. We will further investigate whether the metabolism of LDAs in the lens is altered with age and/or hyperglycemia (Aim 3). We will also augment the metabolism of LDAs in a human lens epithelial cell line (HLEC) by overexpressing a relevant glutathione-Stransferase isozyme (which conjugates the LDAs to GSH), and aldehyde dehydrogenase

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(which catalyzes LDA oxidation), and ask whether such augmentation abrogates oxidative injury (Aim 4). Completion of our proposal will clearly establish the role of oxidative stress in the age related cataractogenesis, especially the mechanism through which ROS-induced injury is propagated. The use of NYTC should provide the basis for novel and more targeted therapeutic strategies for ameliorating cataractogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BRAIN IMMUNE INTERACTIONS IN TYPE 2 DIABETES Principal Investigator & Institution: Freund, Gregory G.; Pathology; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2004; Project Start 01-MAR-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Type 2 diabetes mellitus (DM) is the sixth leading cause of death in the United States. Recently type 2 DM has been linked to subacute chronic inflammation as shown by elevated levels of inflammatory cytokines like interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha in persons with preand frank diabetes. In addition, glucocorticoid levels are increased in type 2 DM indicating activation of the hypothalamic-pituitary-adrenal (HPA) axis. New research from our laboratory shows that the BKS.Cg-m +/+ Leprdb (db/db) mouse model of type 2 DM has marked alterations in sickness behavior and innate immunity. We found that db/db mice are hyper-responsiveness [sic] to lipopolysaccharide (LPS) demonstrating increased fever and reduced social exploration. We also observed that these mice are more sensitive to IL-1beta showing increased loss of social exploration when compared to similarly treated heterozygote control (db/+) mice. Importantly, we have identified potential mechanisms to account for these abnormalities. These causes include hyperinsulinemia-induced serine phosphorylation of insulin receptor substrates (IRSs) blocking cytokine action and hyperglycemia-dependent protein kinase C (PKC)delta activation negatively regulating innate immunity. Therefore, the objective of this research project is to examine the hypothesis that type 2 DM induces a stress disorder that enhances brain responsivity to pro-inflammatory cytokines. The long-term goal of this project is to understand the mechanism by which type 2 DM augments innate immunity, inflammation and sickness behavior. These objectives and goals will be pursued in the following four Specific Aims. In Objective 1, we will examine the physiologic cause of increased fever and loss of social exploration in LPS-challenged db/db mice. In Objective 2, we will determine how hyperinsulinemia in pre-diabetes negatively regulates signaling of the anti-inflammatory cytokine IL-4. In Objective 3, we will investigate the mechanism by which hyperglycemia augments innate immunity. In Objective 4, we will use a pharmacologic approach to reduce susceptibility to increased fever and sickness behavior in db/db mice. These studies are needed to understand how diabetes-associated chronic inflammation affects the neuroimmune system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CARBOHYDRATE AND PROTEIN METABOLIC PATHWAYS Principal Investigator & Institution: Landau, Bernard R.; Professor of Medicine and Biochemistry; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-MAY-1978; Project End 31-MAR-2005 Summary: (Provided by applicant): Carbohydrate, protein and lipid abnormalities characterize diabetes mellitus. Long-term objectives are to develop and apply novel methods significantly advancing understanding of those metabolic processes and their

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regulation in physiological and pathological states in human, and particularly in diabetes. Advantage is taken of 2H2O use to quantitate the pathways followed. Methods have been introduced for carbohydrate and lipid. The major new goal is to develop and apply a method for quantitating protein metabolism. The method for quantitating carbohydrate metabolism will also be further extended. Focus then is on 1) the quantitation of protein synthesis and proteolysis; 2) the contribution to glucose production of gluconeogenesis whose increase in diabetes has been related to the degree of hyperglycemia and 3) the extent of simultaneous hepatic glycogen synthesis and breakdown, called glycogen cycling, which could help explain decreased liver glycogen content found in type 2 diabetes and exacerbate hyperglycemia on glucose ingestion. There are 4 specific aims: 1) To develop and apply a method for quantitating the extent transaldolase reactions contribute to estimates of gluconeogenesis; 2) To evaluate the validity of a method using glucose isotopomers, introduced as a simple method to measure the contribution of gluconeogenesis, in comparison with 2H2O use; 3) To develop a method for quantitating glycogen cycling in the fed state by measuring, along with the rate of hepatic glycogen deposition on glucose intake, how much of the glycogen is formed directly from the glucose, how much from three carbon compounds, and how much from glycogen that is reconverted to glycogen, i.e. glycogen cycling; 4) To develop a method to estimate protein synthesis from labeling of protein by 2H2O, and proteolysis from loss of that label. Initial application of this method will be to renal failure patients undergoing hemodialysis, in whom ingested 2H2O can be removed by dialysis to readily follow loss of incorporated label without continued synthesis of labeled protein. Application first to the renal failure state is done with recognition that nephropathy is a major complication in the diabetic and the potential benefit of a simple method for evaluating the effects of the therapeutic approaches on protein dynamics in that condition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR MECHANISM OF DIABETIC NEPHROPATHY Principal Investigator & Institution: Feng, Lili; Professor; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: The objective of this proposal is the understanding of cellular mechanisms associated with the progression of diabetic nephropathy. Diabetic nephropathy is the single largest cause of end-stage renal failure in the United States. The disease is believed to be triggered by hyperglycemia in diabetes mellitus, Previous studies by others and us have show that increased expression of cytokines and growth factors play an important role in the development of kidney disease. The mitogen- activated protein kinase (MAP kinase) family members are involved in the activation of cytokines and growth factors in renal cells exposed to high glucose, but also participate in the subsequent signal transduction of these cytokines and growth factors to mediate further cellular changes. Inhibition of a MAP kinase family member, p38, by a selective inhibitor dramatically suppressed the progression of diabetic nephropathy in a rat model (streptozotocin-induced diabetes), and activation of p38 significantly accelerated the development of diabetic nephropathy. In this application, we propose to carry out studies designed to determine the function of each MAP kinase family member in diabetic nephropathy. Specifically, we will address the role of these MAP kinases in high glucose-induced gene expression and in growth factor- and cytokine- induced renal cell activation, utilizing biochemical, molecular biological, and immunological approaches. In vivo experiments will be performed to confirm the results obtained in the

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in vitro studies and to develop a better understanding to the role of MAP kinases in various stages of the pathogenesis of diabetic nephropathy. Insights gained in the proposed studies will lead to the development of new therapeutic strategies to this lifethreatening disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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 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: CLONING OF A TYPE 2 DIABETES MODIFIER IN OBESE MICE Principal Investigator & Institution: Leibel, Rudolph L.; Professor and Head; Pediatrics; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Type 2 diabetes mellitus (T2DM) affects over 5% of the US population, causing tremendous suffering with annual direct medical costs of over $100 billion. In both humans and rodents, susceptibility to T2DM in the context of obesity is powerfully influenced by genes that have not been identified. The inherent complexity of identifying such susceptibility genes in humans led us to use a biallelic

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system in enetically obese mice to identify candidate genes and pathways for T2DM that can then be tested in humans. In F2 progeny of a B6/DBA murine cross segregating for Lep-ob, we mapped a T2DM locus to a region of murine Chr1 (p<10[-8]), syntenic to human lq23. This mouse interval lies in the middle of, and is about 1/10th the physical size of, the human interval at lq23 repeatedly identified as containing diabetes susceptibility genes in human linkage studies. The diabetic endophenotypes of the obese F2 progeny of this cross are maintained in the genetically obese members of a B6.DBA N12 congenic line segregating about 5 Mb of DBA DNA from the mouse region 1at 86. The associated phenotypes in the congenic animals are: hypoinsulinemic hyperglycemia, elevated HbA1c, and hypoplastic/hypotrophic beta cells. We propose to systematically identify and analyze all genes in the DBA congenic interval, using informatics and molecular biological techniques that we have developed. The steps will include: 1.) accession and analysis of all DNA sequence for the B6.DBA congenic interval that will be further reduced by fine mapping. 2.) identification of all transcripts by computational techniques, confirmed by expression analysis in pooled organ RNAs. 3.) sequence comparisons between B6 and DBA to identify all non-synonymous coding variants in these transcripts. Identification and sequence comparison of canonical promoter elements in 1500 bp 5' of coding sequences. 4.) computational assessment of effects of coding and non-coding variants on secondary protein structure/function and transcription. 5.) analysis of in vivo/in vitro beta cell function and skeletal muscle insulin response at 30 and 60 days in congenic animals by interval DBA dose. 6.) based upon in vitro in vivo studies, quantitative gene expression analysis (B6 v. DBA) of selected transcripts in selected organs using quantitative PCR. 7.) in vitro analysis of the functional consequences of candidate coding and regulatory sequence variants. 8.) for the most compelling sequence variants, preparation of transgenic B6 knock-ins of the DBA alleles and assessment of the relevant diabetes phenotypes in the progeny. 9.) in over 5000 individuals who have participated in studies of T2DM linked to 1q23, examine orthologous candidate genes. If successful, this project could identify a major gene (and possibly a novel pathway) for diabetes susceptibility in the context of obesity. Such a gene could be used for anticipatory diagnosis and prevention, and the design of therapeutic agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTROL OF PANCREAS GROWTH/DEVELOPMENT Principal Investigator & Institution: Kim, Seung K.; Associate Professor; Developmental Biology; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 15-JUN-2001; Project End 31-MAY-2005 Summary: (Scanned from the applicant's abstract) Growth and function of the mammalian endocrine pancreas are regulated by intercellular signaling pathways. Juvenile and adult pancreatic islet cell growth and function adapt to maintain euglycemia in response to host growth, hyperglycemia, insulin resistance and obesity, and failure by the endocrine pancreas to compensate for these states can lead to diabetes mellitus. While control of endocrine pancreas growth and function are crucial for glucose homeostasis, little is known about the genes that maintain pancreatic endocrine cell growth, differentiation, and function to prevent beta-cell failure. The overall goal of this proposal is to elucidate pancreatic intercellular signaling mechanisms that govern islet cell growth and function. This study will focus on Smad2, a gene encoding an essential component in the transforming growth factor-beta (TGF-beta) signaling pathway, which has been previously shown to regulate embryonic pancreas development and adult pancreas function. In mice with a germline Smad2 null allele,

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generated by conventional gene disruption strategies, embryonic endocrine pancreas development and adult-stage endocrine pancreas function are impaired. Experiments in this application will test the hypothesis that Smad2-mediated TGF-beta signals regulate pancreatic cell interactions that are crucial for pancreatic beta-cell development and function. This proposal's specific aims are to: (1) Elucidate roles of Smad2 in endocrine pancreas growth and function by using recently-developed in vivo gene targeting methods to inactivate Smad2 in a defined set of pancreatic endocrine cells. (2) Determine if Smad2-mediated TGF-beta signals prevent beta-cell failure, by measuring compensatory beta-cell growth and insulin secretion after Smad2 inactivation in insulin resistant animals. (3) Assess changes in pancreatic development and function following Smad2 over-expression in specific pancreatic endocrine cells. (4) Determine if TGF-beta signaling maintains post-natal bet-cell functions, by inactivating Smad2 specifically in adult stage animals using novel in vivo gene disruption methods. Treatment for inadequate beta-cell function, whether from autoimmunity, or from failure to compensate for increased insulin resistance, might be improved by therapies that stimulate beta-cell growth and regulated insulin secretion. The genetic, molecular and physiologic analyses of Smad2-mediated TGF-beta signaling will add to our understanding of the principles of vertebrate organogenesis, and may lead to new cellreplacement strategies for diabetes mellitus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEPRESSION AND BRAIN STRUCTURE IN TYPE 1 DIABETES Principal Investigator & Institution: Jacobson, Alan M.; Senior Vice President; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): There is growing evidence that type 1 diabetes leads to an increased prevalence of depressive disorders and preliminary data suggesting that the metabolic disturbances associated with diabetes, both severe hypoglycemia and persistent hyperglycemia, lead to changes in brain structure and cognition. These findings, together with research on structural changes in the brain among depressed patients without diabetes, suggest that diabetes could cause structural changes in the brain that lead to depression. No studies have evaluated mechanisms underlying the etiology of depression among patients with type 1 diabetes. Using a cross sectional research design, we propose to study six groups of subjects: All subjects (N = 180) will be ages 30-40, right-handed and matched according to age, gender and SES. Diabetic patients will have between a 15-25 year history of types of diabetes. There will be three groups of diabetic subjects without psychiatric history: 1. Well controlled (0-1 episodes of severe hypoglycemia; mean HbA1c over history of diabetes equal to or 3 episodes of severe hypoglycemia; mean HbA1c over time equal to or 9.0%; 0-1 hypoglycemic episodes). A fourth group of diabetic subjects with a history of unipolar major depression and who equally represent the glycemic control characteristics of the other three diabetic groups will also be studied. In addition, two non-diabetic control groups (history of depression; no psychiatric history) will also be studied. We will assess these patients as to brain structure, using Magnetic Resonance Imaging (MRI); depression, using the Structured Clinical Interview for DMS IV (SCID); and cognition using the Wechsler Adult Intelligence Scale III (WAIS III) and other neuropsychological tests of memory, psychomotor speed and mental efficiency. We will also evaluate medical factors (e.g., glycemic control-HbA1c; and history of severe hypoglycemia). We will examine whether: 1) structural abnormalities are more common in diabetic subjects compared to the matched community controls; 2) there is a relationship between

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diabetes specific medical variables, such as long-term glycemic control, and brain structure abnormalities; 3) structural abnormalities are more common in diabetic patients with a history of unipolar major depression than diabetic patients without a history of depression; and 4) the frequency of structural abnormalities in the brain among diabetic patients with a lifetime history of unipolar depression differs from the depression control group. The proposed research will, for the first time, provide evidence regarding the linkage between structural changes in the brain and depressive disorder in diabetes, and evidence about the relationship of type I diabetes and its attendant metabolic disturbances to structural changes in the brain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPMENT OF DIABETIC CARDIOMYOPATHY IN GLUT4 +/MICE Principal Investigator & Institution: Charron, Maureen J.; Professor of Biochemistry; Biochemistry; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 31-MAR-2005 Summary: (Scanned from the applicant's abstract) Mice with a single knockout allele of GLUT4(+/-) on a low fat diet develop type II diabetes including hyperinsulinemia, hyperglycemia, hyperleptinemia, mild hypertension, cardiomyopathy and liver steatosis with age. These pathologies occur independent of obesity, dyslipidemia, pancreatic failure and hepatic insulin resistance. We propose to conduct the first in vivo longitudinal study which examines critical molecular/metabolic/energetic alterations leading to diabetic cardiomyopathy. This addresses the important interplay between whole body metabolism and circulating factors that regulate cellular processes which result in end organ pathology. The central hypothesis is global reduction of GLUT4 expression and/or function leads to alterations in cardiac insulin action, glucose metabolism and energetics mediated by reductions in the activity of PPARgamma and Akt/PKB which result in altered contractile function and diabetic cardiomyopathy. Altered substrate use with increased reliance upon fatty acid metabolism is associated with increased oxidative stress and mitochondrial uncoupling that result in diminished energy reserves. Insulin sensitizer treatment with BRL49653, a thiazolidinedione (TZD) that activates PPARg, will improve whole body glucose homeostasis and cardiac function through alterations in AktJPKB activity, substrate usage and expression of uncoupling protein (UCP) and glucose transporter (GLUT) genes/proteins. These studies will provide unique insight into molecular, metabolic, and morphologic alterations in GLUT4+/- hearts as mice progress to diabetes that should facilitate development of therapeutics to prevent and/or minimize diabetic cardiomyopathy in humans. To accomplish these goals we have four specific aims. Each aim will identify alterations in insulin action through Akt/PKB, GLUT4- and GLUTx1 translocation, substrate partitioning/trafficking, and GLUT and UCP2/3 gene/protein expression in hearts of GLUT4+/- and control mice. Molecular and cellular analyses will be correlated with morphologic and hemodynamic changes in heart and alterations in whole body glucose homeostasis and circulating serum factors (e.g. leptin, insulin, T3/T4, glucose, free fatty acids) as mice progress from normal (N/N) to prediabetic (N/H) to overt diabetic (H/H) phenotypes. Effects of short term treatment with the TZD BRL49653 (PPARg agonist) on these parameters will be defined before significant alterations in body weight or adiposity can be measured. The latter studies will determine the mechanism of action of TZDs in the heart and may reveal novel therapeutic targets and applications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIABETES THERAPY TO IMPROVE BMI AND LUNG FUNCTION IN CF Principal Investigator & Institution: Moran, Antoinette M.; Professor; Pediatrics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: The majority of cystic fibrosis (CF) patients now survive beyond childhood, and CF related diabetes (CFRD), due to insulin deficiency, is common. CFRD without fasting hyperglycemia (FH) is found in 25 percent of CF adults and is associated with increased morbidity and mortality. BMI and pulmonary function deteriorate much more rapidly in these patients than in CF patients with normal glucose tolerance. Insulin deficiency alters protein and fat metabolism resulting in loss of weight and lean body mass and contributing to pulmonary disease and clinical decline. Preliminary isotopic data have shown that insulin and, to a lesser extent, the oral diabetes agent repaglinide acutely improve protein synthesis in patients with CFRD without FH. The objective of this research is to recruit 150 adult patients with CFRD without fasting hyperglycemia for a multi-center, twelve month, placebo- controlled intervention trial testing the ability of insulin or repaglinide to improve BMI and stabilize pulmonary function. It will test the hypotheses that: 1. Participants receiving either insulin or repaglinide will increase their BMI compared to control participants. 2. Insulin will be more effective than repaglinide at increasing BMI. 3. The increase in BMI will be primarily due to increased muscle mass. 4. The increase in BMI will be accomplished without significant changes in dietary macronutrient or calorie composition. 5. Insulin or repaglinide therapy will prevent pulmonary function decline compared to both control subjects and to their own baseline as measured the previous year. This will be associated with improvement in NIH clinical score and will be directly related to weight gain and increase in thigh muscle volume. 6. Participants receiving insulin or repaglinide will improve hand grip strength, and this will be directly related to weight gain and increase in thigh muscle volume. If it can be shown that insulin or repaglinide also improves body mass and pulmonary function, it would have a major impact on the current therapy and prognosis for adult CF patients. The question of whether these patients should receive diabetes therapy was given the highest priority for future research funding at a national consensus conference on CFRD Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DOES HYPERGLYCEMIA PREDICT PANCREATIC CANCER DIAGNOSIS? Principal Investigator & Institution: Chari, Suresh T.; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Pancreatic cancer causes glucose intolerance and diabetes in up to 80% of patients. Pancreatic cancer induced diabetes (PaCDM) is often asymptomatic, of short duration (50 years of age may have PaCDM. We propose to establish whether newly elevated fasting blood glucose (FBG) is indicative of underlying pancreatic cancer as evidenced by diagnosis of pancreatic cancer within 3 years of the FBG measurement. If so, this would provide an entirely novel approach to screening for sporadic pancreatic cancer. We hypothesize that the 3-year likelihood of diagnosis of pancreatic cancer will be high in subjects: a) equal to or > 50 years of age with newly elevated FBG, b) with elevated fasting glucose who have known risk factors for pancreatic cancer (e.g. smoking), and/or c) who manifest an abrupt increase in FBG in

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serial measurements over time. We will identify visits to Mayo Clinic between years 1988 to 2002 by subjects equal to or >50 years of age who resided in its surrounding catchment area and had a routine physical examination that included a FBG. Preliminary data reveal that about 150,000 different subjects made >300,000 such visits during this time period providing >1 million person-years of follow-up. We will electronically retrieve clinical, and laboratory data and examine 3-year follow-up from date of FBG measurement to identify those diagnosed with pancreatic cancer. We expect 340 to 510 pancreatic cancer events in this cohort. Our Specific Aims are: Aim 1A). To test if FBG drawn during routine physical examination predicts likelihood of underlying pancreatic cancer and to test for non-linearity of this association. Aim 1B) To establish a FBG threshold that predicts a high 3-year likelihood of diagnosis of pancreatic cancer. Aim 2). To estimate the extent to which known risk factors for pancreatic cancer (age, smoking, obesity and family history) modify the likelihood of underlying pancreatic cancer in subjects with FBG greater than the threshold defined by Aim 1B. Aim 3). To test if patterns of change in serial measurements of FBG over time predict likelihood of underlying pancreatic cancer. The clinical and research implications of this study are considerable. These data may lead to delineation of individuals who have a high likelihood of existing pancreatic cancer, and who may be ideal candidates for more intensive screening or early detection regimens. The research described in this application is 100% relevant to pancreatic cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DYSLIPIDEMIA DYSFUNCTION

AND

RETINAL

ENDOTHELIAL

CELL

Principal Investigator & Institution: Busik, Julia V.; Physiology; Michigan State University 301 Administration Bldg East Lansing, Mi 48824 Timing: Fiscal Year 2003; Project Start 15-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Diabetic retinopathy represents the leading cause of blindness in adults. Diabetic retinopathy is a disease of the retinal microvessels characterized by capillary occlusions, microaneurysms, selective loss of pericytes, acellular capillaries, hypertrophy of the basement membrane, angiogenesis and neovascularization. While the initial determinants of retinal microvascular damage are not well understood, recent studies suggest that diabetic retinopathy is a low-grade chronic inflammatory disease. As such, recent studies document increased leukocyte attachment and transmigration into the vascular intima. The increased adherence of leukocytes to endothelial cells likely involves induction of specific adhesion molecules, such as ICAM-1. The factors elevating cellular adhesion molecules are not well defined, but likely involve hyperglycemia and dyslipidemia associated with diabetes mellitus. Our preliminary studies show that treating human retinal vascular endothelial (hRVE) cells with specific fatty acids leads to the induction of ICAM-1, as well as alterations in several signaling pathways. We hypothesize that exposure of hRVE cells to specific fatty acids leads to the formation of specific bioactive lipids that cause alterations in cell signaling and gene expression and lead to increased expression of adhesion molecules and leukocyte attachment. To test this hypothesis, the following aims are proposed: 1) To evaluate the effects of fatty acids and glucose on adhesion molecule expression and cell signaling in hRVE cells. 2) To correlate changes in adhesion molecule expression and cell signaling to the production of specific bioactive lipids. The outcome of this work will lead to a better understanding of how diabetic dyslipidemia contributes to altered hRVE cell phenotype and the onset and progression of diabetic retinopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECT OF DIABETES AND HYPERTENSION ON ISCHEMIC INJURY Principal Investigator & Institution: Schaffer, Stephen W.; Professor of Pharmacology; Pharmacology; University of South Alabama Mobile, Al 366880002 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: (Adapted from the Investigator's Abstract): Diabetic patients have a two-fold higher mortality rate following myocardial infarction than their non-diabetic counterparts. Despite this, the effect of diabetes on ischemic injury is controversial. In some studies, ischemia reperfusion injury is actually reduced in diabetic models. One likely source of this variability is in the levels of cardioprotective and cardiotoxic factors in the diabetic animal. A major goal of the proposed research is to identify some of the regulatory factors found in the diabetic heart. Preliminary data suggest that one of the important factors is hyperglycemia. The proposal introduces the hypothesis that glucose enhances the production of diacylglycerol, leading to activation of protein kinase C, followed by up regulation of the cardioprotective factor, Bcl-2. PKC and Bcl-2 levels will be monitored by Western blot analysis. In addition, the role of catecholamines and angiotensin-2 as factors augmenting ischemic damage and reversing glucoseinduced up regulation of Bcl-2 will be examined. The extent of apoptosis, necrosis, mitochondrial membrane potential changes and caspase activation will be examined in the presence of elevated glucose and following treatment with neurohumoral factors prior to a hypoxic stimulus. Cell culture studies will be complimented by studies using an isolated heart model to test the hypothesis that hypertensive diabetic hearts will be more susceptible to an ischemic insole because of elevated levels of angiotensin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECTS METABOLISM

OF

OVARIAN

SUPPRESSION

ON

SUBSTRATE

Principal Investigator & Institution: Toth, Michael J.; Assistant Professor; Medicine; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Aging is associated with increased risk for heart disease, diabetes and physical disability. In women, the incidence of these age-related conditions increases dramatically after menopause. This has led to the hypothesis that ovarian hormone deficiency contributes to these adverse health outcomes. However, the effect of ovarian hormone deficiency, per se, on risk factors for disease and disability has not been clearly defined. Thus, the primary goal of the proposed studies is to characterize the effect of ovarian hormone deficiency on glucose, insulin, fat and protein metabolism. Our overall hypothesis is that ovarian hormone deficiency alters substrate turnover and utilization in a manner that increases the risk for developing chronic disease and disability. Specifically, alterations in glucose, insulin and fat metabolism increase the risk for developing heart disease and diabetes and changes in protein metabolism reduce lean tissue mass which, in turn, promotes disability. To address our hypothesis, we will measure substrate metabolism using stable isotope tracer methodology in healthy, premenopausal women before and after pharmacological ovarian suppression. Women will be randomized to receive the gonadotropin-releasing hormone agonist leuprolide acetate or placebo. Measurements of substrate metabolism will be performed during both the follicular and luteal phases of the menstrual cycle prior to treatment and 2 months after the initiation of treatment. This experimental paradigm will enable us to investigate the effect of ovarian hormone deficiency, per se,

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on substrate metabolism without the confounding factors present in prior crosssectional, longitudinal and hormone replacement studies. This application consists of 3 separate experiments that will employ this model of ovarian suppression. Experiment I will investigate the effect of ovarian hormone deficiency on the glucose and insulin response to hyperglycemia. Experiment 2 will examine the role of ovarian hormone deficiency in the regulation of whole-body lipolysis under postabsorptive and epinephrine-stimulated conditions. Experiment 3 will examine the effect of ovarian hormone deficiency on whole-body protein metabolism under postabsorptive and simulated-postprandial conditions. Our findings will have direct relevance to understanding the fundamental role of ovarian hormone deficiency in the physiologic and metabolic changes that occur with menopause. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOTHELIAL CELL DYSFUNCTION IN OXIDATIVE STRESS MODELS Principal Investigator & Institution: Caldwell, Robert W.; Professor and Chair; Pharmacology and Toxicology; Medical College of Georgia 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (Provided by applicant): Endothelial cell dysfunction is a primary basis of cardiovascular disease including diabetes mellitus. Evidence suggests that supplemental L-arginine (L-arg) is therapeutically useful in reversing endothelial dysfunction and treating cardiovascular disease, but the mechanism of this effect is unknown. Therefore, we are studying the impact of oxidative injury on endothelial cell transport of L-arg and how it relates to endothelial dysfunction by using experimental models of diabetic coronary artery disease. The normal function of the vascular system depends critically on nitric oxide (NO) production by vascular endothelial cells (EC). However, in conditions associated with oxidative vascular injury such as diabetes mellitus, atherosclerosis, and hyperhomocystememia, excess formation of reactive oxygen species can lead to endothelial dysfunction and reduction in NO bioavailability. NO is produced by NO synthase (NOS) from its substrate L-arg. When L-arg availability to NOS is limiting, NOS acts principally upon 0, to form superoxide (O-), which rapidly combines with NO to form peroxynitrite (ONOO). ONOO- and 02+formation can lead to further formation of O NOS due to oxidation of BH4 (tetrahydrobiopterin), a critical co-factor for NOS. In EC, supply of L-arg to NOS depends mainly on the function of a specific transporter, system y+. Our data show that continued NO oxidant exposure inhibits system y transport of L-arg, reducing availability of L-arg and leading to formation of O2 This EC pathology is reversed with supplemental L-arg. We hypothesize that endothelial cell injury mediated by reactive oxygen species (ROS) reduces L-arg transport function. This reduces L-arg uptake and shifts NOS activity from NO production to O2 - production, leading to further compromise of the L-arg transporter. These deleterious effects can be prevented with supplemental L-arg. Our specific aims will test these hypotheses and further characterize the regulation of L-arg transporter. Aim 1. HYPOTHESIS: Chronic exposure 10 ROS causes dysfunction of the L-arg transporter. To test this hypothesis, we will determine the effects of chronic exposure to NOS agonists, NO donors, 02+-, ONOO- on uptake of [3H]L-arg in A) human coronary artery ECs and B) isolated rabbit hearts perfused by the Langendorff procedure. Aim 2. HYPOTHESIS.- Reduction of L-arg uptake shifts NOS activity from NO production to O - production leading to further compromise of the L-arg transporter. We will use the oxidant treatment protocols of aim 1 to correlate basal and

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NOS agonist-stimulated EC production of NO, O2 - and ONOO- with L-arg transport activity. Aim 3. HYPOTHESIS: Oxidant exposure alters transporter protein expression subcellular distribution and/or molecular interactions with eNOS. Recent studies indicate the principal supply of L-arg to eNOS occurs within caveolae where the L-arg transporter protein CAT1 interacts with eNOS. Thus, oxidant exposure may inhibit Larg transport by altering CAT! expression levels, subcellular compartmentalization and/or protein-protein interactions with eNOS. Interactions of these systems will be tested by experiments exposing HCAEC to the above oxidant treatments and determing the effects on CAT expression, subcellular distribution and molecular interactions with eNOS by using immunoprecipitation, immunoblotting, subcellular fractionation and confocal microscopy. Aim 4. HYPOTHESIS: High glucose/ diabetes causes endothelial dysfunction and reduces the bioavailability of NO by increasing formation of O2 - and ONOO which alters function of the L-arg transporter, oxidizes tetrahydrobiopterin, and shifts eNOS activity from NO to 02 - production. This hypothesis will be tested by the following experiments: A) determining the effects of high glucose/diabetes on L-arg transport in relation to eNOS expression and activity and formation of NO of 02 - and ONOO- in HCAEs exposed to high glucose or control conditions and in the coronary circulation isolated from diabetic rabbit hearts; and B) determining whether supplemental L-arg is effective in preventing the effects of high glucose/diabetes on the above parameters. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EVALUATION OF A NON-INVASIVE GLUCOSE MONITOR Principal Investigator & Institution: Buchert, Janusz M.; Infratec, Inc. 539 Danbury Rd Wilton, Ct 06897 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Sixteen million people in the United States live with the chronic disease diabetes; approximately 5 -10% are children. The seminal Diabetes Control & Complications Trial (DCCT) concluded that frequent glucose monitoring is necessary to reduce the complications of this disease. However, all glucose monitors available require invasive techniques with the most widely used method of selfmonitoring, obtaining blood from a finger stick, causing pain and discomfort which results in poor compliance. The development of a novel, hand-held, non-invasive glucose monitor will provide diabetics with the means for testing their glucose level more frequently, improving their quality of life, and reducing the costs and complications of this chronic disease. This application proposes the development, calibration and clinical validation of an advanced prototype based on a proprietary method of mid-infrared Thermal Emission Spectroscopy (TES). The method and instrument are based on the discovery that natural mid-infrared emissions, from the tympanic membrane, consist of spectral information of blood analytes. In recent years, infrared (IR) spectroscopy has emerged as a potential analytical method of choice for non-invasive glucose monitoring. The specific aims of this Phase I proposal are to develop the optical system and to integrate sensors into an ergonomic form for diabetic self-monitoring. The subsequent clinical studies are designed to demonstrate that a universal calibration for real time accurate measurements is possible for predictive results. The device will be calibrated and validated across a range of glucose concentrations from 40 to 400 mg/dL, using a total of 52 diabetic and normal subjects in hyperglycemic and hypoglycemic protocols. A trained nurse will perform the measurements. Subsequently, 19 diabetic subjects will test themselves using the hyperglycemic protocol in a full predictive study. The hypotheses will test that the

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Hyperglycemia

intra-individual correlation coefficient of the non-invasive predicted serum glucose compared with the clinical laboratory serum glucose measurement will be greater than 0.85, and less than 1 percent of the measurements will fall outside the clinically acceptable range on the Clarke Error Grid. Successful conclusion of Phase I milestones will lead to Phase II clinical studies and modifications for younger pediatric subjects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FACTORS THAT MODIFY INSULIN ACTION Principal Investigator & Institution: Buse, Maria G.; Professor; Medicine; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-MAY-1978; Project End 31-MAR-2003 Summary: "Glucose toxicity" accounts for insulin resistance in uncontrolled Type I diabetes (IDDM) and contributes to insulin resistance in Type II diabetes (NIDDM). Sustained hyperglycemia or hyperinsulinemia cause insulin resistance; glucose and insulin act synergistically in down- regulating insulin-stimulated glucose transport. A hypothesis to be tested in 3T3-Ll adipocytes is that glucose/insulin induced glucose transport desensitization reflects altered subcellular trafficking of the glucose transporter, GLUT4, which may involve impaired GLUT4 translocation and inappropriate association of GLUT4 containing vesicles (GCV) with the plasma membrane. Products of the hexosamine synthesis pathway (HNSP) have been implicated in glucose-induced insulin resistance; glutamine-fructose-6-P amidotransferase (GFAT) is the rate limiting enzyme and UDP-N-acetyl glucosamine (UDP-GlcNAc) the major product. The role of HNSP will be tested by examining whether conditions which increase or decrease flux via HNSP augment or mitigate, respectively, glucose induced insulin resistance. O-GlcNAcylation is a reversible process, involving O-glycosylation of proteins on Ser/Thr residues with monosaccharide GlcNAc. It usually involves phosphorylation sites and may be regulatory. Based on preliminary data in muscles of a mouse model of insulin resistance, over-expressing GLUTI in muscle, the hypothesis will be tested that increased flux via HNSP promotes O-GlcNAcylation of critical proteins involved in insulin- stimulated glucose transport. These may include GSV-associated proteins, possibly GLUT4 itself and/or proteins associated with GSV docking and fusion. Since adaptive regulation usually involves multiple sites, we will test the hypothesis that glucose-induced insulin resistance represents in part down-regulation of the insulin receptor (IR) signaling cascade, attempt to identify the major regulatory sites and critically assess the possible contribution of HNSP to the glucose effect. If warranted, the involvement of modulators of IR signal transduction, I.E. protein kinase C (PKC) isoforms, and candidate protein tyrosine phosphatases (PTP-ases: PTP-1B, SH-PTP2 and LAR) will be examined. GFAT activity is allosterically regulated by UDP-GlcNAc, and is modulated in vivo in muscle by the hormonal and metabolic milieu. The pre- and post-translational regulation of GFAT expression will be studied in muscles of rodent models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETICS OF AUTOIMMUNITY IN BB RATS Principal Investigator & Institution: Greiner, Dale L.; Professor of Medicine; Medicine; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 01-AUG-1995; Project End 31-JUL-2003

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Summary: Insulin-dependent diabetes mellitus (IDDM) in BB rats is characterized by T cell-mediated destruction of pancreatic beta cells, insulin deficiency, and hyperglycemia. Diabetes prone (DP) BB rats develop hyperglycemia spontaneously. Diabetes resistant (DR) BB rats develop diabetes only when challenged with environmental perturbants and provide the only available animal model of virusinduced autoimmune diabetes amenable to study at the genetic level. The only element known to be common to the genetic control of spontaneous or virus-associated IDDM in rat, mouse, and human is the requirement for a permissive major histocompatibility complex (MHC). In the previous grant period, we mapped a major non-MHC locus, designated iddm4, likely to be responsible for autoreactivity in BB rats. Building on that foundation, the goals of this proposal are 1) fine mapping and identification of iddm4 and 2) mapping of loci that determine whether IDDM will occur in animals that are exposed to a diabetogenic virus. We hypothesize that iddm4 is a major IDDM susceptibility locus and will be a critical genetic factor in viral diabetogenesis. Specific Aim No. 1 is to create rat populations for fine mapping iddm4, for identifying additional diabetes-modifying (iddm-m) loci, and for determining their epistatic interactions. This will be done using an iddm4 congenic series and an F2 intercross between (DR x WF)F1 rats. Specific Aim No. 2 is to identify the activities and mechanism of action of iddm4. We determine if adoptive transfer of IDDM by thymocytes and bone marrow is controlled by iddm4. Specific Aim No. 3 is to map the genetic loci that modify the expression of IDDM in response to infection with Kilham rat virus (KRV). We will test iddm4 congenic, backcross, and F2 cohorts for IDDM after infection with KRV. Specific Aim No. 4 is to identify and characterize iddm4. We will use positional cloning, candidate gene, and representational difference analyses as required to identify iddm4. Our belief and ultimate hope is that understanding the genetics of IDDM in BB rats will lead to the identification of analogous loci and genes relevant to the pathogenesis and prevention of human IDDM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GESTATIONAL DIABETES IN WOMEN:TASTE & ENDOCRINE FACTORS Principal Investigator & Institution: Tepper, Beverly J.; Associate Professor; Food Science; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2002; Project Start 08-APR-2002; Project End 31-MAR-2005 Summary: provided by applicant): Gestational Diabetes Mellitus (GDM) is a common complication of pregnancy with serious consequences for maternal and child health. Diet is an integral part of the management of GDM, but current diet strategies for pregnant women with 0DM are poorly defined and often fail. We have shown that GDM increases the preference for sweet taste and dietary intake of sweet foods, which could have important implications for the management of this disease. At the time of diagnosis (-30 30 wk gestational age) pregnant women with GDM showed a higher preference for sweetened dairy drinks compared to pregnant women without GDM. In addition, increased plasma glucose in women with GDM was related to higher preference for the sweet taste of glucose and higher dietary intake of simple sugars as fruit and fruit juices. Because these studies were limited to a single observation point during gestation and excluded women with severe diabetes or those treated with insulin, further studies are needed. The specific aims of this project are: 1) to determine the relationship between hyperglycemia and increased taste preference and dietary intake of sweet foods in GDM, 2) to compare the temporal pattern of taste and dietary changes in women with GDM to those of women without 0DM across pregnancy stages,

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and 3) to relate these taste changes to alterations in gestational hormone and metabolic profiles. A single prospective study will be conducted. We will measure sweet taste preferences, food cravings, dietary intake of sweet foods and plasma indices of selected hormones and metabolites (including insulin, cortisol and leptin) during early, middle and late gestation and at 6-wk and 26 wk post-delivery. Four groups of pregnant women will be studied; overweight women with GDM; normal weight women with GDM; overweight women without GDM and normal weight women without GDM. Non-pregnant controls will also be studied. The long-term goal of this project is to obtain a better understanding of taste changes in GDM to develop better preventative and therapeutic dietary intervention strategies for this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXPRESSION

GLUCOSE

REGULATION

OF

PANCREATIC

ISLET

GENE

Principal Investigator & Institution: Robertson, R Paul.; Scientific Director and Ceo; Pacific Northwest Research Institute 720 Broadway Seattle, Wa 98122 Timing: Fiscal Year 2002; Project Start 01-DEC-1985; Project End 31-MAR-2006 Summary: (provided by applicant) The overall goal of this proposal is to examine the hypothesis that the adverse effects of prolonged exposure of pancreatic islets to supraphysiologic glucose concentrations (i.e. glucose toxicity) is mediated at least in part by glucose oxidation and the subsequent generation of reactive oxygen species (ROS) that can impair insulin gene expression and beta cell function. The four specific aims are: Specific Aim #1: To determine whether intervention with antioxidants after establishment of hyperglycemia in ZDF rats is successful in decreasing plasma markers for oxidative stress, and, if so, also in decreasing plasma glucose levels and restoring islet PDX-1 and insulin mRNA, insulin content, and glucose-induced insulin secretion. We will also determine whether discontinuation of antioxidant treatment is followed by reversion to the pretreatment level of hyperglycemia and defects in beta cell function. Specific Aim #2: To determine whether progression of type 2 diabetes mellitus in db/db mice is accompanied by disruption of the balance between reactive oxygen species and islet antioxidant enzyme gene expression, enzyme levels, and enzyme activity and defects in PDX-1 and insulin gene expression, and to determine whether db/db mice transgenically modified to overexpress intraislet antioxidant enzymes as a preventive measure are protected from glucose toxicity-induced progression of type 2 diabetes. Specific Aim #3: To determine whether prolonged exposure of pancreatic islets to supraphysiologic glucose concentrations disrupts the intracellular balance between reactive oxygen species (ROS) and anti-oxidant enzyme gene expression, enzyme levels, and enzyme activity, thereby causing defective insulin gene expression and to determine whether in vitro overexpression of antioxidant enzymes islets prevents adverse effects of supraphysiologic glucose concentrations on PDX-1 and insulin gene expression, insulin content, and glucose-induced insulin secretion. Specific Aim #4: To ascertain whether measures of oxidative stress correlate positively with the level of hyperglycemia and negatively with residual beta cell function in type 2 diabetic patients; whether the intervention of improving glycemic control in type 2 diabetic patients leads to decreases in markers of oxidative stress and improvements in beta cell function; and whether interventional treatment with an antioxidant drug without changing current conventional drugs used for glycemic control diminishes hyperglycemia and improves beta cell function in poorly controlled type 2 diabetic patients. The methods used to achieve these specific aims will involve studies of insulin secretion, insulin content, PDX-1 and insulin mRNA levels, antioxidant enzyme levels

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and activity, and blood and islet markers for oxidative stress. We will conduct experiments using ZDF rats and antioxidant drugs, rat and human islets with adenoviral infection of cells to overexpress antioxidant enzymes, and db/db mice made transgenic to overexpress antioxidant enzymes, both singly and in combination. At the conclusion of these studies, we hope to have determined whether chronic oxidative stress is a mechanism of action for glucose toxicity in islets. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GLUCOSE, INSULIN IN DIABETIC VASCULAR DISEASE Principal Investigator & Institution: Nadler, Jerry L.; Kenneth R. Crispell Professor of Medicin; Internal Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 30-SEP-1995; Project End 31-JUL-2006 Summary: This program project will investigate the role of hyperglycemia and insulin resistance in the excess cardiovascular disease due to diabetes. The program will utilize innovative and multi-disciplinary approaches to address the overall unifying theme that elevate glucose and/of insulin resistance leads to accelerated cardiovascular disease by increasing oxidative stress and inflammatory signals in the vessel wall. A hypothesis developed in the initial funding period will be expanded to evaluate the role of lipoxygenase (LO) activation in mediating the oxidative and inflammatory changes associated with atherosclerosis and vascular injury. A strength of the program will be the use of both small and large animal models to more clearly evaluate the genetic and molecular mechanisms leading to cardiovascular disease in diabetes. These models will also allow the evaluation of potentially therapeutic to prevent the accelerated atherosclerosis and injury response in people with diabetes. The program involves 4 projects and 3 cores. Project 1 will examine the hypothesis that activation of LO pathway can play a role in atherosclerosis and vascular injury by inducing the transcriptional regulation of key genes which regulate vascular smooth muscle cell migration and matrix remodeling. A unique aspect of this project will be the use of novel ribozymes and animal models to test the in vivo role of oxidative stress and 12-LO in these processes. Project 2 will test the hypothesis that glucose and the diabetic state induce LO expression in aortic endothelial cells and that arachidonic or linoleic acid derived oxidative lipids activate key signalling mechanisms and oxidative phospholipids which lead to the binding of monocytes to the vessel wall. This project will utilize novel ribozymes, mouse, and swine models in the cores. Project 3 will mechanistically evaluate the role of helix-loop-helix transcription factors such as Id3 in accelerated VSMC growth response to injury in insulin resistant and diabetic states. Studies will utilizes chemokines, and chemokine receptors determine monocyte recruitment to atherosclerotic lesions and b) the increased rate of atherosclerosis in diabetes can in part be explained by a more robust or earlier expression of these molecules. A novel aspect of this project will be the use of in isolated perfused carotid artery model and the therapeutic and mechanistic actions of a novel anti- inflammatory agent Lisofylline in appropriate mouse models. The synergy between the projects and use of the cores will greatly accelerate the pace of this research to understand the mechanisms of accelerated macrovascular disease in diabetes. The results form this program should provide new therapeutic advances to reduce the rate of cardiovascular disease in diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Hyperglycemia

Project Title: HAPO: DATA COORDINATING CENTER Principal Investigator & Institution: Dyer, Alan R.; Professor and Associate Chair; Preventive Medicine; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 04-MAY-1999; Project End 31-MAR-2004 Summary: There is a consensus that overt diabetes mellitus (DM), whether or not accompanied by symptoms or signs of metabolic decompensation, is associated with a significant risk of adverse pregnancy outcome. On the other hand, the risk of adverse outcome associated with degrees of glucose intolerance less severe than overt DM is controversial. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study is a basic epidemiologic investigation aiming to clarify unanswered questions on the association of various levels of glucose intolerance during the third trimester of pregnancy and risk of adverse outcomes. Its General Aim -- by means of an international cooperative study involving 16 centers and approximately 25,000 pregnant women -- is to achieve a major advance in knowledge on levels of glucose during pregnancy that place the mother, fetus, and neonate at increased risk. The primary hypothesis is that hyperglycemia during pregnancy, less severe than overt DM, is associated with increased risk of adverse maternal, fetal, and neonatal outcome that is independently related to the degree of metabolic disturbance. Specific Aims of HAPO are: 1. to examine glucose tolerance in a large, heterogeneous, multinational, multicultural, ethnically diverse cohort of women in the third trimester of gestation with medical caregivers "blinded" to status of glucose tolerance (except in those instances where fasting and/or two hour OGTT plasma glucose concentration exceeds a predefined cutoff value); and 2. to derive internationally acceptable criteria for the diagnosis and classification of gestational diabetes mellitus (GDM) based on the specific relationships between maternal glycemia and the risk of specific adverse outcomes that are established through this study. The study is to be accomplished with high quality standardized data collection on the women during the third trimester of gestation (including the OGTT) and at time of delivery for assessment of adverse outcomes, including operative delivery (caesarean section), increased fetal size (macrosomia/obesity), neonatal morbidity (hypoglycemia), and fetal hyperinsulinism. HAPO is to include a Clinical Coordinating Center and Data Coordinating Center, both located at the Northwestern University Medical School in Chicago, as well as a Central Laboratory located in Belfast, United Kingdom. This application requests support for the Data Coordinating Center for HAPO. Cost effectiveness for HAPO is enhanced through cost sharing by colleagues in non-U.S. centers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HIGH GLUCOSE AND ARTERIOLAR KV CHANNELS Principal Investigator & Institution: Liu, Yanping; Medicine; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Hyperglycemia and diabetes are associated with impaired endothelium-dependent dilation of coronary conduit vessels, due in part to quenching of the vasodilator nitric oxide by production excess superoxide. In contrast, little is known regarding the effect of oxidative stress on hyperpolarization-mediated vasodilation. This is important since coronary arteriolar dilation, especially in humans, depends less upon nitric oxide and more upon hyperpolarization via opening of K + channels. Voltage-dependent (Kv) K + channels are one of several K + channels highly

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expressed in coronary vascular smooth muscle (VSM). They play an important role in regulating resting tone and participate in physiological dilation. Much of the vascular dysfunction associated with diabetes and hyperglycemia is due to excess production of reactive oxygen species (ROS). However the extent to which vasomotor responses mediated through K + channels and hyperpolarization are affected by elevations in glucose, and whether this influence involves the production of ROS is not known. The overall aim of this application is to determine the effect of high glucose (either in the tissue medium bathing isolated vessels or in the serum of diabetic rats) on hyperpolarization-mediated coronary dilation and coronary VSM Kv channel activity, and to establish a mechanistic role for superoxide in both the altered channel activity and hyperpolarization-induced dilation of coronary arterioles. Videomicroscopy, membrane potential, patch clamping, and Western blot analysis of isolated coronary arterioles will be used in both rat and dog models to test three specific aims. In aim 1 we shall examine the hypothesis that high glucose reduces both Kv channel activity and the associated dilation to isoproterenol and forskolin in rat coronary arterioles. In aim 2 we shall determine the contribution of superoxide to the reduced Kv channel activity following exposure to high glucose. In aim 3 we shall identify the source of vascular superoxide generation following exposure to high glucose or hyperglycemia. Rat coronary arterioles incubated in normal or high glucose or isolated from diabetic and control rats or dogs are either mounted onto micropipettes for diameter measurements or dissociated into single VSM cells for K + current measurements. Vessels from the same preparations are also saved for Western blot analysis. This combination of pharmacological, electrophysiological and molecular assessment of vascular and cellular function provides a powerful mechanism for studying hyperpolarization-dependent vascular regulatory process. These studies will have important implications with regard to mechanisms of coronary vasomotor regulation in diabetes and provide novel mechanisms of altered coronary vasoregulation. The results may suggest new therapeutic approaches for the treatment of microvascular dysfunction in patients with diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIGH GLUCOSE, DNA, AND DIABETIC COMPLICATIONS Principal Investigator & Institution: Lorenzi, Mara; Associate Professor; Schepens Eye Research Institute Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-AUG-1987; Project End 31-JUL-2004 Summary: (Adapted from applicant's abstract): The long-term objective or our work is to reconstruct the pathogenesis of human diabetic retinopathy at the cellular and molecular level, and thus establish the foundation for preventive strategies rationally targeted. We address in particular the process that leads to capillary closure and obliteration because these are the events that trigger sight-threatening unregulated angiogenesis. Having observed in both human and experimental diabetes accelerated apoptosis of the cells of retinal vessels - pericytes and endothelial cells - we sought to identify relevant molecular events. Two candidate pathways are emerging: one driven by intracellular regulators of apoptosis, and in particular by overexpression of proapoptotic Bax; and one by proinflammatory signals, and in particular by activation of the transcription factor NF-kappaB and overexpression of TNF-alpha. We propose to (1) define in retinal pericytes exposed to high glucose in vitro the respective apoptogenic role of Bax and TNF-alpha overexpression, their relationship to NF-kappaB activation, possible transcriptional regulation by high glucose, and relationship to by-products of accelerated glycolysis; (2) determine if endothelial cells derived from the same retinas as

34

Hyperglycemia

index pericytes respond to high glucose in vitro with the same proapoptotic program; (3) determine--by studying mice with targeted deletion of Bax and rendered diabetic--, whether Bax-mediated apoptosis is instrumental to the development of retinal microangiopathy, and, if so, provide proof of concept that apoptosis is a key cellular event in the development of diabetic retinopathy; (4) examine the retinal expression of TNF-alpha and other cytokines in human and experimental diabetes, and, if warranted, determine--by studying mice with targeted deletion of both TNF-alpha receptors and rendered diabetic--, whether TNF-alpha effects are instrumental or contributory to the development of diabetic retinal microangiopathy. These studies bridge biochemical abnormalities caused by hyperglycemia to altered regulation of apoptogenic molecules, and the latter to the histological lesions that render retinopathy a sight-threatening complication of diabetes. If a chain of causal relationships is established, the studies will bring to the fore targets for rational interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HISTOPATHOLOGY CBF AND NMR ASSESSMENT OF STROKE Principal Investigator & Institution: Helpern, Joseph A.; Professor of Radiology, Psychiatry and p; Nathan S. Kline Institute for Psych Res Psychiatric Research Orangeburg, Ny 10962 Timing: Fiscal Year 2001; Project Start 22-SEP-1993; Project End 31-MAY-2004 Summary: (Verbatim from the Applicant's Abstract) The main goal of this proposal is to investigate to what extent hemodynamic factors are involved in increased tissue damage associated with ischemia under conditions of hyperglycemia. Elevated systemic blood glucose concentrations have been implicated in poor neurological outcome following stroke in experimental animals and humans. Some studies have reported changes in cerebral blood flow (CBF) associated with hyperglycemia and loss of CBF autoregulation has been implicated as a possible complicating factor in poor outcome associated with hyperglycemia in cerebrovascular disease. We have developed a new high-speed MRI technique to monitor CBF continuously and have generated preliminary data which indicate that in rat brain there is an acute increase in CBF with D-glucose infusion with an associated transient loss of autoregulation. These data suggest that impaired hemodynamics may contribute to poor neurological outcome associated with hyperglycemia stroke. This work will improve our understanding of the role of hyperglycemia in stroke and may help lead to new approaches for stroke management. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HUMAN TCR/HLA TRANSGENIC MICE TO PREVENT T1DM Principal Investigator & Institution: Gottlieb, Peter A.; Assistant Professor; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Efforts to prevent and cure type 1 diabetes (TIDM) are directed at understanding the mechanisms, which lead to pancreatic islet cell destruction and how to prevent it. Insulin peptide B9-23 is a critical target antigen in the NOD mouse model of TIDM and in human prediabetic and T1DM patients. Vaccination of subjects with either insulin, insulin B chain or an altered peptide ligand of B9-23 are currently undergoing clinical trials in new onset T1DM subjects. These therapies were developed based on the effectiveness of these therapies in NOD mice which have similar

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35

but different MHC genes from human subjects. Optimization of the antigen and the protocol to give it may be critically important in discovering the most effective way to prevent diabetes. We propose to develop a humanized mouse model of TIDM in order to develop second generation molecular inhibitors which would potentially be more effective than our current therapeutic approaches. The CW4 human T cell clone responds to insulin peptide B9-23 in the context of DQS. We have established constructs of the T cell receptor and propose to develop a TCR-DQ8 transgenic mouse. The DQ8 background in the two strains we will use have differential expression of DQ8 in dendritic and B cells. We hope to establish a model of TIDM where reactivity to insulin B9-23 in the context of human DQ8 can be explored more fully than is possible in vitro. Our specific aims will be to test whether transgenic TCR-HLA-DQ8 mice develop normal CD4 T cells that can respond to antigen in the context of differential expression of DQ8 on either B cells or on B cells and dendritic cells. Whether these mice develop insulitis and diabetes spontaneously or need additional pertubations such as antigen administration, B7-1 expression, PolylC. or CFA to produce hyperglycemia. Using the known crystal structure of B9-23-HLA-DQ8, we will examine rationally designed peptides of B9-23 to develop inhibitors of this interaction using HLA-DQ8 binding studies, the CW4 T cell clone, other human and transgenic DQ8 clones and hybrids and DQ8- peptide tetramers. As the mice become available and a diabetes model is established, we will test the inhibitors in vitro to determine the efficacy and optimal route, dose and timing of administration. If we are successful in establishing a lead compound, we will then proceed on to preclinical studies to demonstrate safety prior to establishing a protocol for human trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYPERGLYCEMIA AND ADVERSE PREGNANCY OUTCOME Principal Investigator & Institution: Metzger, Boyd E.; Northwestern University 633 Clark Street Evanston, Il 60208

Professor;

Medicine;

Timing: Fiscal Year 2002; Project Start 04-MAY-1999; Project End 31-MAR-2004 Summary: There is a consensus that overt diabetes mellitus (DM), whether or not accompanied by symptoms or signs of metabolic decompensation, is associated with a significant risk of adverse pregnancy outcome. On the other hand, the risk of adverse outcome associated with degrees of glucose intolerance less severe than overt DM is controversial. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study is a basic epidemiologic investigation aiming to clarify unanswered questions on the association of various levels of glucose intolerance during the third trimester of pregnancy and risk of adverse outcomes. Its General Aim, by means of an international cooperative study involving 16 field centers and approximately 25,000 pregnant women, is to achieve a major advance in knowledge on levels of glucose during pregnancy that place the mother, fetus, and neonate at increased risk. The primary hypothesis is that hyperglycemia, less severe than overt DM, is associated with increased risk of adverse maternal, fetal, and neonatal outcome that is independently related to the degree of metabolic disturbance. Specific Aims of HAPO are: 1. To examine glucose tolerance in a large, heterogeneous, multinational, multicultural, ethnically diverse cohort of women in the third trimester of gestation with medical caregivers "blinded" to status of glucose tolerance (except in those instances where fasting and/or two hour OGTT plasma glucose concentration exceeds a predefined cutoff value); and 2. To provide data that can be used to derive internationally acceptable criteria for the diagnosis and classification of gestational diabetes mellitus (GDM) based on the identification of pregnancies at risk for specific adverse outcomes. The study is to be accomplished with

36

Hyperglycemia

high quality standardized data collection on the women during the third trimester of gestation (including the OGTT) and at time of delivery for assessment of adverse outcomes, including fetal hyperinsulinism, fetal obesity (macrosomia), operative delivery (caesarian section), and neonatal morbidity (hypoglycemia). HAPO is to include field centers and regional centers where the participants will be studied, a Clinical Coordinating Center and Data Coordinating Center, both located at the Northwestern University Medical School in Chicago, as well as a Central Laboratory located in Belfast, Northern Ireland. This application requests support for the Clinical Coordinating Center, the field and regional centers and Central Laboratory. Cost effectiveness for the HAPO study is enhanced through cost sharing by colleagues in non-U.S. centers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYPERGLYCEMIA AND OXYGEN BREATHING IN HEAD & NECK CANCER Principal Investigator & Institution: Brizel, David M.; Associate Professor; Radiation Oncology; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HYPERGLYCEMIA-INDUCED MECHANICAL HYPERALGESIA Principal Investigator & Institution: Dobretsov, Maxim; Anesthesiology; University of Arkansas Med Scis Ltl Rock Little Rock, Ar 72205 Timing: Fiscal Year 2004; Project Start 15-MAR-2004; Project End 31-JAN-2007 Summary: (provided by applicant): Pain due to peripheral neuropathy is a common, complication of diabetes that is likely triggered by multifocal hyperglycemic injury of the peripheral nerve. However, mechanisms of this injury are not known, since the systemic effects of diabetic hyperglycemia complicate the direct glucose effects in peripheral nervous system. In the present proposal, we will use a novel animal model of in vivo local and chronic hyperglycemia to test the hypothesis that early mechanical hyperalgesia in diabetes results from hyperglycemia-induced activation of the polyol pathway, leading to impairment of Schwann cell function, damage to paranodal axonglia contacts, and finally, ectopic discharges of large myelinated primary afferent fibers. To address this hypothesis rats will be surgically implanted with an osmotic minipump and hyperglycemia will be maintained in vivo, chronically and locally in either dorsal root ganglion or a segment of sciatic nerve by perfusion with hyperglycemic solution. Behavioral tests will be conducted to measure mechanical hyperalgesia in the foot innervated by the treated nerve and compared to the contralateral foot. Electrophysiological, biochemical and immunohistological experiments will characterize functional, metabolic and structural nerve changes, respectively, and determine their rote as mechanisms of local hyperglycemia-induced mechanical hyperalgesia. The occurrence of mechanical hyperalgesia will also be compared in a model of streptozotocin-induced diabetes (systemic hyperglycemia). Data collected in this study will advance our understanding of the early pathogenesis of hyperglycemiainduced neuropathic pain symptoms. The results will provide strong support for the idea that diabetic neuropathy may result from a direct and local hyperglycemic damage in peripheral nerve. Of potential clinical significance is that this information may lead to development of new approaches for early detection and diagnosis of developing

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diabetic neuropathy and novel preventive approaches in the treatment of painful neuropathy. Finally, the animal model of local hyperglycemia developed in this study should be a useful instrument in studies of symptoms of diabetic neuropathy other than mechanical hyperalgesia and, more generally, in studies and tests of the effects of physiologically and pharmacologically active compounds on peripheral sensory function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDENTIFICATION OF NOVEL AUTOANTIGENS IN TYPE 1 DIABETES Principal Investigator & Institution: Levisetti, Matteo G.; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Type 1 diabetes is an autoimmune disease characterized by the progressive destruction of pancreatic beta-cells that leads to insulinopenia and hyperglycemia. In spite of extensive study, little is known about the initial beta-cell autoantigens that trigger the autoimmune response. This application focuses on identifying the antigens that the immune system targets early in the pathogenesis of diabetes. Specific Aim 1: Characterize autoantibodies to beta cell antigens and identify the antigens. We plan on producing monoclonal antibodies from NOD mice of various ages that are reactive with beta cell surface antigens. These antibodies will be characterized and then used to identify the target antigens present on the surface of the beta cells. These beta cell target antigens will be cloned, sequenced and expressed in cell lines by transfection, and in systems that will allow purification of protein for experimentation. Specific Aim 2: Characterize the T cell reactivity against autoantigens that are identified by the monoclonal antibodies. The generation of peptides, and/or protein, from identified beta-cell autoantigens will allow for the pursuit of autoreactive T cells from the spleen, peripancreatic lymph nodes and islet infiltrates of NOD mice. T cell reactivity against all beta cell autoantigens that are identified will be characterized at the level of protein and T cell peptide epitopes will be characterized. Specific Aim 3: Evaluate the pathogenic role of autoantibodies and T cells. The functional role played by any identified beta-cell antigens in the pathogenesis of diabetes, and the antibodies and T cells which target them, will be examined. The phenotype of T cells reactive with identified antigens will be explored and characterized. Together these aims may lead to an understanding of the early pathologic events in Type 1 diabetes, specifically of the beta-cell antigens that are involved, which is essential for the development of preventive and therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IGF-1 AND DIABETIC HEART Principal Investigator & Institution: Kajstura, Jan; Associate Professor; Medicine; New York Medical College Valhalla, Ny 10595 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Verbatim from the application): The long-term objective of this application is to demonstrate that diabetic cardiomyopathy is characterized by myocyte death in which the local renin-angiotensin system (RAS) plays a primary critical role. Hyperglycemia induced by streptozotocin administration is anticipated to activate the transcription factor p53, respectively, by glycosylation and phosphorylation of the Cterminal of this protein. Enhanced p53 function may upregulate p53-dependent genes,

38

Hyperglycemia

such as bax, angiotensinogen and AT1 receptor, leading to the synthesis and secretion of Ang II and the sustained phosphorylation of the tumor suppressor. This vicious cycle may promote the chronic generation of Aug II and an increased susceptibility of cells to die. The induction of bax and the downregulation of bcl-2 by p53 may potentiate not only apoptosis, but also myocyte necrosis, resulting in restructuring of the ventricular wall, chamber dilation and impaired cardiac hemodynainics. Importantly, Aug Ilmediated responses may involve the formation of reactive oxygen species (ROS). ROS may constitute the ultimate signal in the activation of the cell death pathways. Insulinlike growth factor-i (IGF-1) opposes the consequences of p53 by phosphorylating its Nterminal and by stimulating transcription of mdm2 that may lead to the interaction of Mdzn2 and p53 proteins. Mdm2-p53 complexes attenuate p53 function, Ang II concentration, ROS generation, increase in Bax, decrease in Bcl-2 and, ultimately, cell death and ventricular remodeling. These hypotheses will be tested by performing studies in normal mice and transgenic mice overexpressing IGF-1 following the imposition of diabetes. In vivo studies will be complemented with in vitro experiments utilizing myocyte cultures infected with adenoviral vectors overexpressing human mutated p53 or human wild-type p53. These cells will be exposed to high concentration of glucose to establish a cause and effect relationship between triggers of cell death, i.e., glucose and Aug II, and factors preventing, i.e., mutated p53, and promoting, i.e., wild type p53, cell death mechanisms. These multiple analyses should allow to establish whether the myocyte RAS is fundamentally implicated in the development and progression of diabetic cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPAIRED GLUCOSE TOLERANCE CAUSES NEUROPATHY Principal Investigator & Institution: Singleton, John R.; Associate Professor; Neurology; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 20-AUG-2002; Project End 31-JUL-2005 Summary: (provided by the applicant): Sensory neuropathy, often with pain, is a common neurologic patient. In developed countries, type-2 diabetes is the most frequently-defined cause of sensory neuropathy. We have found that 36 of 72 prospectively evaluated patients with otherwise idiopathic peripheral neuropathy have Impaired Glucose Tolerance (IGT). This is a significantly greater frequency of IGT (50%) than reported in large epidemiological studies of the age-matched general population (14%). IGT, defined as a 2-hour Oral Glucose Tolerance Test (OGTT) between 140 and 200 mg/dl, represents an intermediate defect in glucose metabolism, which correlates with insulin resistance syndrome, and has been shown to carry an independent risk for cardiovascular morbidity. Patients with IGT almost uniformly have a painful sensory neuropathy, linking them to the phenotype of early diabetic neuropathy. The recently completed Diabetes Prevention Program (DPP) shows that intensive diet and exercise modification can slow progression from IGT to diabetes. The Diabetes Control and Complications Trial (DCCT) clearly shows that neuropathy onset and severity correlates with glycemic control in diabetes. In the DCCT, aggressive treatment of hyperglycemia prevented or slowed the progression of neuropathy. We hypothesize that the postprandial hyperglycemia, identified by IGT, causes or contributes to a painful, small fiber neuropathy, which is indistinguishable from that observed in early frank diabetes, and that aggressive treatment to normalize hyperglycemia will slow or prevent progression of neuropathy. The purpose of this Clinical Pilot Study is to lay the groundwork for a prospective clinical trial in patients with IGT, and neuropathy, to determine if intensive exercise and diet counseling alone, or with a glucose-lowering

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agent, can stabilize or reverse neuropathy. We have three specific aims:1. Confirm the statistical association between IGT and neuropathy using control subjects with chronic pain, matched for age and body mass index.2. Characterize the clinical, electrodiagnostic, and histologic phenotype of neuropathy associated with IGT.Define the progression of neuropathy associated with IGT using two validated measures of neuropathy severity (cold detectiort threshold and nerve conduction velocity), and validate the use of intraepidermal nerve fiber countin as a measure of small fiber neuropath progression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTRACELLULAR GLYCATION AND DIABETIC COMPLICATIONS Principal Investigator & Institution: Brownlee, Michael A.; Anita and Jack Saltz Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-APR-1984; Project End 31-JUL-2006 Summary: The long-term objectives of the proposed work are to elucidate the mechanisms by which hyperglycemia-induced intracellular reactive oxygen species (ROS) produce diabetic retinopathy. The specific research proposed in this application will elucidate the role played by ROS-induced glyoxalase I substrates, which are precursors of intracellular advance glycation endproducts and mediators of hyperglycemia-induced angiopoietin-2 gene expression in retinal Muller cells. Specific Aim 1 will evaluate the effect of hyperglycemia-induced intracellular reactive oxygen species (ROS) on glyoxalase I substrates, advanced glycation endproducts derived from these substrates, and diabetic retinopathy in uncoupling protein-2 (UCP-2) knockout and glyoxalase I transgenic mice. Streptozotocin diabetes will be induced in UCP-2 knockout, glyoxalase I transgenic, and wild type mice. Retinal concentrations of intracellular oxidative stress products, ROS-induced glyoxalase I substrates, and glyoxalase-I substrate-derived AGEs will be determined in diabetic and non-diabetic mice. Retinopathy will be assessed by semi-quantitative RT-PCR and in situ hybridization at early time-points, and by quantitative morphology at late time-points. Specific Aim 2 will evaluate the effect of inhibition of hyperglycemia- induced ROS on glyoxalase I substrates, advanced glycation endproducts derived from these substrates, and diabetic retinopathy in uncoupling protein-2 (UCP-2) knockout, glyoxalase I transgenic, and wild type mice. Streptozotocin diabetes will be induced in UCP-2 knockout, glyoxalase I transgenic, and wild type mice. In selected groups of these animals, hyperglycemia-induced intracellular ROS will be inhibited by treatment with either MnTBAP or EUK8, structurally distinct SOD/catalase mimetic compounds. Retinal endpoints will be assessed as described in Specific Aim 1. Specific Aim 3 will characterize the mechanism of Angiopoietin 2 transcriptional control by glyoxalase I substrates in cultured primary retinal Muller cells. A hyperglycemia-responsive mouse angiopoietin-2-luciferase reporter vector has been constructed which contains 2.5kb 5'flanking sequence. Progressive deletions from the 5' end of the Ang-2 promoter will be constructed using restriction endonucleases or PCR methods. The glyoxalase-I substrate responsive region will be identified, and known transcription factor binding sequences altered by site- directed mutagenesis. EMSA will be performed with indicated consensus oligonucleotides from the glyoxalase-I responsive region. Supershift experiments will use commercially available antibodies. IP-westerns of cell extracts will be immunoblotted with antibodies to glyoxalase I-substrate- derived advanced glycation endproducts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ISLET-KIDNEY TRANSPLANTS FOR TREATMENT OF DIABETIC ESRD Principal Investigator & Institution: Sachs, David H.; Senior Investigator; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Pancreatic islet transplantation is less efficient than whole organ pancreas transplantation in reversing the hyperglycemia of diabetes. One of the major reasons for this disparity is the loss of islets to ischemic injury during the time it takes for the islets to revascularize in the recipient. We have recently developed techniques for constructing composite "islet kidneys" (IK) by transplantation of autologous islets under the kidney capsule 2-3 months prior to transplantation of the composite organ into pancreatectomized miniature swine. Transplantation of IKs was found to restore euglycemia to pancreatectomized recipients immediately, and to maintain both renal and islet function long-term. Our preliminary data indicate further that a single living donor pancreas contains sufficient islets to support the insulin requirements of both the donor and recipient of such a prevascularized IK. The goal of this combined R21/R33 proposal is to perfect and optimize this approach in preclinical models (R21) and then to extend the procedure to the treatment of diabetic patients with end-stage renal disease. Specifically, in phase I (R21) we will: 1) Determine the optimal donor pancreatectomy requirements for clinical applicability; 2) Compare the efficacy of IK in maintaining euglycemia following tolerance induction vs. standard maintenance immunosuppression; 3) Establish an IK transplantation model in baboons and assess the ability of allogeneic IK transplantation to reverse hyperglycemia in diabetic baboons. In phase II (R33) we will: 1) Develop laparoscopic techniques for partial pancreatectomy, preparation of IK and IK removal for transplantation; and 2) Extend IK technology to the treatment of a major subset of patients with type 1 diabetes whose disease has progressed to end-stage renal failure. The research team assembled for this "bench-tobedside" approach includes: 1) basic scientists in the Transplantation Biology Research Center, who have been responsible for the preliminary data on which the application is based, 2) clinicians at the Massachusetts General Hospital involved in transplantation and diabetes research, and 3) consultants with outstanding expertise related to the techniques to be developed. We anticipate that the use of pre-vascularized islets as part of a composite islet-kidney transplant may provide a new and effective treatment modality for patients with class I diabetes and end-stage renal disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIPID METABOLISM IN THE ETIOLOGY OF TYPE 2 DIABETES Principal Investigator & Institution: Dobbins, Robert L.; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAR-2004 Summary: (Scanned from the applicant's description) Type 2 diabetes mellitus has major clinical and social impact, but its underlying pathophysiology is poorly understood. Since the disease is diagnosed as a disorder of carbohydrate metabolism, i.e., hyperglycemia, the possible contribution of abnormal lipid metabolism to its etiology has been largely overlooked. The predominant, obesity-related form of diabetes is characterized by hyperinsulinemia, resistance to insulin-mediated glucose disposal in skeletal muscle, and elevated plasma free fatty acid and triglyceride levels. It has been suggested that a derangement of lipid metabolism is an early event contributing to the development of both hyperinsulinemia and insulin resistance. Our laboratory has

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demonstrated the essential role that plasma fatty acids play in sustaining normal glucose-stimulated insulin secretion in fasted subjects, and has also utilized novel 1-H NMR spectroscopic techniques to illustrate the strong correlation between intramyocellular lipid (IMCL) content and skeletal muscle insulin resistance. In the current proposal, we seek to expand on this theme by investigating the effects of highfat feeding, pharmacologic inhibition of lipid oxidation, and leptin administration on insulin secretion and insulin sensitivity in rats and determining how these changes might be linked to alterations in muscle and islet triglyceride content. Because deficiencies of leptin and/or leptin signaling can precipitate the development of obesity/diabetes mellitus, it is conceivable that the primary function of leptin is to control lipid oxidation and lipolysis in a manner that prevents tissue lipid accumulation, thus maintaining normal glucose metabolism. We will administer leptin intracerebroventricularly to rats consuming a high fat diet and determine if this reverses the development of hyperinsulinemia and insulin resistance. Parallel measurements of IMCL, muscle P13-kinase activation and islet triglyceride levels will seek to establish a direct link between fat dissipation and improved function in these tissues. Future studies will explore the biochemical pathways through which leptin regulates lipid metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIVER GLUCOSE FLUX IN OBESITY AND DIABETES Principal Investigator & Institution: Shiota, Masakazu; Molecular Physiol & Biophysics; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 20-FEB-2002; Project End 31-JAN-2007 Summary: Excessive postprandial hyperglycemia and a defect in hepatic glucose uptake are common features of obesity and type 2 diabetes. Glucokinase is critical to the entry of glucose into the liver. We hypothesize that the defect in hepatic glucose uptake seen in obesity related type 2 diabetes results from impaired regulation of glucokinase activity. This proposal contains experiments designed to further our understanding of the relationship between impaired hepatic glucose uptake and the regulation of glucokinase in obese-type 2 diabetes mellitus. To quantify the altered distribution of glucokinase and its regulatory protein in the cell and to evaluate the impairment of hepatic glucose metabolism and the disturbance of glucose homeostasis in type 2 diabetes, we will use isotopic and chronic catheterization techniques, as well as glucose and pancreatic damp techniques in conscious pre-diabetic (10 weeks old) and diabetic (13 weeks old) ZDF rats. In some experiments, we will use adenoviral gene transfection technique is maniplate glucokinase levels with the liver in vivo. We will estimate the whole body glucose turnover rate, hepatic glucose phosphorylation and glycogen synthesis using [3H]glucose. The intracellular distribution of glucokinase and its regulatory protein will be estimated immunohistochemically. The proposal has four aims. First, we propose experiments to clarify the effect of insulin, glucose, and/or the portal signal on glucokinase translocation and glucose metabolism in the liver on lean and pre-diabetic ZDF rats. Second, we will examine the role of lipid levels and TNFalpha on glucokinase translocation, glucose phosphorylation, and hepatic glucose disposition in pre-diabetic ZDF rats. Thirdly, we will clarify the influence of glycogenolytic and gluconeogenic flux on glucokinase translocation and glucose metabolism in the liver. Fourthly, we will examine the effects of increasing free (unbound) glucokinase in the cytoplasm of the liver on hepatic glucose metabolism. Tosee experiments should shed light on the pathogenic role that impaired glucokinase

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regulation plays in the defective liver response to glucose in obesity related type 2 diabetes mellitus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MATRIX METALLOPROTEINASES AND DIABETIC NEPHROPATHY Principal Investigator & Institution: Thrailkill, Kathryn M.; Arkansas Children's Hospital Res Inst Research Institute Little Rock, Ar 72202 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that are involved in the breakdown and remodeling of extracellular matrix (ECM). Dysregulation of MMP activity has been implicated in many pathologic processes characterized by degradation of connective tissue matrices, including rheumatoid arthritis, periodontal disease and metastatic cancer. Recent studies both in vitro and in animal models of diabetes suggest that hyperglycemiamediated alterations in MMP secretion, activation or action may also contribute to the development of diabetes-related complications including diabetic retinopathy and nephropathy. Based on these findings one can hypothesize that the mesangial accumulation and renal hypertrophy characteristic of diabetic nephropathy may result from reduced matrix degradation caused by a hyperglycemia-mediated suppression of renal MMP activity. In fact, preliminary clinical data from our laboratory confirm that in children with type 1 DM, serum MMP-2 concentrations are suppressed in the face of uncontrolled hyperglycemia, yet normalize with near-normalization of blood glucose levels. In the present study, we propose to investigate the hypothesis that MMPs are involved in the pathogenesis of diabetic nephropathy by measuring concentrations of specific MMPs (MMP-2, -8 and -9), concentrations of the naturally occurring inhibitors of MMPs (Tissue Inhibitor of Matrix Metalloproteinases, TIMP-1 and -2), and concentrations of the MMP-activated growth factor, insulin-like growth factor-I (IGF-I) in the serum and urine of patients with type 1 DM. We will examine levels of MMPs, TIMPs, and IGF-I in these biologic fluids among diabetic patient subgroups, ages 14-40 years, chosen to represent various time points in the natural history of d abet c nephropathy. Moreover, we will examine the correlation between observed differences in MMPFl'lMP/IGFconcentrations and differences in glycemic control at the time of study, as indicated by HbA1 c measurements and concurrent (72 hour) Continuous Subcutaneous Glucose Monitoring (CGMS). We anticipate that this study will provide preliminary evidence to establish a link between dysregulation of MMP activity and the pathogenesis of nephropathy in type 1 DM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MAXIMAL SUBSTRATE UTILIZATION RATES IN PRETERM NEONATES Principal Investigator & Institution: Thureen, Patti J.; Associate Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2004; Project Start 03-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Current nutritional strategies for very preterm infant in this country are resulting in postnatal growth failure from which the neonate does not recover by the time of hospital discharge. Undernutrition, particularly insufficient protein intake during critical development periods adversely affects longterm neurodevelopmental and health outcomes. Efforts to optimize nutritional support,

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therefore, particularly in the first weeks of life, are critical to reversing nutritionally related adverse outcomes in this vulnerable population. The overarching hypothesis of this proposal is that there are a variety of nutritional and metabolic strategies for different types of infants and different types of postnatal conditions and disease states that will optimize anabolism, reduce morbidity and maximize growth in very preterm and critically ill neonates. The fundamental research goal of this proposal is to determine optimal early nutritional management approaches that will maximize protein accretion in extremely premature neonates. Specific Aim 1 will test the hypothesis that relatively high amino acid intake initiated in the immediate neonatal period and sustained at fetal delivery rates through close monitoring of nutrient intake will result in improved growth outcomes compared when compared to both historical controls that are not monitored. Specific Aim 2 will determine the energy intake that will optimize protein accretion at any given amino acid intake. Specific Aim 3 will address the metabolic effects of exogenous insulin administration in early neonatal hyperglycemia on protein accretion and lactate production. Specific Aim 4 will develop methodology to increase acceptability of protein metabolism studies in vulnerable neonatal populations. This work proposed in this award builds on the candidate's past landmark research in improving early neonatal nutrition. The candidate has developed a unique set of research experiences and skills that will allow for successful conduct of complex nutritional investigations in unstable preterm neonates. The candidate has an extensive record of both funding in clinical investigation and mentoring trainee physicians in patient-oriented research. A mid-career clinical investigator award would expand the time the candidate has for patient-oriented research on determining safe and efficacious anabolism-promoting strategies in very preterm and critically ill neonates during the immediate postnatal course, allow for training of young investigators who wish to pursue independent research careers in neonatal nutrition and metabolism, and advance the candidate's career goals of optimizing nutrition and metabolism in this vulnerable population of infants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS BY WHICH GDM LEADS TO DIABETES IN OFFSPRING Principal Investigator & Institution: Simmons, Rebecca A.; Associate Professor; Pediatrics; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) In the human, diabetic pregnancy induces marked abnormalities in glucose homeostasis and insulin secretion in the fetus that results in aberrant fetal growth. Studies have suggested that there are long-term consequences for the offspring of diabetic mothers. We have developed a model of gestational diabetes (GDM) in the rat to determine whether an altered metabolic intrauterine milieu is directly linked to the development of diabetes later in life. Uteroplacental insufficiency is induced in the pregnant rat on day 19 of gestation. Offspring are growth retarded at birth, however they catch-up by 5- 7 weeks of age. At 8 weeks of age they are bred to normal males. During pregnancy these animals develop hyperglycemia, hyperinsulinemia, and hyperlipidemia accompanied by impaired glucose tolerance and insulin resistance. Offspring, (F2's) are heavier at birth and remain heavy throughout life. F2's are insulin resistant very early in life and glucose homeostasis is progressively impaired. F2 rats go on to develop diabetes as adults. Although F2 animals display marked insulin resistance, the failure of the Beta-cell to compensate for defects in insulin action is the essential factor coincident with onset of diabetes. This failure of the Beta-

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cell to compensate may be due to a lack of compensatory increase in insulin secretion, an increased rate of cell death, a reduction in the rate of Beta-cell proliferation, or a combination of these events. The mechanism(s) underlying this lack of Beta-cell compensation and eventual decrease in Beta-cell mass in F2 animals are the focus of this proposal. We hypothesize that mitochondrial DNA damage from hyperglycemia via the production of reactive oxygen species (ROS) results in further escalation of genetic damage in the mitochondria, specifically in mutations. A self- reinforcing cycle of progressive deterioration in mitochondrial function leads to a corresponding decline in Beta-cell function. Finally, a threshold in mitochondrial dysfunction and ROS production is reached and Beta-cell death occurs. The onset of diabetes ensues when a critical level of abnormal Beta-cell insulin secretion combined with Beta-cell loss is reached. We will test the hypothesis that GDM does in fact cause mitochondrial dysfunction, oxidative stress, and deletions in mtDNA in the Beta-cell of the offspring, and whether these effects act synergistically to lead to the development of the Beta-cell failure and type II diabetes. To link the damage to the mitochondria caused by hyperglycemia to the Beta-cell phenotype observed in type II diabetes we will induce Beta-cell failure in vitro by transferring damaged mitochondria from F2 animals into Beta-cells from unaffected. non-F2 animals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF ENDOTHELIAL DYSFUNCTION IN DIABETICS Principal Investigator & Institution: Beckman, Joshua A.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 13-AUG-1999; Project End 31-JUL-2004 Summary: Vascular disease is the principal cause of death and disability among the 12 million patients in the United States with diabetes mellitus. Macrovascular complications, including myocardial infarction, stroke, and amputation are the leading cause of morbidity and mortality among this cohort of patients. Reduced bioavailability of endothelium-derived nitric oxide has been implicated in atherogenesis and may be a fundamental factor in the development of vascular disease in diabetes. Increased degradation of nitric oxide by reactive oxygen radicals and inhibition of nitric oxide synthase via activation of protein kinase C are each potential mechanisms to account for decreased nitric oxide. The sponsor's laboratory has demonstrated impaired endothelium-dependent vasodilation in patients with diabetes mellitus and in healthy, nondiabetic subjects with experimental hyperglycemia. Further experiments showed that vitamin C improved endothelium-dependent vasodilation implicating a culpable role for superoxide. The soluble, glutathione-dependent antioxidant pathway, responsible for detoxification of polar peroxides, is also adversely affected by hyperglycemia and may represent a specific physiologic mechanism causing, in part, the impaired endothelial function demonstrated in diabetes mellitus. This proposal will examine the effect of ebselen, a glutathione peroxidase mimetic on endothelial function in subjects with diabetes mellitus (type I and type II) and healthy, age-matched controls to determine if polar peroxides play an important role in endothelial dysfunction in diabetes. Hyperglycemia causes the up-regulation of protein kinase C isoform beta2 (PKC beta2) which may phosphorylate nitric oxide synthase, reducing its activity. This proposal will also examine the role of LY333531, a PKC beta2 inhibitor, on endotheliumdependent vasodilation in forearm resistance and conduit vessels in subjects with type I and type II diabetes mellitus and age-matched health controls. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF RISK TO DIABETIC NEPHROPATHY IN BLACKS Principal Investigator & Institution: Price, Deborah A.; Assistant Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-JUL-2005 Summary: (adapted from the application) African Americans carry a 3-6 fold increased risk of developing nephropathy as a complication of diabetes mellitus (DM), essential hypertension (HTN), and many other etiologies of renal disease. Although an increased frequency and severity of HTN and socioeconomic factors that limit health care probably contribute, multiple observations indicate that alternative factors are also involved. Fields ranging from epidemiology and therapeutic trials to molecular biology and genetics indicate that the renin-angiotensin system (RAS) contributes to the risk of nephropathy via mechanisms that include but go beyond HTN, perhaps involving the contribution of the RAS to growth and repair, hyperplasia, and hypertrophy. Our proposal is based on several unanticipated observations. First, in healthy African Americans, age-adjusted renal plasma flow (RPF) was substantially less than in Caucasians, assessed in an identical protocol. Moreover, despite a high salt diet, African Americans displayed an enhanced renal vasodilator response to angiotensin-converting enzyme (ACE) inhibition with captopril, which enhanced renal vascular responsiveness to angiotensin II (Ang II). Also, blacks do not increase their RPF when changing to a higher salt intake. This pattern--which clearly differs from that in Caucasians and is similar to our preliminary observations in patients with DM suggests activation of the RAS. Second, in our non-insulin-dependent DM (NIDDM) patients, our preliminary data suggest a range of hitherto unrecognized RAS abnormalities reflecting inappropriate activation and autonomous renin release. Most surprising is the paradoxical extreme RAS activation at the renal tissue level in Type II DM patients with very low plasma renin activity (PRA) and nephropathy. Evidence for a functional contribution comes from hemodynamic measurements made during pharmacological interruption of the RAS with ACE inhibitors and Ang II antagonists, and during Ang II infusion. In Type II DM, race is a critical determinant of risk. Third, we have made observations which indicate that acute hyperglycemia activates the intrarenal renin system and induces striking Ang II-dependent vasoconstriction. Fourth, we have evidence that the risk of advanced nephropathy in Type I DM is related to genetic variability in the eNOS gene. Our hypothesis is that the increase in risk of nephropathy represents an interaction between predisposition to polymorphic genes and environmental factors. Our goal in this study is to explore preliminary evidence that RAS activation and the combination with other polymorphic genes accounts for many Type II DM features involving renal risk and racial differences in risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: METABOLIC CONSEQUENCES OF SECURIN DISRUPTION Principal Investigator & Institution: Melmed, Shlomo R.; Professor and Director; CedarsSinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 900481804 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Cell cycle-dependent securin proteins regulate sister chromatid separation by inhibiting separin function. We isolated and have characterized pituitary tumor transforming gene (PTTG) from rat pituitary tumor cells, and PTTG is functionally homologous to yeast securin. PTTG is overexpressed in several tumor types, and also in some normal replicating tissues (including testis, lympocytes). When the PTTG gene was deleted, resultant knockout mice were viable, fertile and exhibited

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splenic and testicular hypoplasia and thrombocytopenia. Surprisingly, after 6 months, male PTTG -/- mice do not gain weight, develop profound hyperglycemia, hypoinsulinemia, and hypo-leptinemia with intact insulin sensitivity. In preliminary experiments, pancreatic beta cells appear hypoplastic with diminished islet insulin immunoreactivity, and no evidence for autoimmune islet involvement. This proposal aims to study the role of mammalian securin in pancreatic beta cell function by assessing insulin transcription, secretion and action, regulation of adipocyte hormones and assessment of pancreatic beta cell development and replication, and pancreatic regeneration. As securin-deficient diabetes is restricted to male mice, intact or gonadectomized PTTG -/- animals will be treated with sex steroids, and their impact on glycemia and pancreatic function assessed. These studies highlight the role of a cell cycle-regulating protein in pancreatic beta cell development and function. In the context of this unique genetic background, these experiments identify securin as a critical factor for pancreatic cell function and provide insights into a novel monogenic cause of diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METABOLIC REGULATION OF PEPCK ISOZYMES Principal Investigator & Institution: Hanson, Richard W.; Professor of Biochemistry; Biochemistry; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: The interaction of glucose and lipid metabolism in humans is critical for maintaining normal energy balance. Diabetes has long been known to involve impairment in lipid metabolism that contributes in an ill-defined manner to the complications of the disease. J. Denis McGary, in a provocative article entitled What if Minkowski had been Ageusic? An Alternative Angle on Diabetes, (1) suggested traditional research on diabetes had the wrong emphasis and that insulin resistance and hyperglycemia might best be understood if viewed from the context of an abnormality on lipid metabolism. A decreased rate of fatty acid re-esterfication by adipose tissue could be a critical factor in regulating the delivery of fatty acids to the liver. In 1968, we first described a pathway for the re- esterfication of fatty acids in adipose tissue, termed glyceroneogenesis, that has subsequently been shown to be a significant factor in the generation of 3-glycerolphosphate required for triglyceride synthesis in both adipose tissue and liver. This pathway may play an important role in the control of triglyceride synthesis in adipose tissue and liver and control the flux of fatty acids from adipose tissue during starvation. The tissue-specific expression of the gene for the rat controlling step in this pathway, PEPCK, has been ablated in mice causing the development of fatty liver and a lack of normal growth. The research described in this grant application will explore the physiological significance of glyceroneogenesis in mammalian tissues and establish the role of PEPCK in the regulation of diabetes by controlling the rate of free fatty acid delivery to the liver. In addition, the role of PEPCK in tissue such as kidney, small intestine, brain, skeletal muscle and brown adipose tissue will be determined using genetically modified mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR MECHANISMS OF ATHEROGENESIS IN DIABETES Principal Investigator & Institution: Heinecke, Jay W.; Professor; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-SEP-1976; Project End 31-MAR-2007

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Summary: (provided by applicant): Atherosclerotic vascular disease is the leading cause of death among people with diabetes mellitus. One important mechanism may involve oxidative stress because elevated blood glucose is the hallmark of diabetes and glucose promotes glycoxidation reactions in vitro. Moreover, glycoxidation products accumulate in tissues of diabetic animals and humans. The overall goal of this research proposal is to identify the biochemical pathways through which glucose accelerates glycoxidative stress. We plan to investigate four specific questions. First, we will determine whether diabetic hyperglycemia produces a distinct pattern of oxidation products in human atherosclerotic lesions. Our GUMS analyses of vascular tissue isolated from diabetic primates strongly suggests that hyperglycemia creates localized oxidative stress in the artery wall. To determine whether glucose-enhanced oxidative pathways also contribute to human atherosclerosis, we will use mass spectrometry to quantify glycoxidation products in vascular tissue. Second, we will identify the patterns of protein oxidation products that arise when peptides are exposed to reactive intermediates implicated in diabetic vascular disease. This arm of the project will complement our in vivo work by identifying markers of biochemical pathways that are triggered by hyperglycemia and that also oxidize proteins and LDL in vitro. Third, we will use mouse models to determine the role of glycoxidation in protein oxidation, AGE formation, and the development of diabetic vascular disease. Finally, we will use cultured human macrophages to identify glycoxidized proteins and proteins whose expression is markedly affected by hyperglycemia. These experiments should identify intracellular proteins that are vulnerable to glycoxidation. They will also directly test the hypothesis that glucose-stimulated superoxide production by mitochondria regulates macrophage gene expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MONOCYTE COMPLICATIONS

VEGF

&

PKC,

MARKERS

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DIABETIC

Principal Investigator & Institution: King, George L.; Professor and Acting Director; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Hyperglycemia is the major cause of diabetic microvascular complications including retinopathy, nephropathy and neuropathy. Early diagnosis of microvascular complications in these tissues has been difficult due to the long duration of disease required for the onset of clinical symptoms and the general inaccessibility of vascular and neurological tissues for analysis. Animal studies have clearly demonstrated that microvascular pathologies in the retina and renal glomeruli can manifest years before the onset of clinical symptoms. Activation of protein kinase C (PKC), specifically the B isoforms and increases in VEGF levels in the retina and renal glomeruli have been shown to correlate with severity of hyperglycemia induced vascular pathologies in diabetic animals. However, due to tissue access problems, almost all of the data regarding the increases in PKC activities and VEGF levels have been measured in vascular tissues from animal models of diabetes. Plasma levels of PKC do not exist and plasma VEGF levels do not consistently correlate with corresponding levels in the microvascular tissues. Recently, we have measured PKC activities in the circulating mononuclear cells and they correlated with the severity of diabetic retinopathy and nephropathy in type 1 and 2 diabetic patients. In addition, the expression of VEGF levels in the circulating monocytes from humans and diabetic rats can be increased by PKC activation. Similarly, increases in PKC activation and, potentially, VEGF expression in the circulating monocytes responded in parallel to

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diabetes in the vascular tissues of retina, renal glomeruli and arteries. In addition, monocyte activation has been noted by multiple studies in the cardiovascular and microvascular circulations including the retina and renal glomeruli from diabetic animals. Thus, we are proposing to test the hypothesis that increases in PKC activation and VEGF levels in the circulating monocyte are similar to those found in the retina and renal glomeruli in response to hyperglycemia or diabetes. Therefore, the ability to measure VEGF levels and PKC activities in circulating monocytes, which can be easily accessed, could be used as surrogate markers of diabetic microvascular disease especially diabetic retinopathy and nephropathy. We are proposing to test three specific aims in diabetic and control patients 1) To correlate VEGF levels with PKC activity in circulating monocyte with severity of retinopathy and nephropathy. 2) To determine whether glycemic control can alter the activation of PKC and VEGF levels in circulating monocytes. 3) To correlate PKC activity and VEGF levels in circulating monocytes with VEGF level in the ocular fluids obtained during surgery. These data can provide definitive evidence to determine whether further studies are needed to establish these two parameters in the circulating monocyte as surrogate markers of diabetic microvascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTICENTER NETWORK OF MATERNAL-FETAL MEDICINE UNITS Principal Investigator & Institution: Carpenter, Marshall W.; Director, Maternal Fetal Medicine, Assoc; Women and Infants Hospital-Rhode Island 101 Dudley St Providence, Ri 02905 Timing: Fiscal Year 2002; Project Start 03-APR-2001; Project End 31-MAR-2006 Summary: (provided by applicant): WIH and the Department of Obstetrics and Gynecology at Brown University School of Medicine have the capability to participate actively as a new member of the Cooperative Multicenter Maternal-Fetal Medicine Units Network. WIH operates one of the nation?s larger obstetrical services. All obstetric care is supported by insurance in Rhode Island. Consequently, the State?s ethnic and racial diversity is reflected among both private and clinic patients. Providing care to 74 percent of the State s patients, WIH s demographic and clinical statistics wholly reflect those of Rhode Island. During fiscal year 1999, 9023 deliveries were performed at WIH, 2099 among WIH Clinic and Maternal-Fetal Medicine patients. Of the total WIH deliveries, 174 had ruptured membranes before 35 weeks, 556 delivered prior to 35 weeks, 207 had multi-fetal pregnancies, 179 had gestational or chronic diabetes, 794 had hypertensive disorders in pregnancy, 539 had asthma or other respiratory disease and 163 had cardiac or vascular disease. The academic faculty and private practice community have had a consistently collaborative relationship providing access to the entire obstetrical population for cohort studies. Consequently, WIH is particularly suited for performance of clinical trials. The Maternal-Fetal Medicine Division is composed of six board-certified and one active candidate for the Maternal-Fetal Medicine boards, all of whom will support Network research protocols. The Division also employs two research nurses and a sonographer, all presently supported by NICHD funding, and three additional clinical nurses, all with extensive experience in cohort research. The Division has successfully enlisted patients (53-100 percent enlistment rates) in complex tocolysis trials and exercise, and metabolic and hemodynamic cohort studies with retention rates of 79-93 percent. The Division has maintained strong clinical and investigational relationships with local and regional private obstetricians, reflected in the proportions of private patients in Divisional cohort

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studies of 54-80 percent. The Division is presently engaged in three multicenter cohort studies funded by NICHD. It was selected by the Network in April 2000 to participate in the Beneficial Effects of Antenatal Magnesium (BEAM) Study to increase patient enlistment in this protocol and is presently beginning to enroll subjects. The Division has been funded as one of five North American sites in an international study of the maternal and perinatal impact of maternal glucose intolerance, the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study. The Division is also a participant in the First and Second Trimester Evaluation of Risk (FASTER) Study examining combined biochemical and sonographic first trimester screening for Down syndrome. WIH and the Maternal-Fetal Medicine Division will enlist subjects for all Network protocols and actively participate in proposing, planning and executing Network studies. Local infrastructure available for participation in multicenter clinical trials at WIH include (1) a large patient volume and highly involved full-time and voluntary obstetrical faculty; (2) robust clinical patient, laboratory, anatomic pathology, and pharmacy databases; (3) a strong history of collaboration between Maternal-Fetal Medicine and Neonatology Divisions; (4) decades-old perinatal tissue samples and anatomic pathology; and (5) a strong Departmental commitment to outcomes research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NATURAL HISTORY OF MICROALBUMINURIA IN TYPE I DIABETICS Principal Investigator & Institution: Krolewski, Andrzej S.; Associate Professor; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 01-FEB-1990; Project End 31-MAR-2004 Summary: Diabetic nephropathy is the major health problem in patients with IDDM. Recent clinical trials have shown that the natural history of diabetic nephropathy in IDDM can be modified by intervening at an early stage, microalbuminuria. Previous research supported by this grant provided strong evidence that the onset of microalbuminuria is determined by a different set of factors than its progression to overt proteinuria. This proposal explores this hypothesis and has the following goals: (1) To identify determinants of the onset of microalbuminuria: We will obtain frequent measurements of relevant exposures and of urinary albumin excretion (ACR) in our cohort of 787 IDDM patients with normoalbuminuria during an additional 5 years of followup. We will examine the relationship between the development of microalbuminuria and novel measures of hyperglycemia exposure, urinary levels of interleukin 6, and cigarette smoking. (2) To identify determinants of progression of microalbuminuria: We will obtain frequent measurements of ACR and will repeat biennial clinical and laboratory measurements in our cohort of 713 IDDM with microalbuminuria during the next 5 years of followup. We will use these new data to examine the relationship between progression of microalbuminuria and novel indices of lipid abnormalities, hyperfibrinogenemia, elevated blood pressure, and treatment with ACE inhibitors. (3) To identify genetic markers associated with the onset of microalbuminuria and its progression: We will collect DNA samples from available parents and IDDM individuals with (a) normoalbuminuria (n=400), (b) new onset microalbuminuria (n=200), (c) microalbuminuria and non-progression (n=400), and (d) microalbuminuria and progression to proteinuria (n=200). These DNA samples will be used to study eNOS, ACE, and ApoE, genes for which we have found linkage association and linkage with advanced nephropathy. We will test the hypothesis that polymorphisms in eNOS and ACE genes contribute to the onset of microalbuminuria

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and polymorphism in ApoE contributes to progression of microalbuminuria to overt proteinuria. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUTRAL LIPID DYSREGULATION OF THE PANCREATIC BETACELL Principal Investigator & Institution: Poitout, Vincent; Associate Professor; Pacific Northwest Research Institute 720 Broadway Seattle, Wa 98122 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Scanned from the applicant's description) Type 2 diabetes mellitus is characterized by chronic hyperglycemia and is often associated with elevated plasma lipid levels. The overall objective of this proposal is to ascertain the mechanisms whereby prolonged exposure to elevated levels of fatty acids (FA) affects pancreatic beta-cell function in Type 2 diabetes. Previously, we have demonstrated that prolonged exposure to FA impairs insulin gene expression only in the presence of high glucose, and that this is associated with increased neutral lipid synthesis. Specific Aim I: To identify the metabolic intermediate(s) generated along the pathway of neutral lipid synthesis responsible for the impairment of insulin secretion and gene expression upon prolonged exposure to FA. Isolated rat islets, HIT-T15, and betaHC-l3 cells will be cultured for 1 to 7 days in the presence of increasing concentrations of glucose and FA. Pharmacological tools will be used to inhibit or stimulate each step of neutral lipid synthesis, in order to identify the metabolic intermediate(s) generated along the esterification pathway (i.e., long-chain Acyl-CoA, diacyiglycerols, or triacylglycerols) responsible for the FA-induced impairment of beta-cell function. Specific Aim II: To assess whether the glucose-dependent deleterious effects of prolonged exposure to elevated FA on beta-cell function are glucose-specific, and whether the mechanisms of these effects are transcriptional, post-transcriptional, or translational. beta-cell exhaustion will be distinguished from bona fide toxicity in experiments where diazoxide will be used to inhibit insulin release. The glucose-specificity of PA effects will be investigated by using a non-glucose secretagogue to stimulate insulin secretion and insulin gene expression. The glucose-dependent effects of FA on proinsulin biosynthesis, insulin mRNA stability, and endogenous insulin gene transcription will be assessed. The effects of FA on insulin promoter activity will be characterized in HIT-Tl5 and betaHC-13 cells and also investigated in primary islets using the recombinant adenovirus system. Specific Aim III: To determine whether high-fat feeding in hyperglycemic Goto-Kakizaki (GK) rats impairs insulin secretion, insulin biosynthesis, and insulin gene expression, and whether these effects are prevented by normalization of blood glucose levels. GK or control rats will be fed a high-fat diet for 6 weeks, after which insulin secretion, proinsulin biosynthesis, and insulin gene expression will be assessed. Blood glucose levels will be normalized in GK rats by phloridzin administration, in an attempt to prevent the deleterious effects of high-fat diet on betacell function. These experiments will provide important insights into the pathophysiology of beta-cell dysfunction of type 2 diabetes, and have clear implications for the treatment of this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NIACIN, N-3 FATTY ACIDS AND INSULIN RESISTANCE Principal Investigator & Institution: Harris, William S.; Professor; St. Luke's Hospital 4401 Wornall Rd Kansas City, Mo 64111

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Timing: Fiscal Year 2003; Project Start 20-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The insulin resistance syndrome (IRS) afflicts approximately 47 million Americans. Its principal components include central obesity, elevated triglycerides, decreased high density lipoprotein cholesterol (HDL-C) levels, fasting hyperglycemia, and/or hypertension. Individuals with the IRS are at significantly increased risk for developing type 2 diabetes mellitus and/or coronary heart disease (CHD). While diet and exercise can improve some manifestations of the IRS, pharmacotherapy is often needed to normalize other components. In recent studies from our laboratory, niacin and fish oil (n-3 fatty acids, FA) used in combination in individuals with the IRS improved the lipid phenotype, but also, unexpectedly, the mealinduced suppression of free fatty acid (FFA) flux (an important indicator of adipose tissue insulin sensitivity). This project will explore the clinical efficacy of combined (and mono-) therapy with n-3 FA and niacin on CHD risk factors, on triglyceride and FFA kinetics and on glucose disposal rates in subjects with the IRS. We will conduct a single, randomized, parallel-arm, placebo-controlled trial. Subjects with the IRS (per the NCEP ATP-itl guidelines) will be randomly allocated to one of four intervention groups after a one-month dual placebo run-in period. The groups will be: n-3 FA (3.4 g/d), crystalline niacin (3 g/d), the combination, or duat placebo. The latter two groups will include 20 subjects each while the two-monotherapy arms will have 10 subjects each. Effects on endpoints will be determined at baseline and after four months of treatment. The CHD risk factors include serum lipids and lipoproteins; lipoprotein(a); subfractions of HDL and of low density tipoproteins; tissue plasminogen activator and plasminogen activator inhibitor-1; and blood pressure. Triglyceride kinetics will be determined by bolus injection of 2H/5-glycerol, and FFA kinetics by isotope dilution using a constant infusion of 3H-palmitate in the fasting state, after a standard mixed meal and during the hyperinsulinemic-euglycemic clamp procedure used to evaluate glucose disposal rates. At the completion of these studies, we expect to have detailed information on the potential therapeutic efficacy and the kinetic mechanisms of action of these two nutritional agents. This should lead to more effective therapy for the dyslipidemia of insulin resistance and ultimately to reduced risk for CHD in this burgeoning patient population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NONCELL AUTONOMOUS CONTROL OF BETA ISLET CELLS Principal Investigator & Institution: Degregori, James V.; Associate Professor; Biochem & Molecular Genetics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 04-JUN-2003; Project End 31-MAY-2005 Summary: Type I insulin dependent diabetes mellitus (IDDM) is a familial disorder with primarily juvenile onset that is characterized by the autoimmune destruction of beta islet cells in the pancreas, resulting in insufficient insulin secretion and hyperglycemia. Type II or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes, with both genetic and environmental (particularly obesity) factors contributing to its development. The inability of pancreatic beta cells to compensate for increased insulin demand, such as by increased proliferation, in obese individuals appears to contribute to NIDDM. The E2F transcription factor family plays critical roles in the regulation of cell cycle progression. Our recent studies of mice deficient for the E2F1 and E2F2 transcription factors have revealed essential roles for these proteins in the regulation of pancreatic beta cell maintenance. Mice deficient for both E2F 1 and E2F2 develop non-autoimmune insulin dependent diabetes with high penetrance.

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Surprisingly, the requirement for E2F 1 and E2F2 in preventing beta islet cell loss does not appear to be autonomous to islet cells, but instead appears to reside in bone marrow cells, as transplantation ofwildtype bone marrow can prevent or rescue diabetes in E2F1-/-E2F2-/- mice. We propose to characterize the nature of this non-islet autonomous control of beta islet cell maintenance. Understanding how beta islet cell maintenance is influenced by bone marrow derived cells should provide important insight into the design of therapies to boost islet mass and function in patients with either Type I or II diabetes. We propose three specific aims, although the first two aims should represent the bulk of our efforts. The third aim will require a more defined description of the bone marrow derived cell type(s) that mediates islet maintenance, such that at this point the exact mouse mutants to be analyzed is speculative. 1) Prevention of beta islet degeneration in E2F1-/-E2F2-/- mice by transplantation of defined hematopoietic subsets. 2) Further characterization of non-cell autonomous control of beta islet maintenance using islet transplantation. 3) Analysis of beta islet mass and function in mutant mice with defined hematopoietic defects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OXIDANTS, EICOSANOIDS, AND ENDOTHELIUM IN DIABETES Principal Investigator & Institution: Cohen, Richard A.; Associate Professor; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2003 Summary: (provided by applicant): Oxidant stress is widely recognized to play a role in functional alterations that develop in cells exposed to hyperglycemia and hyperlipidemia in the diabetic milieu, and has been implicated as a mechanism that accelerates atherosclerosis in diabetes. The mechanisms by which diabetes increases oxidant stress, and those by which oxidant stress modifies endothelial function are poorly understood. Our preliminary studies establish new insights into how elevated glucose increases oxidant stress and the mechanisms by which its effects on cell function are mediated. Exposure of cultured human endothelial cells to elevated glucose for 7-10 days increases the production of both NO and superoxide anion (O2-), and consequently decreases the bioactivity of NO as indicated by decreased levels of cyclic GMP. Further evidence that NO is inactivated by reacting with O2- to form the reaction product, peroxynitrite (00N0-) is found in the increased levels of its reaction product with tyrosine, 3-o-nitrotyrosine, found in the cells. While the function of many proteins may be affected, we have found that prostacyclin synthase (PGIS) is particularly susceptible to tyrosine nitration; the levels of nitrated PGIS increase and its activity decreases in endothelial cells grown in elevated glucose. This may not only explain why diabetes decreases levels of PGI2, but also why increases have been noted in its precursor PGH2 that activates thromboxane A2 receptors (TPr). Our studies have shown that activation of TPr can modulate ICAM-1 and VCAM-l expression in human endothelial cells. The expression of adhesion molecules is enhanced by 02-, and indeed, exposure to elevated glucose enhances adhesion molecule expression. Thus, oxidant stress induced by elevated glucose may modulate the activity of PGIS and stimulation of TPr, thereby modulating adhesion molecule expression. Indeed, we have found that blockade of TPr inhibits atherosclerosis in the Apo E deficient mouse, a model in which diabetes enhances atherogenesis. There are three specific aims: 1) to determine the mechanism by which elevated glucose and fatty acids increases production of NO and 02- and causes tyrosine nitration and inactivation of PGI synthase, 2) to determine the role of TPr stimulation by eicosanoid products due to endothelial cell oxidant stress and PGI synthase inactivation in causing the increased leukocyte adhesion and apoptosis caused

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by high glucose and fatty acids, and 3) to determine if oxidant stress and PGI synthase inactivation contributes to the increased atherogenesis caused by diabetes in transgenic mouse models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OXIDATIVE STRESS AND POST-MI HEART FAILURE IN DIABETES (PILOT) Principal Investigator & Institution: Hill, Michael F.; Meharry Medical College 1005-D B Todd Blvd Nashville, Tn 37208 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: Patients with Diabetes Mellitus (DM) manifest an increased incidence of congestive heart failure (CHF) following myocardial infarction (MI), which presages a reduced survival rate. This has been shown not to be due to a greater extent of infarction associated with DM. The long-term goals of our studies is to understand the mechanisms that contribute to the progressive deterioration of cardiac function and eventual development of CHF in the diabetic heart following an MI. The current project is based on observations that hyperglycemia secondary to diabetes and non-diabetic post-MI heart failure are associated with increased oxidative stress and an antioxidant deficit. Based on these observations, we propose that the coexistence of diabetes and MI exacerbates the existing imbalance between the antioxidant defense system and freeradical production already present in each of these pathologies individually, leading to a quantitative deficiency of antioxidants that predisposes the surviving diabetic myocardium to cumulative, uncontrolled oxidant damage and subsequent failure after MI. The specific aims of the proposed project are: 1) to assess myocardial enzymatic and non-enzymatic antioxidants and concomitant oxidative stress in the remaining, viable diabetic myocardium after MI; 2) to determine the protein expression of the myocardial antioxidant enzymes, and 3) to determine the effects of long-term antioxidant therapy on the occurrence of heart failure following MI in the diabetic heart. The proposed studies will be conducted in streptozotocin (STZ)-induced diabetic rats using the wellestablished coronary-artery ligation model of post-MI heart failure. The objectives of these studies are to delineate the mechanisms by which diabetes adversely affects the functioning of the surviving myocardium after MI and to establish novel therapies aimed at reversing the functional deficit associated with diabetes during the post-MI period. The results of this project will provide a new understanding of the factors that contribute to CHF among diabetics with MI and may form the basis for developing more effective therapeutic interventions for the management of diabetic MI patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: 'PARENT-CHILD CO-REGULATION OF PEDIATRIC DIABETES' Principal Investigator & Institution: Gonder-Frederick, Linda A.; Associate Professor; Psychiatric Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Successful diabetes management relies on a process of self-regulation in which treatment behavior is guided by feedback about changing blood glucose (BG) levels and decision-making. The processes involved in selfregulation have been studied extensively in adults with Type 1 Diabetes Mellitus (T1DM), leading to the development of sophisticated research tools that have significantly advanced our understanding and ability to predict clinical outcome.

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Additionally, this research has led to the development of a highly effective, empirically based, psychobehavioral intervention, Blood Glucose Awareness Training (BGAT), developed by our research team, that improves self-regulation and clinical outcome in adults with T1DM. Unfortunately, the processes involved in the self-regulation of pediatric diabetes have received virtually no empirical attention. The purpose of the proposed project is to correct this scientific neglect by adapting the conceptual and methodological tools used in adult studies to 1) investigate the process of diabetes regulation by school-aged children (6-11 yrs) with T1DM and their parents and 2) develop and test an intervention to enhance the skills critical to this process. This is an important population to target for this line of inquiry because: 1) children with T1DM and their parents appear to be far less accurate than adult patients in symptom and BG detection; 2) As a group, pediatric patients are more likely to suffer from negative clinical sequelae (e.g., severe hypoglycemia (SH) and DKA); and, 3) Early intervention could have greater public health care benefit by achieving more reductions in acute and long-term complications, health care utilization, and disability. Phases 1A and 1B of the proposed project will provide the first systematic and comprehensive study of symptom recognition, BG detection, decision-making, and subsequent clinical sequelae in schoolaged children with T1DM and their parents. A theoretical model of co-regulation of pediatric diabetes is proposed and tested, in which the behaviors of both parent and child influence the sequence of events that determine avoidance or occurrence of negative outcomes, such as extreme hypo- and hyperglycemia. Based on the findings of these studies and our current BGAT for adults, Phase 1 C will pilot test a translation of this intervention designed for parents of school-aged children with T1DM, BGAT for parents (BGAT-P). This intervention will take advantage of the critical role parents play as the primary teachers of children about diabetes management by including training activities for parents to do with their children designed to improve children's ability to recognize BG symptoms, detect extremes in BG, and make appropriate self-treatment decisions. Based on the findings from this pilot study, and feedback from parents, in Phase 2 BGAT-P will be further refined and tested in a controlled clinical trial to assess its short-term efficacy. Phase 3 is a 12-month follow-up study to determine whether the improvements found in Phase 2 are maintained over time and also to assess the impact of BGAT-P on future clinical negative events, including frequency of SH and DKA experienced by children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOBIOLOGY OF MACROVASCULAR DISEASE IN DIABETES Principal Investigator & Institution: Chait, Alan; Professor of Medicine; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-SEP-1976; Project End 31-MAR-2002 Summary: The overall objective of this research program is to gain understanding of the genetic, cellular, biochemical and molecular nature of premature atherosclerosis in diabetes mellitus. There are five interrelated projects: (1) The role of hyperglycemia, diabetic nephropathy and the development of central obesity with intensive insulinization in determining the levels, distribution and composition of lipoproteins: It is proposed that part of the excess incidence of premature disease is related to the dyslipidemia that results from these variables in diabetes; (2) Therole of diabetes on the interaction between lilpoproteins and proteoglycans of the artery wall: It is hypothesized that alterations in lipoprotein and or proteoglycans as a results of diabetes will facilitate their interaction in such a manner that would result in the retention of lipoprotein in the artery wall in diabetes; (3) The effect of diabetes on HDL-mediated

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cholesterol efflux: This project will evaluate how modifications of lipoproteins affect two distinct pathways of cholesterol efflux from cells, passive desorption and apolipoprotein-mediated efflux, and will focus on how changes in HDL structure in diabetes affects HDL function; (4) The role of non-enzymatic glycation of endothelial cell matrix proteins on the signaling pathways activated by physiologic fluid flow: The major hypothesis is that nonenzymatic glycation of extracellular matrix proteins makes them "slippery" and unable to participate normally in the transduction of physicochemical signals in response to fluid flow, which is the primary determinant of the production of endothelial-derived nitric oxide, a critical mediator of vascular homeostasis; (5) Molecular mechanisms of oxidation damage in diabetes: The hypothesis is that oxidant stress due to glucose autoxidation and/or protein glycation results in highly specific biologically active reaction products that can be used to detect glucose-mediated oxidative damage in vivo. This focus on the effects of diabetes on basic biological mechanisms of atherosclerosis should help establish which alteration are preventable or reversible, and will provide a rational basis for the prevention of this major complication of diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEROXISMAL AND MITOCHONDRIAL B-OXIDATION IN OBESITY Principal Investigator & Institution: Lee, Wai-Nang P.; Professor; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 90502 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-JUL-2004 Summary: Peroxisomal and mitochondrial beta-oxidation are two principal pathways of fatty acid oxidation which regulate the nature and concentration of intracellular acylCoA and energy rich molecules. The integration of these two systems permits the animal to adapt to a wide range of nutrient composition without suffering from hyperglycemia or hyperlipidemia. This application proposes to investigate the role of these two pathways in the adaptation to nutrient composition and in the development of obesity and diabetes in the Zucker obese and diabetes model. Specific Aim 1: Test the hypothesis that the contribution of peroxisomal and mitochondrial beta-oxidation varies depending on the chain length and desaturation of the fatty acid (nutrient specific). Specific Aim 2: Test the hypothesis that two hormonal systems (insulin and leptin) affect fatty acid synthesis and oxidation differently to regulate gluconeogenesis and lipogenesis. Specific Aim 3: To examine peroxisomal and mitochondrial oxidation in obesity and diabetes using Zucker obese and Zucker diabetic models. Specific Aim 4: To test the hypothesis that the effect of PPAR ligands on fatty acid oxidation interacts with the leptin receptor signaling pathway to improve both glucose and lipid metabolism. A key feature of this proposal is the use of [1-13C]- and [U-13C]-fatty acids and mass spectral technologies to determine the relative contributions to the acetyl-CoA pool from fatty acyl chain shortening and elongation (peroxisomes) to mitochondrial betaoxidation. These studies should provide new conceptual and experimental tools for the study of fatty acid oxidation regulation, a central issue in the pathophysiology of obesity and Type II diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PGC-1 AND THE CONTROL OF HEPATIC GLUCONEOGENESIS Principal Investigator & Institution: Spiegelman, Bruce M.; Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAR-2007

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Summary: (provided by applicant): Hepatic gluconeogenesis a very important component at glucose homeostasis. Glucose synthesis and secretion by the liver is induced during fasting; it is strongly suppressed by insulin and is inappropriately activated in both type 1 and type 2 diabetes. Hepatic gluconeogenesis is a major contributor to the hyperglycemia of diabetes, particularly in the fasted state. We have recently shown that key gluconeogenic agents/hormones - cyclic AMP and glucocorticoids - induce the transcriptional coactivator PGC-1. When expressed at physiological levels in primary hepatocytes or liver in vivo, PGC-1 activates the entire program of gluconeogenesis including the secretion of glucose. These data suggest that PGC-1 is a central target of the gluconeogenic hormones, linking these agents to the transcriptional activation of PEPCK and other key genes. For Specific Aims, we will first examine in detail how PGC-1 regulates the PEPCK promoter. In particular, we will utilize a variety of hormonal conditions and the PEPCK promoter to determine the key transcriptional factor targets for PGC-1 docking. Interactions between PGC-1 and HNF4alpha glucocorticoid receptor and/or other components will he studied in close molecular detail, investigating critical amino acids residues that serve to form the coactivator/transcription factor pairing. Our second aim will he to critically analyze the genetic role of PGC-1 in gluconeogenesis through construction of liver-specific transgenic mice expressing PGC-1, and a liver-specific PGC-1 knock-out. Mice will he studied for the activation of key genes of gluconeogenesis and metabolism of glucose in vivo, utilizing glucose clamp techniques and tracers. These mice will also be valuable to study the genetic relationship between PGC-1 and potential transcription factor targets, utilizing crosses between the PGC-1 transgenic mice and transcription factor knock-out mice. Our last major aim will be to study how gluconeogenic hormones regulate PGC-1 transcription, utilizing transfection of PGC-1 promoters into hepatocytes treated with insulin, cyclic AMP and glucocorticoids. We are especially interested in determining whether insulin suppresses PGC-1 expression through FKHR, CREB or potentially novel factors. Novel and important components regulating the PGC-1 promoter will be isolated, cloned and characterized. These studies together should provide critical insights into mechanisms controlling the process of gluconeogenesis. This also has the clear potential to lead to the development of new anti-diabetes drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PILOT STUDY--GENES MEDIATING PANCREATIC BETA CELL MASS Principal Investigator & Institution: Brillantes, Anne-Marie B.; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 31-JAN-2008 Summary: The goals of this pilot/feasibility grant are two-fold: i) to optimize in vitro protocols for the study of replicating and apoptotic beta cells from cultured mouse pancreatic islets, and ii) to identify functionally relevant cellular and molecular mechanisms employed by pancreatic beta cells to adapt to hyperglycemia and increased insulin demand. To date, downstream beta cell-specific transcripts for glucosestimulated signaling pathways controlling beta cell growth, replication and survival remain largely unknown. By exploiting the divergent beta cell phenotypes of the diabetes susceptible C57BLKS/J (KS) mice and the diabetes resistant C57BL6/J (B6) mice in response to hyperglycemia, the PI proposes to identify functionally relevant beta cell genes and signaling pathways involved in the control of compensatory beta cell mass. The PI hypothesizes that distinct beta cell adaptive phenotypes characterizing these two inbred mouse strains are mediated by allelic differences that result in the discordant

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regulation of beta cell-specific gene transcripts in response to glucose-stimulation. In Aim 1, she will develop sensitive immunoflourescence-based protocols to characterize differential glucose- and/or growth factor-mediated beta cell replication and/or apoptosis rates between KS and B6 islets to guide vetting of candidate genes identified in Aim 2. In Aim 2, she will generate a list of candidate molecules associated with the success or failure of beta cell adaptation to excess glucose stimulation by using massive parallel analysis of gene expression in pancreatic islets of B6 and KS mice. She will narrow the selection of candidate genes by virtue of their discordant regulation in response to hyperglycemia between the two strains, their position in divergent areas of the B6 and KS genome, and their consistent regulation across several experimental models of hyperglycemia. In Aim 3, she will functionally analyze candidate genes using in vitro islet expression studies to identify genes whose altered expression can mediate predicted changes in beta cell replication or apoptosis. In follow-up experiments, candidate genes that show functional relevance to beta cell replication or apoptosis will be tested in vivo using using transgenic mouse experiments. Elucidating the cellular and molecular mechanisms of beta cell adaptation to glycemic stress will ultimately contribute to the development of therapeutic strategies directed towards the prevention and cure for diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PLACENTAL GLUCOSE TRANSPORT IN DIABETIC PREGNANCIES Principal Investigator & Institution: Illsley, Nicholas P.; Professor; Ob/Gyn & Women's Health; Univ of Med/Dent Nj Newark Newark, Nj 07103 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Diabetes in pregnancy is associated with a number of perinatal problems such as macrosomia and neonatal hypoglycemia. There is also evidence suggesting that diabetes or even impaired glucose tolerance during pregnancy may be risk factors for the development of diabetes in the offspring. It is clear that the perinatal consequences of gestational diabetes are not simply a function of maternal hyperglycemia, since macrosomic infants are frequently born to mothers whose diabetes is well controlled. Preliminary research suggests that there are increases in the expression and activity of GLUT1 glucose transporters in the syncytial basal membrane of placental tissue from women whose diabetes is adequately controlled. Thus there appear to be continuing perturbations in a system intimately involved in fetal growth and development. It is hypothesized that elevated fetal glucose, resulting from maternal fetal hyperglycemia, causes, through stimulation of fetal growth factors, increased fetoplacental growth including increased expression of the basal membrane GLUT1 glucose transporter, the rate-limiting barrier to placental glucose transport. The resultant increase in transplacental glucose flux prolongs fetal hyperglycemia and leads to continued derangement of the fetal growth axis, despite normalization of maternal plasma glucose. This project is designed to explore this hypothesis by investigating the expression and activity of the human placental GLUT1 glucose transporter in diabetic pregnancies. Aim number 1 : To characterize the changes in placental glucose transporter expression and activity in diabetic pregnancy and to correlate these parameters with measures of maternal glycemic status and fetal growth factors. Aim number 2 : To assess the functional consequences of changes in glucose transporter expression and activity for the placental transfer of glucose. Aim number 3 : To establish the mechanisms responsible for the changes in glucose transporter expression and activity through transcriptional and posttranscriptional modulation and through short term regulatory events. Aim number 4 : To examine the mechanisms governing the (re)distribution of

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transporters between microvillous and basal membranes. The information obtained from these experimental approaches will significantly advance our understanding of the fetal response to maternal diabetes and the factors generating adverse perinatal consequences. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PODOCYTE DYSFUCTION IN DIABETIC GLOMERULOPATHY Principal Investigator & Institution: Chen, Sheldon C.; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: Dr. Sheldon Chen is currently conducting his research in the laboratory of Dr. Faud N. Ziyadeh at the University of Pennsylvania, which boasts a world-renowned biomedical community and provides state- of- the-art facilities, superb human resources, and outstanding technical support. By completing the proposed project, Dr. Chen hopes to acquire new technical expertise, improve his ability to synthesize data into a credible paradigm, hone his critical thinking skills, and afterwards pursue novel or related research that expands upon his findings. After an additional year of mentored fellowship research training, he will join the faculty of the Renal Division at the University of Pennsylvania, where he hopes to mature into a fully-independent academic physician-scientist. Diabetic kidney disease remains the number one cause of renal failure in the United States. As the defining metabolic abnormality in diabetes mellitus, high blood glucose undoubtedly plays an important role in the pathogenesis of diabetic nephropathy. Our laboratory has discovered that Transforming Growth Factorbeta (TGF-beta) mediates much of the injuries effect of hyperglycemia, and the two metabolic factors may conspire to cause even greater renal damage. The podocyte is a highly specialized epithelial cell in the glomerulus that synthesizes part of the glomerular basement membrane (GBM) and regulates the macromolecular permeability across the glomerular filtration barrier. Podocyte dysfunction secondary to the deleterious environment of the diabetic milieu may contribute to the GBM thickening and increased macromolecular permeability leading to proteinuria in diabetic glomerulopathy. Recent cell culture advances have allowed us to study the in vitro podocyte in its fully differentiated state. We propose to examine the effects of high glucose and exogenous TGF-beta on the cultured, differentiated mouse podocyte with respect to the altered expression of type IV collagen and vascular endothelial growth factor (VEGF), two proteins that are likely involved in the pathophysiology of GBM thickening and diabetic proteinuria. Northern analysis will be used to quantitate the gene expression, and immunoblotting and ELISA will be used to measure the protein production of the component alpha chains of collagen IV and the isoforms of VEGF in response to high glucose and TGF-beta treatment. Whether high glucose and TGF-beta have synergistic effects will also be investigated. The cellular mechanisms underlying the high glucose-induced expression of the TGF-beta signaling receptor (preliminary data), which may explain the hypothesized high glucose/ TGF- beta synergy, will be elucidated by the nuclear runoff technique, analysis of promoter activity by luciferase reporter assay, and electrophoretic mobility shift assay. Lastly, specific inhibitors of TGF-beta will be used to determine whether some of the high glucose effects may be mediated by the TGF-beta system in the podocyte. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: POST-DPP FOLLOW-UP STUDY Principal Investigator & Institution: Crandall, Jill; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2003; Project Start 15-AUG-1994; Project End 31-JAN-2008 Summary: (provided by applicant): The Diabetes Prevention Program is a multicenter controlled clinical trial examining the efficacy of an intensive life-style intervention or metformin to prevent or delay the development of diabetes in a population selected to be at high risk due to the presence of impaired glucose tolerance (IGT). Development of diabetes, defined by 1997 ADA criteria, is the primary outcome while cardiovascular disease and its risk factors are important secondary outcomes. The DPP began recruitment in mid-1996. At the time of this application, total study exposure is a mean of approximately 3 years (range 2 to 5) with a total of approximately 10,000 patient years in the 3,234 volunteers in the 3-arm study. On the basis of a statistically significant and clinically compelling decrease in the development of diabetes in the life-style intervention and metformin-treated groups (58% and 31% reductions, respectively) compared with the placebo treated group, the DPP Data Monitoring Board and NIDDK ended the masked treatment phase of the study in May, 2001, one year earlier than originally planned. This application is designed to take further advantage of the scientifically and clinically valuable cohort of DPP volunteers and the large volume of data collected during the study. The highly compliant DPP cohort, including 45% minorities, is the largest IGT population ever studied. Moreover, the subcohort that has developed diabetes (n approximately 700) has been followed from near the exact time of diabetes onset. Clinically important research questions remain in the wake of the DPP. The carefully collected, centrally measured and graded data in this cohort should help to answer, definitively, a number ofvolunteers with impaired glucose tolerance and volunteers whose diabetes developed during the DPP to determine the natural history of diabetic complications. This analysis will be epidemiologic in nature with all groups being pooled with prior treatment being used as a co-variate. Finally, the same data will be used to examine the effects of gender, age, and race/ethnicity on diabetes and its vascular complication. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROJECT SUGAR2: HEALTH EVENTS & COSTS IN DIABETIC BLACKS Principal Investigator & Institution: Brancati, Frederick L.; Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-SEP-1994; Project End 31-MAR-2005 Summary: (Adapted from Investigator's Abstract) Diabetes mellitus imposes a major burden on the public health of the United States, leading annually to over 300,000 deaths and over $130 billion in costs. This burden falls disproportionately upon ethnic minority groups, particularly African Americans, who are at excess risk for the development of type 2 diabetes and for a variety of its most serious complications. Suboptimal health care in terms of access, quality, and adherence, appears to be an important contributing factor. Over the past 5 years, the investigators have developed and tested a multifaceted behavioral approach to enhance health care for urban African Americans with diabetes. In this approach, a Nurse Case Manager/Community Health Worker team works to identify and surmount barriers to optimal care on both the patient side (e.g., inadequate health knowledge, insufficient finances, distracting life events, nonadherence) and the primary care provider side (e.g., suboptimal monitoring or

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treatment of hyperglycemia, hypertension, or dyslipidemia). Preliminary analyses indicate that this intensive team approach, compared to usual care alone, produces substantial improvement in metabolic control, therefore offering the promise of health benefits 5-15 years hence. Yet however attractive the projected long-term benefits, economic realities compel managed care organizations to focus on actual benefits and costs in the short term, i.e., the two to four year interval which corresponds to both concrete financial planning and average duration of enrollment. Therefore, the investigators propose to conduct a randomized, controlled trial within a managed care organization to determine the effects of an Intensive Intervention (executed by a Nurse Case Manager/Community Health Worker team) on metabolic control, on the occurrence of diabetes-related health events and health care utilization, and on direct health care costs. The participants will be 800 African American adults with type 2 diabetes who receive primary care within a managed care organization in inner-city Baltimore, and who are at elevated risk for diabetic complications (e.g., suboptimal glucose or blood pressure control, missed primary care appointments, recent hospitalizations). The investigators hypothesize that within 3 years the up-front costs of the Intensive Intervention will be largely offset by savings related to reduced rates of ER visits, hospitalizations, and surgical procedures which result from improved metabolic control and other enhancements of primary care. If so, the investigators state that this project will provide strong evidence for the adoption of the Intensive Intervention locally and in other managed care organizations which provide care for high-risk urban minority populations. They further state that it would thereby contribute to nationwide efforts aimed a eradicating the excess risk of diabetic complications in African Americans and serve as a model for translational research related to other chronic medical conditions in minority populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTEASE INHIBITOR-INDUCED HYPERLIPIDEMIA IN AIDS Principal Investigator & Institution: Brown, Virgil W.; Professor of Medicine; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 28-SEP-2000; Project End 31-JUL-2005 Summary: (Adapted from the applicant's abstract) HIV-protease inhibitors (PI) prevent the maturation of nascent virions and are thus very effective in blocking further infection in HIV-positive patients. Significant reductions in mortality from AIDS have been achieved with the use of PI. Cross-sectional studies, however, have suggested accelerated atherosclerosis in HIV-positive patients receiving PI therapy and this may be associated with high prevalence of several risk factors for atherosclerosis: hyperlipidemia, hyperglycemia, insulin resistance and fat redistribution. The exact mechanisms underlying these metabolic changes are not known. Based on homology studies, HIV-protease inhibitors may interfere with the function of the low density lipoprotein receptor-related protein (LRP) and the cytoplasmic retinol binding protein (CRBP). LRP is responsible for the hepatic uptake of intestinal lipoproteins transporting dietary fats and fat- soluble vitamins such as vitamin A. Inside the cell, the transport of retinoic acid by CRBP may interact with peroxisome proliferator activator receptor (PPAR) and thus affect the production of apoC-III and the differ- entiation of adipocytes. Using non-radioactive tracers, we propose to examine the changes in lipoprotein metabolism associated with HIV infection and the therapeutic use of PI. The metabolism of oral retinol will be examined with respect to the effect of PI on LRP. The production of apoC-III, a PPAR- regulated apolipoprotein linked to hypertriglyceridemia and diabetes, will be examined with respect to its association in

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PI-induced hypertriglyceridemia. While hyperlipidemia may be associated with atherosclerosis, it cannot explain the accelerated progression of the disease. Changes in physiological and biochemical responses with oxidative stress associated with postprandial lipemia will be examined as a possible mechanism for accelerated disease progression. A comprehensive longitudinal study with new markers for CAD will also be conducted to characterize the progression of the risk factors with PI. In a subset of patients with hyperlipidemia, the efficacy of combined therapy with vitamin A, fibrates, and thiazoladinediones will be evaluated. These are specific agents that are effective in reducing triglyceride as well as improving insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTECTIVE MECHANISMS IN THE CEREBRAL VASCULAR WALL: ROL Principal Investigator & Institution: Faraci, Frank M.; Professor; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: Nitric oxide (NO) plays a major role in cerebral vascular structure and function and the bioactivity of NO depends, in part, on its interaction with superoxide. The role of superoxide in models of brain injury has received considerable attention, but the role of superoxide within the wall of cerebral blood vessels is poorly understood. The overall goal of these studies is to utilize novel approaches to examine the role of cytosolic superoxide dismutase (CuZn-SOD) and mitochondrial (Mn- SOD) within the cerebral vascular wall. Studies are proposed to examine the hypothesis that CuZn-SOD plays a critical role in normal function of cerebral blood vessels. Pharmacological approaches and genetically- altered mice will be used to alter activity of CuZN-SOD and thus begin to define the role of this isoform of SOD. Angiotensin II may contribute to oxidative stress in blood vessels during chronic hypertension. Using a transgenic mouse model that over-expresses human renin and human angiotensinogen (R+/A+) as well as CuZn-SOD, we will examine the hypothesis that superoxide and activity of CuZn-SOD influence structure and function in carotid artery and cerebral circulation during hypertension Mn-SOD is expressed in high levels in endothelium and cerebral arteries express more Mn-SOD than extracranial blood vessels, but the functional significance of Mn-SOD is not known. Studies are propose to examine the hypothesis that Mn-SOD protects cerebral endothelium and vascular function under basal conditions. Additional experiments will examine the hypothesis that Mn-SOD limits superoxide and endothelial dysfunction in response to hyperglycemia, which increases superoxide in mitochondria. Mn-SOD is unique among the SODs in that expression of Mn-SOD is increased in response to oxidative stress. Thus, we will also examine the hypothesis that Mn-SOD is up-regulated and limits increases in superoxide and vascular dysfunction in response to lipopolysaccharide (endotoxin), a model of inflammation that generates oxidative stress in the vessel wall. Thus, modern molecular approaches will be used to define the role of CuZn- and Mn-SOD in cerebral blood vessels under normal conditions and in models of hypertension, inflammation, and diabetes. These studies may provide greater insight into the role of superoxide and SODs in cerebral vascular biology as well as mechanisms of vascular dysfunction believed to contribute to carotid artery disease, cerebral vascular dysfunction, and stroke. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROTEIN NITRATION IN THE PLACENTA Principal Investigator & Institution: Myatt, Leslie; Professor; Obstetrics and Gynecology; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Preeclampsia and pregestational diabetes are both associated with oxidative stress in the placenta which may lead to alterations in vascular function in the fetal-placental circulation and with altered trophoblast function. Both the syncytiotrophoblast and the vascular endothelium are sites of nitric oxide (NO) synthesis. The superoxide anion may regulate the bioactivity of NO as superoxide scavenges NO. The interaction of NO and superoxide however produces a relatively long-lived potent pro-oxidant the peroxynitrite anion which is highly toxic, being able to inhibit mitochondrial electron transport, oxidize protein sulphydryls groups, initiate lipid peroxidation and nitrate tyrosine residues on proteins, thus inhibiting signal transduction pathways. Peroxynitrite will damage the vasculature altering reactivity and may give rise to vascular dysfunction. Protein nitration may be a physiologic regulatory mechanism that may affect protein function or prevent further phosphorylation. Previously we have shown nitrotyrosine residues in the vascular endothelium and villous stroma of placentae from pregnancies complicated by preeclampsia or pregestational diabetes. Treatment of the placental vasculature in vitro with authentic peroxynitrite altered vascular reactivity, blunting responses to both vasoconstrictors and vasodilators, a finding similar to that in pregnancies complicated by preeclampsia or pregestational diabetes suggesting that peroxynitrite in vivo damages the fetal-placental vasculature. Using a proteomics approach we have found, with 2D gel electrophoresis and immunoprecipitation, that phospho p38 MAP kinase appears to be nitrated in the placenta and greater nitration is found in the preeclamptic placenta. Using functional assays we have shown that nitration appears to inhibit p38 MAP kinase catalytic activity. In addition we have identified p53 and PARP as nitrated proteins in these placentae. Using in vitro perfusion, cell culture and proteomic approaches we will test the overall hypothesis that generation of oxidative stress by hypoxia, hypoxia/reoxygenation or hyperglycemia leads to increased peroxynitrite synthesis and action which in turn gives increased nitration of placental proteins (specifically p38 MAP Kinase, p53 and PARP) and alters their function in the placental vascular endothelium and syncytiotrophoblast. We will use site-directed mutagenesis to identify the tyrosine residues that are nitrated in p38 MAP kinase and the functional significance of this. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RACE, RENIN, GENES, RISK, AND DIABETIC NEPHROPATHY Principal Investigator & Institution: Hollenberg, Norman K.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 17-AUG-1998; Project End 31-JUL-2004 Summary: African Americans carry a 3-6 fold increased risk of developing nephropathy as a complication of diabetes mellitus (DM), essential hypertension (HTN), and probably other conditions. Although an increased frequency and severity of HTN and socioeconomic factors that limit health care probably contribute, multiple observations indicate that more important alternative factors are also involved. Fields ranging from epidemiology and therapeutic trials to molecular biology and genetics indicate that the renin-angiotensin system (RAS) contributes to the risk of nephropathy via mechanisms that include but go beyond HTN, perhaps involving the contribution of the RAS to

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growth and repair hyperplasia, and hypertrophy. Our application is based on several unanticipated observations. First, in healthy African Americans, age- adjusted renal plasma flow (RPF) was substantially less than in Caucasians, assessed in an identical protocol. Moreover, despite a high salt diet, African Americans displayed an enhanced renal vasodilator response to angiotensin-converting enzymic (ACE) inhibition with captopril, which enhanced renal vascular responsiveness to angiotensin II (Ang II). This pattern (which clearly differs from that in Caucasians and is similar to our preliminary observations in patients with DM) suggests activation of the RAS. Second, in our noninsulin- dependent Type 2 DM patients, our preliminary data suggest a range of hitherto unrecognized RAS abnormalities reflecting inappropriate activation and autonomous renin release. Most surprising is the paradoxical extreme RAS activation at the renal tissue level Type 2 DM patients with very low plasma renin activity (PRA) and nephropathy. Evidence for a functional contribution comes from hemodynamic measurements made during pharmacological interruption of the RAS with ACE inhibitors and Ang II antagonists, and during Ang II infusion. In Type 2 DM, race is a critical determinant of risk. Third, we have made observations which indicate that acute hyperglycemia activates the intrarenal system and induces striking Ang II-dependent vasoconstriction. Our hypothesis is that the increase in risk of nephropathy represents an interaction between genetic predisposition based on the increased frequency of an angiotensinogen (AGT) gene polymorphism that favors renin system activation, an action of obesity and insulin resistance to amplify the effect of the polymorphism on AGT; and the renal effects of hyperglycemia to activate the intrarenal system in a setting which would favor local intrarenal Ang II production. Our goal in this study is to explore preliminary evidence that RAS activation accounts for many Type 2 DM features involving renal risk, and racial differences in risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF NET HEPATIC GLUCOSE UPTAKE IN VIVO Principal Investigator & Institution: Cherrington, Alan D.; Professor & Chair; Molecular Physiol & Biophysics; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-APR-1991; Project End 31-MAR-2005 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RENAL CONTROL OF BLOOD PRESSURE IN EARLY DIABETES Principal Investigator & Institution: Brands, Michael W.; Professor; Physiology and Endocrinology; Medical College of Georgia 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2008 Summary: (provided by applicant): We have shown that the first onset of hyperglycemia in diabetes causes significant renal vasoconstriction and hypertension if it occurs under conditions of chronic nitric oxide (NO) synthesis inhibition. Those deleterious consequences of hyperglycemia are prevented by antioxidant treatment with the superoxide (SO) dismutase mimetic, tempol. The underlying hypothesis is that onset of hyperglycemia in early diabetes induces an angiotensin II-dependent, superoxide-mediated right-shift in the renal pressure-natriuresis relationship, and that nitric oxide is an important counteracting force that prevents hypertension. The experiments in this project will determine the mechanisms for these important interactions by testing the central hypothesis that nitric oxide counteracts angiotensin II-

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dependent, superoxide-mediated renal vasoconstriction to prevent hypertension during hyperglycemia early in diabetes. Experiments will test this by testing the 3 subhypotheses that: 1. Nitric oxide is required to prevent renal vasoconstriction and hypertension at the onset of diabetes. Our L-NAME, ACh, and glomerular filtration rate (GFR) data support this, but to better implicate NO and define the site(s) for its control of renal function in early diabetes, we will: a. measure renal blood flow 24 hr/d to quantify the changes in resistance and filtration fraction; b. determine the time-, glucose, and insulin-dependent changes in eNOS and nNOS; c. determine when, and if, vasodilatory prostaglandins assume the vasoprotective role of NO; d. determine the roles of eNOS vs. nNOS using knockout mice and infusion of antagonists. 2. Angiotensin II increases sensitivity to renal vasoconstriction and hypertension during hyperglycemia and is required for those responses to occur. Our evidence supports this role, but to determine Angll's importance independent of L-NAME-induced increases we will determine: a. whether low-sodium intake exacerbates the sensitivity of diabetic rats to NOS inhibition; b. the link between GFR and blood pressure by using decreased kidney mass to control GFR; c. whether onset of diabetes causes hypertension in rats with Angll hypertension; d. the superoxide-independent component of Angll's influence on MAP and renal resistance. 3. Superoxide induces a renal vasoconstrictor and hypertensive influence at the onset of hyperglycemia. We have shown that tempol prevents hypertension in L-NAME-treated diabetic rats, but to more specifically implicate SO, with or w/o NOS blockade, we will determine: a. whether antioxidant treatment can prevent hypertension without decreasing renin secretion; b. whether knockout of SO dismutase-1 (SOD1) exacerbates the hypertensive response; c. whether increased SOD1 in transgenic mice protects against hypertension similar to tempol; d. the role of NADPH oxidase, by measuring p22 phox expression and the effect of apocynin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETINAL OXYGENATION IN DIABETIC RETINOPATHY Principal Investigator & Institution: Berkowitz, Bruce A.; Professor; Anatomy and Cell Biology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Current treatments for diabetic retinopathy are not entirely successful. We reason that therapies could be more rapidly developed and evaluated than is currently possible if a patient's risk of developing retinopathy could be predicted early in the course of the disease. We have developed a unique functional magnetic resonance imaging (fMRI) technique that measures the change in partial pressure of oxygen (deltaPO2) in the vitreous humor while the subject breathes carbogen (95% O2: 5% CO2). Using this acute retinal "stress" test, we have shown that carbogen breathing in rats and mice at 3-4 months of diabetes (before the appearance of retinal lesions) produces a significantly reduced retinal deltaPO2 compared to normals. A subnormal deltaPO2 is consistent with the presence of hypoxia but it cannot yet be unambiguously interpreted as a measure of hypoxia. In addition, in 3 month diabetic rats, aminoguanidine (AMG) treatment prevented the decrease in retinal deltaPO2. AMG is known to prevent retinal lesion formation in diabetic rats and inhibit the activity of both the inducible form of nitric oxide synthase (iNOS) and protein kinase C (PKC) (among other actions). Hypothesis: Subnormal retinal deltaPO2 in experimental diabetes is correlated with retinal hypoxia (Aim 1), and increased iNOS and PKC activity (Aims 2 and 3) but precedes the appearance of histopathology. Specific Aim 1) To compare retinal PO2 and deltaPO2 before, and at 2 wks, and 3 and 9 months of

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diabetes in rats. fMRI and a carbogen challenge will be used to measure the retinal deltaPO2. To measure PO2, a perfluorocarbon droplet will be injected into the preretinal vitreous over superior or inferior retina and 19F magnetic resonance spectroscopy performed. Specific Aim 2) To compare the retinal deltaPO2 (at 3 months) and histology (at 3 and 15 months) in normal and diabetic rats with and without treatment with a selective iNOS inhibitor (L-NIL (L-N(6)-(1-iminoethyl)lysine)), and in normal, diabetic, and diabetic iNOS knockout mice. Specific Aim 3) To compare the retinal deltaPO2 (at 3 months) and histology (at 3 and 15 months) in normal and diabetic rats with and without treatment with a selective PKC inhibitor (LY333531). In addition, we will compare retinal deltaPO2 in normal mice, transgenic mice that overexpress PKC beta II, diabetic mice, and diabetic PKC beta II-knockout mice. The results of the proposed studies will prove whether or not changes in retinal deltaPO2 correlate with the development of retinal hypoxia or multiple biochemical abnormalities that are associated with diabetic retinopathy but cannot be measured in vivo by existing techniques. The results of these studies could lead to the development of a non-invasive real time method for the early evaluation of diabetic retinopathy and its treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF 12-LIPOXYGENASE IN DIABETIC NEPHROPATHY Principal Investigator & Institution: Natarajan, Rama D.; Professor; City of Hope National Medical Center Duarte, Ca 91010 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by the applicant): Several factors contribute to the pathogenesis of diabetic nephropathy (DN), including hyperglycemia, advanced glycosylation end products (AGEs), and the rennin angiotensin system. These factors can lead to glomerular expansion and extracellular matrix (ECM) accumulation - the hallmark of DN. However, the specific molecular and signaling mechanisms for these processes are not clear. High glucose (HG) and Angiotensin (AngII) can activate the lipoxygenase (LO) pathway of arachidonate metabolism in vascular smooth muscle cells. 12-LO products have growth-promoting products and can activate protein kinase C (PKC) as well as mitogen activated protein kinases (MAPKs). The major hypothesis is that the 12LO pathway activated by high glucose (HG) and AngII plays a key role in the pathogenesis of DN by regulating the activation of PKC and downstream effector MAPKs in mesangial cells. These events may alter ECM and growth factor synthesis (TGFB1) in key sites such as mesangial cells (MC) which play an important role in DN. 12-LO will be studied since it is the major LO pathway in MC. The specific Aims are 1) To examine the regulation of 12-LO activation and expression in MC by HG (25 mM), AGEs, and AngII. 2) To determine the functional significance of 12-LO activation in rat MC. We will test whether 12-LO products directly increase ECM protein fibronection and TGFB1. We will then test whether the12-LO pathway mediates ECM induced by HG and Ang II by examining the effects of a specific molecular LO inhibitor, namely, a 12-LO ribozyme, as well as examine MC from 12-LO knock out mice. Conversely, we will determine whether over-expressionof 12-LO can increase ECM production in MC by testing adenoviral vector-mediated over-expression of mouse 12-LO in rat MC, ad by testing MC from a new 12-LO transgenic mouse model. 3) To evaluate the signal transduction mechanisms by which 12-LO products mediate pathologic effects in MC. In particular, the role of p38MAPK will be examined. 4) To examine the in vivo relevance of 12-LO activation in the development of DN. We will determine whether 12-LO, p38MAPK and ECM levels are increased in glomeruli from diabetic rats. We will then test the hypothesis that 12-LO knockout mice will develop milder or less frequent

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diabetic renal complications relative to genetically matched controls, and conversely, 12LO transgenic mice will develop more severe diabetic renal complications relative to non-transgenic littermates. Preliminary data showing trophic effects of 12-LO products in vitro in MC, as well as increased expression of 12-LO and p38MAPK family members in vivo in glomeruli from diabetic rats provide strong support for the hypothesis. These integrated in vitro and in vivo studies will provide new information on the mechanisms of glomerular expansion in DN, and thus lead to the development of novel therapies to combat this major complication of diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE COMPLICATIONS

OF

COMPLEMENT

IN

VASCULAR

DIABETIC

Principal Investigator & Institution: Halperin, Jose A.; None; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Epidemiological studies have established that hyperglycemia is responsible for the micro- and macrovascular disease that characteristically complicates human diabetes. However, the mechanism by which hyperglycemia causes vascular complications is poorly understood, in part because of the known absence of adequate animal models of diabetic complications. Indeed, no single animal model of diabetes reproduces the extensive vascular proliferative complications in the combination and intensity seen in humans. Thus, it appears that neither hyperglycemia itself nor the multiple signals activated by hyperglycemia are sufficient to induce in animals human-like vascular diabetic complications. This implies that there must be one or more genes and/or pathways necessary for the development of the diabetic vascular complications in humans that in animals differ substantially in their sensitivity to hyperglycemia and/or glycation. We have identified that the gene encoding for the complement regulatory membrane protein CD59, which inhibits formation of the membrane attack complex (MAC), is structurally different in humans and animals because hCD59 contains a glycation motif, formed by its H44 residue at approximately 5A angstroms from K41. We have shown that the K41-H44 motif makes hCD59 sensitive to inactivation by glycation, and that the H44 residue is not present in CD59 from other species. We postulate that glycation-inactivation of hCD59 due to its unique H44 residue could represent the elusive link between hyperglycemia and vascular proliferative complications of human diabetes. Consistently, high levels of glycated CD59 are found in diabetic urine, plasma and tissues; and glycated CD59 colocalizes with increased MAC deposition in kidneys, nerves and veins from diabetic subjects. Increased MAC deposition in the target tissues releases growth factors and cytokines that stimulate cell proliferation and induce synthesis of collagen type IV by glomerular mesangial cells. Increased MAC-induced mitogenic signals in diabetic tissues would act synergistically with other hyperglycemia-induced pathways causing vascular proliferative diabetic complications. In this application, we propose to use available mCd59KO and transgenic hCD59 mice to further investigate the causative role of glycation-inactivation of hCD59 in the pathogenesis of vascular proliferative complications of diabetes. We will phenotype diabetic mCd59KO, mCd59KO/hCD59WT, and mCd59KO/hCD59GIn44 variant transgenic mice for the development of human diabetic-like vascular disease, Mice will be made diabetic by injection of streptozotocin, and phenotyped by histopathology and parameters of retinal hemodynamic and renal function. We expect that in mCd59KO and in mCd59KO/hCD59WT mice, hyperglycemia will trigger a vascular proliferative

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response comparable to that seen in human diabetes. Instead, the hCD59GIn44 variant (resistant to glycation-inactivation) should protect mCd59KO from hyperglycemiainduced proliferative disease. We expect that these experiments will provide: 1) clear evidence for the role of glycation-inactivation of hCD59 in the pathogenesis of the proliferative vascular complications of diabetes; 2) needed animal models to study mechanism, therapy and prevention of diabetic complications; and 3) strong evidence to support future studies on complement and diabetes in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SECRETION AND BIOSYNTHESIS OF INSULIN Principal Investigator & Institution: Mcdaniel, Michael L.; Professor; Pathology and Immunology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-MAY-1977; Project End 31-JAN-2007 Summary: (provided by applicant) Type 2 diabetes is associated with obesity and elevated plasma levels of free fatty acids (FFA) and triacylglycerides (TAG). Obesity is also associated with the development of insulin resistance in insulin-sensitive tissues that results in hyperglycemia and hyperinsulinemia. b-cell failure in obesity-associated type 2 diabetes is believed to correlate with the intracellular accumulation of lipids that contribute to defects in insulin secretion and/or insulin and growth factor signaling necessary to maintain sufficient b-ceIl mass. The overall goal of this proposal is to define the cellular mechanisms whereby FFA and TAG exert their inhibitory effects on b-cell function in obesity-associated type 2 diabetes. Our recent studies have identified lipoprotein lipase (LpL) in b-cells, a key enzyme for catalyzing the hydrolysis of lipoprotein-associated TAG, to produce FFA for local cellular uptake. Our overall hypothesis is that LpL serves as a gatekeeper for the physiological import of FFA into bcells analogous to that described for adipocytes. Furthermore, our new findings indicate that elevated concentrations of glucose and insulin enhance LpL enzyme activity in bcells that may explain how b-cells continue to accumulate lipids in the setting of hyperglycemia and hyperinsulinemia associated with type 2 diabetes. In specific aim 1, we will: 1) further characterize the ability of nutrients, glucose and amino acids, and insulin to regulate LpL activity, expression and intracellular localization in rodent and human islets and b-cell lines, 2) assess the role of rapamycin, an inhibitor of mTOR, to regulate LpL and: lipid levels, and 3) evaluate LpL function in vivo. In specific aim 2, we will 1) examine the effects of enhanced FFA uptake by overexpression of FATP1 and ACS1, 2) characterize lipid droplet associated proteins, ADRP, perilipins and HSL, and 3) determine the regulation of lipid droplet synthesis and breakdown by phosphorylation and overexpression of lipid droplet associated proteins. Mitochondria exert a major role in glucose-stimulated insulin secretion, and mitochondrial activation is required for normal signal transduction. Recent studies suggest that FFA up-regulate mitochondrial uncoupling proteins (UCP) proposed to dissipate the proton gradient across the mitochondrial inner membrane. In specific aim 3, we will: 1) determine the role of UCP in mediating b-cell function by overexpressing UCP-2 in islets and b-cell lines, 2) assess the modulation of UCP-2 by increased levels of FFA in vitro and in vivo as described in specific aims 1 and 2. This experimental approach will be used to delineate the link between FFA and b-cell mitochondrial dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SUGAR TOXICITY: THE SUPEROXIDE CONNECTION Principal Investigator & Institution: Fridovich, Irwin; James B. Duke Professor Emeritus; Biochemistry; Duke University Durham, Nc 27706

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Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-JUL-2005 Summary: Sugars in their open chain conformations are prone to enolization and subsequent autoxidation that yields 1,2 - dicarbonyls capable of covalently modifying proteins and nucleic acids. Superoxide (02 ) both initiates and propagates the oxidation of enediols. Glycation of proteins and subsequent oxidation of the resultant E-Amino fructosyl-lysine residues yields a variety of products, including 1, 2-dicarbonyls. This is believed to be responsible for the deleterious consequences of the hyperglycemia of poorly controlled diabetes mellitus. Our goals are: to further elucidate this deleterious interaction of O2 with sugars using Escherichia coli as our model. We will: isolate, sequence, and clone the defensive glyoxalase III (glo III); create mutants defective in glo III and explore their resistance to short chain sugars and to O2; create the glo III mutants in the sod A, sod B background, and in the gsh A background and probe how much the lack of SOD and of GSH exacerbates the glo III deficiency; and to use the superoxide dismutase mimic Mn (III) TM-2-PyP to try to alleviate the consequences of these lacks of glo III. We will explore the substrate specificity of Glo III and compare the kinetic parameters of the different substrates. We will try to find competitive inhibitors of Glo III. We will also explore the reason for the extreme sensitivity of Glo III to inactivation by O2 and by H2O2. What we ,learn with E. coli will certainly illuminate the interactions of O2 and sugars in higher organism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THERAPEUTIC ADAPTATION OF INSULIN ACTION IN HUMANS Principal Investigator & Institution: Coker, Robert H.; Geriatrics; University of Arkansas Med Scis Ltl Rock Little Rock, Ar 72205 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): This Mentored Research Scientist Development Award will allow Dr. Coker to extend his work in glucose metabolism performed in animal models into the pathogenesis of insulin resistance in humans. Dr. William J. Evans and Dr. Philip A. Kern will serve as the Co-Mentors for this project. Excessive caloric intake or the lack of physical activity contributes to a positive caloric balance, leading to excess visceral adipose tissue deposition. The pathogenic consequences of visceral obesity usually includes hepatic and skeletal muscle insulin resistance, hyperglycemia, and hyperinsulinemia, and abnormal lipid metabolism eventually leading to type 2 diabetes (T2D). Although caloric restriction and/or exercise training are known to decrease risks associated with T2D, it has been difficult to separate the independent influence of weight loss from exercise training on insulin resistance. We propose to examine the effects of a caloric restriction and/or aerobic exercise training on hepatic and peripheral insulin action using a somatostatin, multi-stage, euglycemic clamp technique in overweight, glucose intolerant men and women. We will recruit 60, 50-80 y old women and men, who will be randomized into one of the following four groups: 1) caloric restriction with weight loss, 2) exercise training without weight loss, 3) exercise training with weight loss, and 4) controls (no dietary or exercise intervention). Dr. Evans has extensive experience in the management of dietary control and exercise training studies. In addition, Dr. Kern will provide specific training in cellular/molecular biology. We will test the hypotheses that 1) caloric restriction will improve hepatic and peripheral insulin action, 2) exercise training without weight loss will only improve peripheral insulin action, 3) exercise training with weight loss will improve hepatic and peripheral insulin action, 4) hepatic insulin action will improve in proportion to the decrease in visceral fat, and that 5) weight loss and exercise training will induce changes in skeletal muscle lipid metabolism through different mechanisms.

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Since people with impaired glucose tolerance are much more susceptible to the development of T2D, understanding the specific influence of the above mentioned therapeutic regimens on the pathogenesis of insulin resistance has extremely important public health implications. Furthermore, the proposed studies, mentors, coinvestigators, and institutional commitment at the University of Arkansas for Medical Sciences provide an outstanding environment for Dr. Coker to develop into an independent basic scientist in diabetes research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METHYLATION

UTEROPLACENTAL

INSUFFICIENCY

ALTERS

DNA

Principal Investigator & Institution: Lane, Robert H.; Professor; Pediatrics; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: The overall objective of this research program is to identify molecular mechanisms that are triggered by uteroplacental insufficiency and lead to adult disease. Human uteroplacental insufficiency causes intrauterine growth retardation, which is associated with adult onset insulin resistance and dyslipidemia independent of social and racial status. Rats rendered IUGR by maternal uteroplacental insufficiency are characterized by altered gene expression of fatty acid metabolizing enzymes prior to the onset of adult hyperglycemia and hypertriglyceridemia. The altered gene expression occurs long after the initial insult and thereby suggests an epigenetic phenomenon. DNA methylation is an important mammalian epigenetic mechanism, and our laboratory has generated preliminary data that demonstrates DNA methylation is altered in the IUGR rat fetus. We therefore hypothesize that uteroplacental insufficiency in the rat and subsequent IUGR alters hepatic and skeletal muscle fetal DNA methylation in a tissue-specific manner, and these changes lead to significant changes in gene expression in the mature rat. To fully test this hypothesis, we propose the following Specific Aims: (1) We will determine the effect uteroplacental insufficiency has upon the process of overall DNA methylation in fetal skeletal muscle and liver; (2) We will investigate fetal DNA methylation differences in specific genes based upon our preliminary data from IUGR fetal skeletal muscle and liver; (3) We will examine methylation differences and their effects in 21 day old and 120 day old control and IUGR rat liver and skeletal muscle. The proposed investigation will identify a molecular mechanism and a specific subset of genes that are altered by the IUGR fetal environment, and it will establish the persistent effect of this mechanism upon these genes. The knowledge gained from this proposal will be used to focus further studies upon the genes and pathways involved using knock in/knock out transgenic technology and may be applicable to screening human IUGR DNA to determine which infants are at high risk to develop the adult morbidities associated with IUGR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VACCINIA VIRUS VACCINE FOR TYPE 1 DIABETES Principal Investigator & Institution: Langridge, William H.; Biochemistry; Loma Linda University Loma Linda, Ca 92350 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Type 1 diabetes is a Thl lymphocyte mediated autoimmune disease that is partially suppressed by oral administration of small amounts of insulin or other diabetes autoantigens. To strengthen this promising

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immunotolerization approach to diabetes prevention, new innovative strategies are needed. In response to RFA-DK-02-023, we propose to determine the feasibility of a recombinant vaccinia virus (rVV) mediated autoantigen delivery system for suppression of Type 1 diabetes. Genes encoding proinsulin (INS) and glutamate decarboxylase (GAD) autoantigens fused to a cholera toxin B subunit (CTB) receptor IJgand in an rVV expression vector will be expressed in intestinal epithelial cells inoculated with rVV. Following enterocyte apoptosis, autoantigen fusion proteins will be taken up by APCs of the subepithelium or released into the gut and targeted via the CTB ligand to intestinal M cells for indirect APC processing. Two specific aims will determine (1) rVV MOl's required to generate optimum autoantigen protein synthesis in enterocyte cells in culture. (2) The efficacy of rVV mediated tolerance for prevention of Type1 diabetes in vivo and the nature of the T cell response underlying diabetes prevention. Prediabetic NOD/LtJ mice will be orally inoculated with rVV encoding CTB-INS and CTB-GAD enterocyte targeted autoantigen fusion proteins to generate maximum levels of protection from diabetes as measured by levels of insulitis and hyperglycemia. Mechanisms of immunity underlying vaccinia mediated autoantigen suppression of diabetes will be investigated by measurement of T lymphocyte responses to mucosal immunization measured by ELISA quantification of IL-10, TGF-beta, IL-2 and IFNgamma cytokines secreted from salivary gland, spleen, pancreas and mesenteric lymphoid cells. CTL and T lymphocyte proliferation in response to vaccina mediated synthesis of INS and GAD will be quantified by flow cytometric analysis of spleen and mesenteric lymph node memory CD4+ and CD8+ lymphocytes. Specific CTL responses to vaccinia infection will be quantified by LDH assays for rVV, CTB, INS and GAD proteins. The results of these experiments will increase our understanding of the immunological mechanisms underlying vaccinia virus mediated immunotolerization against Type 1 diabetes for the long term goal of generating safer, more effective and inexpensive mucosal vaccines for protection against this devastating form of diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VASCULAR INFLAMMATION AND ADVANCED GLYCATION ENDPRODUCTS Principal Investigator & Institution: Taylor, William Robert.; Associate Professor; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): The leading cause of morbidity and mortality in both insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) is atherosclerotic cardiovascular disease. The age-adjusted incidence of myocardial infarction is six times greater in diabetic men, and four times greater in diabetic women than in nondiabetic subjects. This markedly accelerated vascular pathology cannot be fully explained by the well-described coexistence of traditional cardiovascular risk factors. Although the association of chronic hyperglycemia and diabetic micro- and macrovascular disease has been established, the mechanisms of the linkage between hyperglycemia and atherosclerotic vascular pathology have not yet been fully elucidated. Diabetes, as a disease state, presents a potentially very complex metabolic stimulus to the cellular components of the arterial wall. The functionally relevant components of the altered metabolic milieu of diabetes include not only changes in glucose and insulin levels, but may also include "secondary" metabolic abnormalities that occur as a result of the primary abnormalities in insulin and glucose metabolism. Advanced glycation endproducts (AGEs) are the late products of the modification of proteins, lipids and nucleic acids by reducing sugars. They have been

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implicated as an important component of the metabolic abnormalities resulting in diabetic vasculopathy. The central hypothesis of this proposal is that AGEs have an important, and potentially central, role in the accelerated vasculopathy of NIDDM and IDDM via the regulation of redox-sensitive proinflammatory cell signaling pathways. The proposed studies will systematically explore AGE-mediated regulation of redox state and proinflammatory gene products in vascular disease and determine the functionally relevant molecular events responsible for the proatherogenic effects in-vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

11[beta]-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. by Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, Best R, Brown R, Edwards CR, Seckl JR, Mullins JJ.; 1997 Dec 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25139

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ATP-sensitive K+ channels that are blocked by hypoglycemia-inducing sulfonylureas in insulin-secreting cells are activated by galanin, a hyperglycemia-inducing hormone. by de Weille J, Schmid-Antomarchi H, Fosset M, Lazdunski M.; 1988 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=279757

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Bordetella pertussis-induced Alteration of the Normal Hyperglycemic Response of Mice to 3[prime prime or minute],5[prime prime or minute]-Adenosine Phosphate. by Cronholm LS, Fishel CW.; 1968 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=315124

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Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state. by Chiasson JL, Aris-Jilwan N, Belanger R, Bertrand S, Beauregard H, Ekoe JM, Fournier H, Havrankova J.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151994

3 4

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

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

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Evidence that Down-Regulation of [beta]-Cell Glucose Transporters in Non-InsulinDependent Diabetes May be the Cause of Diabetic Hyperglycemia. by Orci L, Ravazzola M, Baetens D, Inman L, Amherdt M, Peterson RG, Newgard CB, Johnson JH, Unger RH.; 1990 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=55292

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Generation of chemotactic factors by Rhizopus oryzae in the presence and absence of serum: relationship to hyphal damage mediated by human neutrophils and effects of hyperglycemia and ketoacidosis. by Chinn RY, Diamond RD.; 1982 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=347866

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High Fat Diet-Induced Hyperglycemia: Prevention by Low Level Expression of a Glucose Transporter (GLUT4) Minigene in Transgenic Mice. by Ikemoto S, Thompson KS, Takahashi M, Itakura H, Lane MD, Ezaki O.; 1995 Apr 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42111

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How hyperglycemia promotes atherosclerosis: molecular mechanisms. by Aronson D, Rayfield EJ.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116615

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Human munc13 Is a Diacylglycerol Receptor that Induces Apoptosis and May Contribute to Renal Cell Injury in Hyperglycemia. by Song Y, Ailenberg M, Silverman M.; 1999 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30485

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Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. by Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M.; 2000 Oct 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17322

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Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. by Du X, Matsumura T, Edelstein D, Rossetti L, Zsengeller Z, Szabo C, Brownlee M.; 2003 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=198524

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Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress. by Hayden MR, Tyagi SC.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151667

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Islet Amyloid Formation Associated with Hyperglycemia in Transgenic Mice with Pancreatic Beta Cell Expression of Human Islet Amyloid Polypeptide. by Verchere CB, D'Alessio DA, Palmiter RD, Weir GC, Bonner-Weir S, Baskin DG, Kahn SE.; 1996 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39637

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Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells. by Zalzman M, Gupta S, Giri RK, Berkovich I, Sappal BS, Karnieli O, Zern MA, Fleischer N, Efrat S.; 2003 Jun 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165862

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Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene. by Yamada M, Saga Y, Shibusawa N, Hirato J, Murakami M, Iwasaki T, Hashimoto K, Satoh T, Wakabayashi K, Taketo MM, Mori M.; 1997 Sep 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23510

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The enhancement of the hyperglycemic effect of S-nitrosoglutathione and S-nitrosoN-acetylpenicillamine by vitamin C in an animal model. by McGrowder D, Ragoobirsingh D, Dasgupta T.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130025

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

A combined high-fiber, low-glycemic index diet normalizes glucose tolerance and reduces hyperglycemia and hyperinsulinemia in adults with hepatic cirrhosis. Author(s): Barkoukis H, Fiedler KM, Lerner E. Source: Journal of the American Dietetic Association. 2002 October; 102(10): 1503-7; Discussion 1507-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12396175

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A randomized controlled trial using glycemic plus fetal ultrasound parameters versus glycemic parameters to determine insulin therapy in gestational diabetes with fasting hyperglycemia. Author(s): Garcia-Patterson A, Corcoy R, Balsells M, Altirriba O, Adelantado JM, Cabero L, de Leiva A. Source: Diabetes Care. 2002 July; 25(7): 1261; Author Reply 1261-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12087047

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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Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Author(s): Parsons MW, Barber PA, Desmond PM, Baird TA, Darby DG, Byrnes G, Tress BM, Davis SM. Source: Annals of Neurology. 2002 July; 52(1): 20-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12112043

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Acute hyperglycemia and activation of the beta-adrenergic system exhibit synergistic inhibitory actions on growth hormone (GH) releasing hormone-induced GH release. Author(s): Park C, Yang I, Woo J, Kim S, Kim J, Kim Y, Park S. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 June; 148(6): 635-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12773135

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Acute hyperglycemia causes intracellular formation of CML and activation of ras, p42/44 MAPK, and nuclear factor kappaB in PBMCs. Author(s): Schiekofer S, Andrassy M, Chen J, Rudofsky G, Schneider J, Wendt T, Stefan N, Humpert P, Fritsche A, Stumvoll M, Schleicher E, Haring HU, Nawroth PP, Bierhaus A. Source: Diabetes. 2003 March; 52(3): 621-33. Erratum In: Diabetes. 2003 May; 52(5): 1307. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12606501

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Acute, short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type II diabetes mellitus. Author(s): Gresele P, Guglielmini G, De Angelis M, Ciferri S, Ciofetta M, Falcinelli E, Lalli C, Ciabattoni G, Davi G, Bolli GB. Source: Journal of the American College of Cardiology. 2003 March 19; 41(6): 1013-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12651051

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Addition of nateglinide to rosiglitazone monotherapy suppresses mealtime hyperglycemia and improves overall glycemic control. Author(s): Fonseca V, Grunberger G, Gupta S, Shen S, Foley JE. Source: Diabetes Care. 2003 June; 26(6): 1685-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766094

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Admission hyperglycemia as a prognostic indicator in trauma. Author(s): Yendamuri S, Fulda GJ, Tinkoff GH. Source: The Journal of Trauma. 2003 July; 55(1): 33-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12855878

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Aldose reductase mediates cytotoxic signals of hyperglycemia and TNF-alpha in human lens epithelial cells. Author(s): Ramana KV, Friedrich B, Bhatnagar A, Srivastava SK. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2003 February; 17(2): 315-7. Epub 2002 December 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12490536

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Anabolic potential of fibroblasts from chronically inflamed gingivae grown in a hyperglycemic culture medium in the presence or absence of insulin and nicotine. Author(s): Soory M, Tilakaratne A. Source: J Periodontol. 2003 December; 74(12): 1771-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14974818

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Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Author(s): Krinsley JS. Source: Mayo Clinic Proceedings. 2003 December; 78(12): 1471-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14661676

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Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction. Author(s): Iwakura K, Ito H, Ikushima M, Kawano S, Okamura A, Asano K, Kuroda T, Tanaka K, Masuyama T, Hori M, Fujii K. Source: Journal of the American College of Cardiology. 2003 January 1; 41(1): 1-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12570936

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Association between twin pregnancy and hyperglycemia in a multiethnic community in New Zealand. Author(s): Simmons D, Yapa M. Source: Diabetes Care. 2002 May; 25(5): 934-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11978694

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Association of GYS1 and beta(3)-AR gene with postprandial hyperglycemia and serum uric acid in type 2 diabetes mellitus. Author(s): Wang G, Li Q, Niu T, Chen C, Xu X. Source: Chinese Medical Journal. 2002 September; 115(9): 1308-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12411100

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Association of hyperglycemia and insulin with diabetic cardiovascular complications. Author(s): Khamaisi M, Wainstein J, Hancu N, Milicevic Z, Raz I. Source: Isr Med Assoc J. 2003 February; 5(2): 116-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12674662

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Association of hyperglycemia and markers of hepatic dysfunction with dextrose infusion rates in Korean patients receiving total parenteral nutrition. Author(s): Kim H, Son E, Kim J, Choi K, Kim C, Shin W, Suh O. Source: American Journal of Health-System Pharmacy : Ajhp : Official Journal of the American Society of Health-System Pharmacists. 2003 September 1; 60(17): 1760-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503112

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Atrial fibrillation can cause major hyperglycemia. Author(s): Rigalleau V, Baillet L, Hocini M, Gin H. Source: Diabetes & Metabolism. 2002 June; 28(3): 239-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12149605

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Case report: somatostatin producing teratoma, causing rapidly alternating extreme hyperglycemia and hypoglycemia, and ovarian somatostatinoma. Author(s): Gregersen G, Holst JJ, Trankjaer A, Stadil F, Mogensen AM. Source: Metabolism: Clinical and Experimental. 2002 September; 51(9): 1180-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12200764

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Cerebral energy metabolism during transient hyperglycemia in patients with severe brain trauma. Author(s): Diaz-Parejo P, Stahl N, Xu W, Reinstrup P, Ungerstedt U, Nordstrom CH. Source: Intensive Care Medicine. 2003 April; 29(4): 544-50. Epub 2003 March 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12655390

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Cerebral injury in association with profound iatrogenic hyperglycemia in a neonate. Author(s): Efron D, South M, Volpe JJ, Inder T. Source: European Journal of Paediatric Neurology : Ejpn : Official Journal of the European Paediatric Neurology Society. 2003; 7(4): 167-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865056

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Chorea associated with non-ketotic hyperglycemia and hyperintensity basal ganglia lesion on T1-weighted brain MRI study: a meta-analysis of 53 cases including four present cases. Author(s): Oh SH, Lee KY, Im JH, Lee MS. Source: Journal of the Neurological Sciences. 2002 August 15; 200(1-2): 57-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12127677

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Chorea due to nonketotic hyperglycemia. Author(s): Hamide A, Kumarsamy R, Srimannarayana J, Mathew J, Das AK. Source: Neurology India. 2002 June; 50(2): 213-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12134194

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Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN beta cell line and human islets of Langerhans. Author(s): Hribal ML, Perego L, Lovari S, Andreozzi F, Menghini R, Perego C, Finzi G, Usellini L, Placidi C, Capella C, Guzzi V, Lauro D, Bertuzzi F, Davalli A, Pozza G, Pontiroli A, Federici M, Lauro R, Brunetti A, Folli F, Sesti G. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2003 July; 17(10): 1340-2. Epub 2003 May 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12738810

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Clinical significance of targeting postprandial and fasting hyperglycemia in managing type 2 diabetes mellitus. Author(s): Fonseca V. Source: Current Medical Research and Opinion. 2003; 19(7): 635-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14606987

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Clinical significance, pathogenesis, and management of postprandial hyperglycemia. Author(s): Gerich JE. Source: Archives of Internal Medicine. 2003 June 9; 163(11): 1306-16. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796066

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Common mechanisms in the damaging effects of hypoxia and hyperglycemia on neuronal function. Author(s): Kostyuk EP, Kostyuk PG. Source: Fiziol Zh. 2002; 48(1): 102-11. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11928624

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Comparison of hyperglycemia, hypertension, and hypercholesterolemia management in patients with type 2 diabetes. Author(s): Grant RW, Cagliero E, Murphy-Sheehy P, Singer DE, Nathan DM, Meigs JB. Source: The American Journal of Medicine. 2002 June 1; 112(8): 603-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12034408

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Concurrent hyperglycemia does not influence the long-term prognosis of unresectable hepatocellular carcinomas. Author(s): Li XP, Chen Z, Meng ZQ, Huang WX, Liu LM. Source: World Journal of Gastroenterology : Wjg. 2003 August; 9(8): 1848-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12918136

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Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Author(s): Monnier L, Lapinski H, Colette C. Source: Diabetes Care. 2003 March; 26(3): 881-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12610053

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Control of postprandial hyperglycemia: optimal use of short-acting insulin secretagogues. Author(s): Carroll MF, Izard A, Riboni K, Burge MR, Schade DS. Source: Diabetes Care. 2002 December; 25(12): 2147-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453952

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Control of post-prandial hyperglycemia--an essential part of good diabetes treatment and prevention of cardiovascular complications. Author(s): Hanefeld M, Temelkova-Kurktschiev T. Source: Nutr Metab Cardiovasc Dis. 2002 April; 12(2): 98-107. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12189909

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Coxsackievirus-mediated hyperglycemia is enhanced by reinfection and this occurs independent of T cells. Author(s): Horwitz MS, Ilic A, Fine C, Rodriguez E, Sarvetnick N. Source: Virology. 2003 September 30; 314(2): 510-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14554080

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Cutaneous vascular function during acute hyperglycemia in healthy young adults. Author(s): Charkoudian N, Vella A, Reed AS, Minson CT, Shah P, Rizza RA, Joyner MJ. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 2002 October; 93(4): 124350. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12235021

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Delayed recovery of diabetic chorea following correction of hyperglycemia. Author(s): Saleh MM, Zacks ES, Katz JS. Source: Journal of Neurology. 2002 September; 249(9): 1323-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12242567

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Detection of undiagnosed diabetes and other hyperglycemia states: the Atherosclerosis Risk in Communities Study. Author(s): Schmidt MI, Duncan BB, Vigo A, Pankow J, Ballantyne CM, Couper D, Brancati F, Folsom AR; ARIC Investigators. Source: Diabetes Care. 2003 May; 26(5): 1338-43. Erratum In: Diabetes Care. 2003 August; 26(8): 2489. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716785

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Diabetic ketoacidosis and persistent hyperglycemia as long-term complications of Lasparaginase-induced pancreatitis. Author(s): Hsu YJ, Chen YC, Ho CL, Kao WY, Chao TY. Source: Zhonghua Yi Xue Za Zhi (Taipei). 2002 September; 65(9): 441-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12433031

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Dyslipidemia, but not hyperglycemia, induces inflammatory adhesion molecules in human retinal vascular endothelial cells. Author(s): Chen W, Jump DB, Grant MB, Esselman WJ, Busik JV. Source: Investigative Ophthalmology & Visual Science. 2003 November; 44(11): 5016-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14578429

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Early detection of infantile pre-type 1 diabetes case with transient hyperglycemia. Author(s): Hirai H, Kaino Y, Ito T, Takemoto K, Ishimaru A, Watanabe S, Kida K. Source: Diabetes Research and Clinical Practice. 2002 August; 57(2): 83-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12062851

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Effect of acute hyperglycemia on the ischemic preconditioning effect of prodromal angina pectoris in patients with a first anterior wall acute myocardial infarction. Author(s): Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Nishioka K, Umemura T, Nakamura S, Yoshida M. Source: The American Journal of Cardiology. 2003 August 1; 92(3): 288-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12888134

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Effect of consumption of finger millet on hyperglycemia in non-insulin dependent diabetes mellitus (NIDDM) subjects. Author(s): Lakshmi Kumari P, Sumathi S. Source: Plant Foods for Human Nutrition (Dordrecht, Netherlands). 2002 Fall; 57(3-4): 205-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12602929

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Effect of hyperglycemia on the basal cytosolic free calcium level, calcium signal and tyrosine-phosphorylation in human T-cells. Author(s): Boldizsar F, Berki T, Miseta A, Nemeth P. Source: Immunology Letters. 2002 June 3; 82(1-2): 159-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12008048

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Effect of hyperglycemia on tumoral uptake of F-18 FDG. Author(s): Dave NN, Walia R, Shor M, Ali A. Source: Clinical Nuclear Medicine. 2002 September; 27(9): 682-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12192297

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Effect of mild hyperglycemia +/- meta-iodo-benzylguanidine on the radiation response of R3230 Ac tumors. Author(s): Lee I, Glickson JD, Dewhirst MW, Leeper DB, Burd R, Poptani H, Nadal L, McKenna WG, Biaglow JE. Source: Advances in Experimental Medicine and Biology. 2003; 530: 177-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14562715

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Effects of acute hyperglycemia on endothelium-dependent vasodilation in patients with diabetes mellitus or impaired glucose metabolism. Author(s): Kim SH, Park KW, Kim YS, Oh S, Chae IH, Kim HS, Kim CH. Source: Endothelium : Journal of Endothelial Cell Research. 2003; 10(2): 65-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791513

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Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Author(s): Williams LS, Rotich J, Qi R, Fineberg N, Espay A, Bruno A, Fineberg SE, Tierney WR. Source: Neurology. 2002 July 9; 59(1): 67-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12105309

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Effects of admission hyperglycemia on stroke outcome in reperfused tissue plasminogen activator--treated patients. Author(s): Alvarez-Sabin J, Molina CA, Montaner J, Arenillas JF, Huertas R, Ribo M, Codina A, Quintana M. Source: Stroke; a Journal of Cerebral Circulation. 2003 May; 34(5): 1235-41. Epub 2003 April 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12677014

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Effects of isolated post-challenge hyperglycemia on mortality in American Indians: the Strong Heart Study. Author(s): Lu W, Resnick HE, Jain AK, Adams-Campbell LL, Jablonski KA, Gottlieb AM, Robbins DC, Howard BV. Source: Annals of Epidemiology. 2003 March; 13(3): 182-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12604162

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Efficacy and safety of nateglinide in type 2 diabetic patients with modest fasting hyperglycemia. Author(s): Saloranta C, Hershon K, Ball M, Dickinson S, Holmes D. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 September; 87(9): 4171-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12213867

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Electrical stimulation improves insulin responses in a human skeletal muscle cell model of hyperglycemia. Author(s): Aas V, Torbla S, Andersen MH, Jensen J, Rustan AC. Source: Annals of the New York Academy of Sciences. 2002 June; 967: 506-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12079881

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Elevated free fatty acids impair glucose metabolism in women: decreased stimulation of muscle glucose uptake and suppression of splanchnic glucose production during combined hyperinsulinemia and hyperglycemia. Author(s): Shah P, Vella A, Basu A, Basu R, Adkins A, Schwenk WF, Johnson CM, Nair KS, Jensen MD, Rizza RA. Source: Diabetes. 2003 January; 52(1): 38-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12502491

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Essential pathogenic role of endogenous IL-18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL-18-binding protein: Fc construct. Author(s): Nicoletti F, Di Marco R, Papaccio G, Conget I, Gomis R, Bernardini R, Sims JE, Shoenfeld Y, Bendtzen K. Source: European Journal of Immunology. 2003 August; 33(8): 2278-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12884303

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Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment. Author(s): Ceriello A, Taboga C, Tonutti L, Quagliaro L, Piconi L, Bais B, Da Ros R, Motz E. Source: Circulation. 2002 September 3; 106(10): 1211-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12208795

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Factors responsible for development from normal glucose tolerance to isolated postchallenge hyperglycemia. Author(s): Suzuki H, Fukushima M, Usami M, Ikeda M, Taniguchi A, Nakai Y, Matsuura T, Kuroe A, Yasuda K, Kurose T, Seino Y, Yamada Y. Source: Diabetes Care. 2003 April; 26(4): 1211-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12663599

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Fasting hyperglycemia predicts the magnitude of postprandial hyperglycemia: implications for diabetes therapy. Author(s): Carroll MF, Izard A, Riboni K, Burge MR, Schade DS. Source: Diabetes Care. 2002 July; 25(7): 1247-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12087032

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Fatality from olanzapine induced hyperglycemia. Author(s): Meatherall R, Younes J. Source: J Forensic Sci. 2002 July; 47(4): 893-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12137003

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Gestational diabetes mellitus and lesser degrees of pregnancy hyperglycemia: association with increased risk of spontaneous preterm birth. Author(s): Hedderson MM, Ferrara A, Sacks DA. Source: Obstetrics and Gynecology. 2003 October; 102(4): 850-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14551018

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Ginger reduces hyperglycemia-evoked gastric dysrhythmias in healthy humans: possible role of endogenous prostaglandins. Author(s): Gonlachanvit S, Chen YH, Hasler WL, Sun WM, Owyang C. Source: The Journal of Pharmacology and Experimental Therapeutics. 2003 December; 307(3): 1098-103. Epub 2003 October 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14534370

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Glucose clearance is delayed after hyperglycemia in healthy elderly men. Author(s): Krishnan RK, Evans WJ, Kirwan JP. Source: The Journal of Nutrition. 2003 July; 133(7): 2363-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12840207

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Glucose monitoring at the arm: risky delays of hypoglycemia and hyperglycemia detection. Author(s): Jungheim K, Koschinsky T. Source: Diabetes Care. 2002 June; 25(6): 956-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12032098

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Glycogen synthase deficiency (glycogen storage disease type 0) presenting with hyperglycemia and glucosuria: report of three new mutations. Author(s): Bachrach BE, Weinstein DA, Orho-Melander M, Burgess A, Wolfsdorf JI. Source: The Journal of Pediatrics. 2002 June; 140(6): 781-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12072888

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Helicobacter pylori-independent effect of hyperglycemia on gastric mucosal atrophy. Author(s): Kawamura A, Adachi K, Takashima T, Fujishiro H, Yuki M, Ishihara S, Kinoshita Y. Source: The American Journal of Gastroenterology. 2002 September; 97(9): 2479-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12358286

Studies

83

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Hepatocyte growth factor preserves beta cell mass and mitigates hyperglycemia in streptozotocin-induced diabetic mice. Author(s): Dai C, Li Y, Yang J, Liu Y. Source: The Journal of Biological Chemistry. 2003 July 18; 278(29): 27080-7. Epub 2003 May 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12746445

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Hyperglycemia affects flicker-induced vasodilation in the retina of healthy subjects. Author(s): Dorner GT, Garhofer G, Huemer KH, Riva CE, Wolzt M, Schmetterer L. Source: Vision Research. 2003 June; 43(13): 1495-500. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12767316

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Hyperglycemia and early reperfusion therapy. Author(s): Tanne D, Schwammenthal Y. Source: Stroke; a Journal of Cerebral Circulation. 2003 May; 34(5): 1235-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12733513

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Hyperglycemia and heart dysfunction: an oxidant mechanism contributing to heart failure in diabetes. Author(s): Esposito K, Marfella R, Giugliano D. Source: J Endocrinol Invest. 2002 May; 25(5): 485-8. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12035949

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Hyperglycemia and hypertriglyceridemia in real world patients on antipsychotic therapy. Author(s): Gupta S, Steinmeyer C, Frank B, Madhusoodanan S, Lockwood K, Lentz B, Keller P. Source: American Journal of Therapeutics. 2003 September-October; 10(5): 348-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12975719

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Hyperglycemia and insulin resistance: possible mechanisms. Author(s): Tomas E, Lin YS, Dagher Z, Saha A, Luo Z, Ido Y, Ruderman NB. Source: Annals of the New York Academy of Sciences. 2002 June; 967: 43-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12079834

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Hyperglycemia and no-reflow phenomenon in acute myocardial infarction. Author(s): Zijlstra F, van der Horst IC, van't Hof AW, Bilo HJ. Source: Journal of the American College of Cardiology. 2003 June 18; 41(12): 2300; Author Reply 2300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12821266

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Hyperglycemia and outcomes from pediatric traumatic brain injury. Author(s): Cochran A, Scaife ER, Hansen KW, Downey EC. Source: The Journal of Trauma. 2003 December; 55(6): 1035-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14676647

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Hyperglycemia and oxidative stress: complex relationships with attractive prospects. Author(s): Leverve X. Source: Intensive Care Medicine. 2003 April; 29(4): 511-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12800829

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Hyperglycemia and retinopathy of prematurity in very low birth weight infants. Author(s): Garg R, Agthe AG, Donohue PK, Lehmann CU. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 2003 April-May; 23(3): 186-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12732854

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Hyperglycemia and stroke outcome: vindication of the ischemic penumbra. Author(s): Ginsberg MD. Source: Annals of Neurology. 2002 July; 52(1): 5-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12112040

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Hyperglycemia as a cardiovascular risk factor. Author(s): Haffner SJ, Cassells H. Source: The American Journal of Medicine. 2003 December 8; 115 Suppl 8A: 6S-11S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678859

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Hyperglycemia attenuates erythromycin-induced acceleration of solid-phase gastric emptying in healthy subjects. Author(s): Petrakis IE, Kogerakis N, Vrachassotakis N, Stiakakis I, Zacharioudakis G, Chalkiadakis G. Source: Abdominal Imaging. 2002 May-June; 27(3): 309-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12173362

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Hyperglycemia exacerbates muscle protein catabolism in burn-injured patients. Author(s): Gore DC, Chinkes DL, Hart DW, Wolf SE, Herndon DN, Sanford AP. Source: Critical Care Medicine. 2002 November; 30(11): 2438-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12441751

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Hyperglycemia exaggerates ischemia-reperfusion-induced cardiomyocyte injury: reversal with endothelin antagonism. Author(s): Verma S, Maitland A, Weisel RD, Li SH, Fedak PW, Pomroy NC, Mickle DA, Li RK, Ko L, Rao V. Source: The Journal of Thoracic and Cardiovascular Surgery. 2002 June; 123(6): 1120-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12063458

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Hyperglycemia from olanzapine treatment in adolescents. Author(s): Bloch Y, Vardi O, Mendlovic S, Levkovitz Y, Gothelf D, Ratzoni G. Source: Journal of Child and Adolescent Psychopharmacology. 2003 Spring; 13(1): 97102. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12804130

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Hyperglycemia in acute illness. Author(s): Dhatariya K. Source: Jama : the Journal of the American Medical Association. 2003 March 12; 289(10): 1244; Author Reply 1244. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12633184

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Hyperglycemia in acutely ill patients. Author(s): Montori VM, Bistrian BR, McMahon MM. Source: Jama : the Journal of the American Medical Association. 2002 November 6; 288(17): 2167-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12413377

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Hyperglycemia, bronchial artery sclerosis, and lung function. Author(s): Funk GC, Doberer D, Petkov V, Block LH. Source: American Journal of Respiratory and Critical Care Medicine. 2004 February 1; 169(3): 427; Author Reply 427. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14739135

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Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. Author(s): Cakir M, Altunbas H, Karayalcin U. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 March; 88(3): 1402; Author Reply 1402. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12629138

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Hyperglycemia-induced protein kinase signaling pathways in vascular smooth muscle cells: implications in the pathogenesis of vascular dysfunction in diabetes. Author(s): Srivastava AK. Source: Advances in Experimental Medicine and Biology. 2001; 498: 311-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11900384

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Impact of acute hyperglycemia on left ventricular function after reperfusion therapy in patients with a first anterior wall acute myocardial infarction. Author(s): Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Nishioka K, Umemura T, Nakamura S, Yoshida M. Source: American Heart Journal. 2003 October; 146(4): 674-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14564322

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Impairment of human ether-a-go-go-related gene (HERG) K+ channel function by hypoglycemia and hyperglycemia. Similar phenotypes but different mechanisms. Author(s): Zhang Y, Han H, Wang J, Wang H, Yang B, Wang Z. Source: The Journal of Biological Chemistry. 2003 March 21; 278(12): 10417-26. Epub 2003 January 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12531891

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In vitro reversal of hyperglycemia normalizes insulin action in fat cells from type 2 diabetes patients: is cellular insulin resistance caused by glucotoxicity in vivo? Author(s): Buren J, Lindmark S, Renstrom F, Eriksson JW. Source: Metabolism: Clinical and Experimental. 2003 February; 52(2): 239-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12601640

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Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Author(s): Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D. Source: Circulation. 2002 October 15; 106(16): 2067-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12379575

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Influence of acute hyperglycemia in human sepsis on inflammatory cytokine and counterregulatory hormone concentrations. Author(s): Yu WK, Li WQ, Li N, Li JS. Source: World Journal of Gastroenterology : Wjg. 2003 August; 9(8): 1824-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12918129

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Intrauterine hyperglycemia is associated with an earlier diagnosis of diabetes in HNF-1alpha gene mutation carriers. Author(s): Stride A, Shepherd M, Frayling TM, Bulman MP, Ellard S, Hattersley AT. Source: Diabetes Care. 2002 December; 25(12): 2287-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453975

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Intrauterine hyperglycemia modifying the development of (monogenic) diabetes? Author(s): Tuomi T, Groop L. Source: Diabetes Care. 2003 April; 26(4): 1295-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12663611

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Isolated post-challenge hyperglycemia in patients with normal fasting glucose concentration exaggerates neointimal hyperplasia after coronary stent implantation. Author(s): Nakamura N, Ueno Y, Tsuchiyama Y, Koike Y, Gohda M, Satani O. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 January; 67(1): 61-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12520154

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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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Lisofylline, a novel antiinflammatory compound, protects mesangial cells from hyperglycemia- and angiotensin II-mediated extracellular matrix deposition. Author(s): Bolick DT, Hatley ME, Srinivasan S, Hedrick CC, Nadler JL. Source: Endocrinology. 2003 December; 144(12): 5227-31. Epub 2003 August 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12960000

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Management of hyperglycemia and diabetes in an outpatient cardiology practice. Author(s): Jabbour S, Bedell SE, Alharethi R, Goldberg R. Source: Cardiology. 2002; 97(4): 183-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12145472

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Management of hyperglycemia in minority children with type 2 diabetes mellitus. Author(s): Castells S. Source: J Pediatr Endocrinol Metab. 2002 April; 15 Suppl 1: 531-40. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12017228

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Maternal hyperglycemia leads to gender-dependent deficits in learning and memory in offspring. Author(s): Kinney BA, Rabe MB, Jensen RA, Steger RW. Source: Experimental Biology and Medicine (Maywood, N.J.). 2003 February; 228(2): 152-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12563021

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Maternal low birth weight and gestational hyperglycemia. Author(s): Bo S, Marchisio B, Volpiano M, Menato G, Pagano G. Source: Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 2003 April; 17(2): 133-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12737674

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Measuring and managing hyperglycemia in pregnancy: from glycosuria to continuous blood glucose monitoring. Author(s): Mazze RS. Source: Semin Perinatol. 2002 June; 26(3): 171-80. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12099306

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Metabolic abnormalities (hypertension, hyperglycemia and overweight), lifestyle (high energy intake and physical inactivity) and endometrial cancer risk in a Norwegian cohort. Author(s): Furberg AS, Thune I. Source: International Journal of Cancer. Journal International Du Cancer. 2003 May 10; 104(6): 669-76. Erratum In: Int J Cancer. 2003 May 10; 104(6): 799. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12640672

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Metabolic side effects of antipsychotics: focus on hyperglycemia and diabetes. Author(s): Buse JB. Source: The Journal of Clinical Psychiatry. 2002; 63 Suppl 4: 37-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11913675

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Metformin blunts stress-induced hyperglycemia after thermal injury. Author(s): Gore DC, Wolf SE, Herndon DN, Wolfe RR. Source: The Journal of Trauma. 2003 March; 54(3): 555-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634538

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Molecular understanding of hyperglycemia's adverse effects for diabetic complications. Author(s): Sheetz MJ, King GL. Source: Jama : the Journal of the American Medical Association. 2002 November 27; 288(20): 2579-88. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12444865

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Monocyte and neutrophil adhesion molecule expression during acute hyperglycemia and after antioxidant treatment in type 2 diabetes and control patients. Author(s): Sampson MJ, Davies IR, Brown JC, Ivory K, Hughes DA. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2002 July 1; 22(7): 1187-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12117736

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Munchausen's syndrome by proxy web-mediated in a child with factitious hyperglycemia. Author(s): Vanelli M. Source: The Journal of Pediatrics. 2002 December; 141(6): 839. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12461506

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Muscle uridine diphosphate-hexosamines do not decrease despite correction of hyperglycemia-induced insulin resistance in type 2 diabetes. Author(s): Pouwels MJ, Span PN, Tack CJ, Olthaar AJ, Sweep CG, van Engelen BG, de Jong JG, Lutterman JA, Hermus AR. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 November; 87(11): 5179-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12414889

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Normokalemia and hyperglycemia in subarachnoid hemorrhage patients resuscitated from prehospital cardiopulmonary arrest. Author(s): Inamasu J, Nakamura Y, Saito R, Kuroshima Y, Mayanagi K, Ohba S, Ichikizaki K. Source: Resuscitation. 2002 September; 54(3): 255-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12204458

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Olanzapine and quick-response hyperglycemia. Author(s): Abdullah N, Voronovitch L, Taylor S, Lippmann S. Source: Psychosomatics. 2003 March-April; 44(2): 175-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12618540

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Olanzapine associated weight gain, hyperglycemia and neuroleptic malignant syndrome: case report. Author(s): Malyuk R, Gibson B, Procyshyn RM, Kang N. Source: International Journal of Geriatric Psychiatry. 2002 April; 17(4): 326-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11994885

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On the failure of insulin to affect hyperglycemia during cardiac surgery. Author(s): Schricker T. Source: Anesthesia and Analgesia. 2002 December; 95(6): 1823-4; Author Reply 1824. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12456474

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Outcomes and perioperative hyperglycemia in patients with or without diabetes mellitus undergoing coronary artery bypass grafting. Author(s): Estrada CA, Young JA, Nifong LW, Chitwood WR Jr. Source: The Annals of Thoracic Surgery. 2003 May; 75(5): 1392-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12735552

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Oxidative DNA damage by hyperglycemia-related aldehydes and its marked enhancement by hydrogen peroxide. Author(s): Murata M, Mizutani M, Oikawa S, Hiraku Y, Kawanishi S. Source: Febs Letters. 2003 November 6; 554(1-2): 138-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14596928

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Perioperative hyperglycemia is a strong correlate of postoperative infection in type II diabetic patients after coronary artery bypass grafting. Author(s): Guvener M, Pasaoglu I, Demircin M, Oc M. Source: Endocrine Journal. 2002 October; 49(5): 531-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12507271

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Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Author(s): Baird TA, Parsons MW, Phanh T, Butcher KS, Desmond PM, Tress BM, Colman PG, Chambers BR, Davis SM. Source: Stroke; a Journal of Cerebral Circulation. 2003 September; 34(9): 2208-14. Epub 2003 July 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12893952

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Postchallenge hyperglycemia but not hyperinsulinemia is associated with angiographically documented coronary atherosclerosis in Korean subjects. Author(s): Kim HK, Lee SK, Suh CJ, Yoon HJ, Lee KY, Park HY, Kang MH. Source: Diabetes Research and Clinical Practice. 2003 February; 59(2): 129-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12560162

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Postprandial hyperglycemia and insulin sensitivity differ among lean young adults of different ethnicities. Author(s): Dickinson S, Colagiuri S, Faramus E, Petocz P, Brand-Miller JC. Source: The Journal of Nutrition. 2002 September; 132(9): 2574-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12221211

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Postprandial hyperglycemia and risk of atherosclerosis. Author(s): Mikhail N. Source: Jama : the Journal of the American Medical Association. 2002 August 28; 288(8): 955; Author Reply 955. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12190355

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Post-prandial hyperglycemia--the real challenge in diabetes. Author(s): Singh SK. Source: J Assoc Physicians India. 2002 November; 50: 1457; Author Reply 1457-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12583492

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Poststroke hyperglycemia: natural history and immediate management. Author(s): Gray CS, Hildreth AJ, Alberti GK, O'Connell JE; GIST Collaboration. Source: Stroke; a Journal of Cerebral Circulation. 2004 January; 35(1): 122-6. Epub 2003 December 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671236

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Prevalence of postprandial hyperglycemia in adolescents: a population-based study. Author(s): Brickman WJ, Holland JS, Silverman BL. Source: Diabetes Care. 2002 October; 25(10): 1887-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12351500

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Quetiapine-associated hyperglycemia and hypertriglyceridemia. Author(s): Domon SE, Cargile CS. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2002 May; 41(5): 495-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12014779

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Relationship between serum carotenoids and hyperglycemia: a population-based cross-sectional study. Author(s): Suzuki K, Ito Y, Nakamura S, Ochiai J, Aoki K. Source: J Epidemiol. 2002 September; 12(5): 357-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12395879

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Resolution of hyperglycemia on risperidone discontinuation: a case report. Author(s): Mallya A, Chawla P, Boyer SK, DeRosear L. Source: The Journal of Clinical Psychiatry. 2002 May; 63(5): 453-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12019673

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Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells. Author(s): Zalzman M, Gupta S, Giri RK, Berkovich I, Sappal BS, Karnieli O, Zern MA, Fleischer N, Efrat S. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 June 10; 100(12): 7253-8. Epub 2003 May 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12756298

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Rhabdomyolysis, pancreatitis, and hyperglycemia with ziprasidone. Author(s): Yang SH, McNeely MJ. Source: The American Journal of Psychiatry. 2002 August; 159(8): 1435. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12153844

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Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes. Author(s): Di Carli MF, Janisse J, Grunberger G, Ager J. Source: Journal of the American College of Cardiology. 2003 April 16; 41(8): 1387-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12706936

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Role of hyperglycemia in nitrotyrosine postprandial generation. Author(s): Ceriello A, Quagliaro L, Catone B, Pascon R, Piazzola M, Bais B, Marra G, Tonutti L, Taboga C, Motz E. Source: Diabetes Care. 2002 August; 25(8): 1439-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12145247

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Role of the kidney in hyperglycemia in type 2 diabetes. Author(s): Meyer C, Gerich JE. Source: Curr Diab Rep. 2002 June; 2(3): 237-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12643179

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Sertraline-induced hyperglycemia: case report. Author(s): Sansone RA, Sansone LA. Source: International Journal of Psychiatry in Medicine. 2003; 33(1): 103-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12906348

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Severe hyperglycemia after renal transplantation in a pediatric patient with a mutation of the hepatocyte nuclear factor-1beta gene. Author(s): Waller SC, Rees L, Woolf AS, Ellard S, Pearson ER, Hattersley AT, Bingham C. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2002 December; 40(6): 1325-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12460054

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Severe hyperglycemia as a complication of big ICE chemotherapy in a patient with acute myeloblastic leukemia. Author(s): Beyan C, Kaptan K, Cetin T, Nevruz O. Source: Haematologia. 2002; 32(4): 505-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12803126

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Similar symptoms and confounding conditions: benign prostatic hyperplasia versus hyperglycemia. Author(s): Meade-D'Alisera P, Wentland M, Merriweather T, Ghafar M. Source: Urologic Nursing : Official Journal of the American Urological Association Allied. 2001 October; 21(5): 354-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11998301

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Stress hyperglycemia, inflammation, and cardiovascular events. Author(s): Esposito K, Marfella R, Giugliano D. Source: Diabetes Care. 2003 May; 26(5): 1650-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716851

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Subcortical hypointensity in partial status epilepticus associated with nonketotic hyperglycemia. Author(s): Seo DW, Na DG, Na DL, Moon SY, Hong SB. Source: Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging. 2003 July; 13(3): 259-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12889174

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Targeting postprandial hyperglycemia: a comparative study of insulinotropic agents in type 2 diabetes. Author(s): Carroll MF, Gutierrez A, Castro M, Tsewang D, Schade DS. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 November; 88(11): 5248-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14602757

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Thalidomide-associated hyperglycemia and diabetes: case report and review of literature. Author(s): Pathak RD, Jayaraj K, Blonde L. Source: Diabetes Care. 2003 April; 26(4): 1322-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12663627

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The clinical importance of postprandial hyperglycemia. Author(s): Campbell RK, White JR, Nomura D. Source: Diabetes Educ. 2001 September-October; 27(5): 624-6, 632-4, 636-7. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12212013

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The effect of HAART and HCV infection on the development of hyperglycemia among HIV-infected persons. Author(s): Mehta SH, Moore RD, Thomas DL, Chaisson RE, Sulkowski MS. Source: Journal of Acquired Immune Deficiency Syndromes (1999). 2003 August 15; 33(5): 577-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12902801

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The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Author(s): HAPO Study Cooperative Research Group. Source: International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics. 2002 July; 78(1): 69-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12113977

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The influence of diabetes and hyperglycemia on clinical course after intracerebral hemorrhage. Author(s): Passero S, Ciacci G, Ulivelli M. Source: Neurology. 2003 November 25; 61(10): 1351-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638954

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The performance of a risk score in predicting undiagnosed hyperglycemia. Author(s): Park PJ, Griffin SJ, Sargeant L, Wareham NJ. Source: Diabetes Care. 2002 June; 25(6): 984-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12032103

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The potential therapeutic role of insulin in acute myocardial infarction in patients admitted to intensive care and in those with unspecified hyperglycemia. Author(s): Dandona P, Aljada A, Bandyopadhyay A. Source: Diabetes Care. 2003 February; 26(2): 516-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12547892

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The prevalent Glu23Lys polymorphism in the potassium inward rectifier 6.2 (KIR6.2) gene is associated with impaired glucagon suppression in response to hyperglycemia. Author(s): Tschritter O, Stumvoll M, Machicao F, Holzwarth M, Weisser M, Maerker E, Teigeler A, Haring H, Fritsche A. Source: Diabetes. 2002 September; 51(9): 2854-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12196481

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The rationale and management of hyperglycemia for in-patients with cardiovascular disease: time for change. Author(s): Trence DL, Kelly JL, Hirsch IB. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 June; 88(6): 2430-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12788838

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The response of antioxidant genes to hyperglycemia is abnormal in patients with type 1 diabetes and diabetic nephropathy. Author(s): Hodgkinson AD, Bartlett T, Oates PJ, Millward BA, Demaine AG. Source: Diabetes. 2003 March; 52(3): 846-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12606529

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Treating hyperglycemia in type 2 diabetes: new goals and strategies. Author(s): Lebovitz HE. Source: Cleve Clin J Med. 2002 October; 69(10): 809-20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12371804

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Tumor oxygenation and acidification are increased in melanoma xenografts after exposure to hyperglycemia and meta-iodo-benzylguanidine. Author(s): Burd R, Lavorgna SN, Daskalakis C, Wachsberger PR, Wahl ML, Biaglow JE, Stevens CW, Leeper DB. Source: Radiation Research. 2003 March; 159(3): 328-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12600235

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UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Author(s): Adler AI, Stevens RJ, Neil A, Stratton IM, Boulton AJ, Holman RR. Source: Diabetes Care. 2002 May; 25(5): 894-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11978687

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Undiagnosed hyperglycemia in clozapine-treated patients with schizophrenia. Author(s): Sernyak MJ, Gulanski B, Leslie DL, Rosenheck R. Source: The Journal of Clinical Psychiatry. 2003 May; 64(5): 605-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12755666

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Unrecognized hypo- and hyperglycemia in well-controlled patients with type 2 diabetes mellitus: the results of continuous glucose monitoring. Author(s): Hay LC, Wilmshurst EG, Fulcher G. Source: Diabetes Technology & Therapeutics. 2003; 5(1): 19-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12725703

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Utility of HbA(1c) levels for diabetes case finding in hospitalized patients with hyperglycemia. Author(s): Greci LS, Kailasam M, Malkani S, Katz DL, Hulinsky I, Ahmadi R, Nawaz H. Source: Diabetes Care. 2003 April; 26(4): 1064-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12663574

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VEGF expression in hypoxia and hyperglycemia: reciprocal effect on branching angiogenesis in epithelial-endothelial co-cultures. Author(s): Kim BS, Chen J, Weinstein T, Noiri E, Goligorsky MS. Source: Journal of the American Society of Nephrology : Jasn. 2002 August; 13(8): 202736. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12138133

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Vitamin B1 blocks damage caused by hyperglycemia. Author(s): Obrenovich ME, Monnier VM. Source: Sci Aging Knowledge Environ. 2003 March 12; 2003(10): Pe6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12844520

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VLDL-triglyceride kinetics during hyperglycemia-hyperinsulinemia: effects of sex and obesity. Author(s): Mittendorfer B, Patterson BW, Klein S, Sidossis LS. Source: American Journal of Physiology. Endocrinology and Metabolism. 2003 April; 284(4): E708-15. Epub 2002 December 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12475756

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Ziprasidone alternative for olanzapine-induced hyperglycemia. Author(s): Spivak B, Alamy SS, Jarskog LF, Sheitman BB, Lieberman JA. Source: The American Journal of Psychiatry. 2002 September; 159(9): 1606. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12202289

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

Finding Nutrition Studies on Hyperglycemia 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 “hyperglycemia” (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 hyperglycemia: •

A randomized controlled trial using glycemic plus fetal ultrasound parameters versus glycemic parameters to determine insulin therapy in gestational diabetes with fasting hyperglycemia. Author(s): Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine, Los Angeles, California, USA. [email protected] Source: Kjos, S L Schaefer Graf, U Sardesi, S Peters, R K Buley, A Xiang, A H Bryne, J D Sutherland, C Montoro, M N Buchanan, T A Diabetes-Care. 2001 November; 24(11): 1904-10 0149-5992

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An unsuspected factor contributing to pizza hyperglycemia. Source: Tatti, P Di Mauro, P Guarisco, R Diabetes-Care. 1993 October; 16(10): 1409-10 0149-5992

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Effect of high carbohydrate intake on hyperglycemia, islet function, and plasma lipoproteins in NIDDM. Author(s): Veterans Administration Medical Center, Center for Human Nutrition, Dallas, Texas. Source: Garg, A Grundy, S M Koffler, M Diabetes-Care. 1992 November; 15(11): 1572-80 0149-5992

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Glucose monitoring at the arm: risky delays of hypoglycemia and hyperglycemia detection. Author(s): German Diabetes Research Institute, Duesseldorf, Germany. Source: Jungheim, K Koschinsky, T Diabetes-Care. 2002 Jun; 25(6): 956-60 0149-5992

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Hemodynamic effects of acute hyperglycemia in type 2 diabetic patients. Author(s): Department of Geriatrics and Metabolic Diseases, Second University of Naples, Italy. [email protected] Source: Marfella, R Nappo, F De Angelis, L Paolisso, G Tagliamonte, M R Giugliano, D Diabetes-Care. 2000 May; 23(5): 658-63 0149-5992

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Hyperglycemia and compositional lipoprotein abnormalities as predictors of cardiovascular mortality in type 2 diabetes: a 15-year follow-up from the time of diagnosis. Author(s): Department of Clinical Nutrition, University of Kuopio, Finland. [email protected] Source: Niskanen, L Turpeinen, A Penttila, I Uusitupa, M I Diabetes-Care. 1998 November; 21(11): 1861-9 0149-5992

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Insulin secretion in normal glucose-tolerant relatives of type 2 diabetic subjects. Assessments using hyperglycemic glucose clamps and oral glucose tolerance tests. Author(s): Department of Internal Medicine, Utrecht University, The Netherlands. [email protected] Source: van Haeften, T W Dubbeldam, S Zonderland, M L Erkelens, D W Diabetes-Care. 1998 February; 21(2): 278-82 0149-5992

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Optimal administration of lispro insulin in hyperglycemic type 1 diabetes. Author(s): Department of Medicine/Endocrinology and Metabolism, University of New Mexico School of Medicine, Albuquerque 87131, USA. [email protected] Source: Rassam, A G Zeise, T M Burge, M R Schade, D S Diabetes-Care. 1999 January; 22(1): 133-6 0149-5992

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Postchallenge hyperglycemia in a national sample of U.S. adults with type 2 diabetes. Author(s): Department of Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Hygiene and Public Health, Baltimore, USA. [email protected] Source: Erlinger, T P Brancati, F L Diabetes-Care. 2001 October; 24(10): 1734-8 0149-5992

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Prevention of early-morning hyperglycemia in IDDM patients with long-acting zinc insulin. Author(s): Institute of Internal Medicine and Metabolic Disease, University of Naples, Italy. Source: Parillo, M Mura, A Iovine, C Rivellese, A A Lavicoli, M Riccardi, G DiabetesCare. 1992 February; 15(2): 173-7 0149-5992

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Role of hyperglycemia in nitrotyrosine postprandial generation. Author(s): Department of Pathology and Medicine, Experimental and Clinical, University of Udine, Udine, Italy. [email protected] Source: Ceriello, A Quagliaro, L Catone, B Pascon, R Piazzola, M Bais, B Marra, G Tonutti, L Taboga, C Motz, E Diabetes-Care. 2002 August; 25(8): 1439-43 0149-5992

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Twice-daily humulin ultralente insulin decreases morning fasting hyperglycemia. Author(s): Department of Pediatrics, Indiana University Medical Center, Indianapolis. Source: Johnson, N B Kronz, K K Fineberg, N S Golden, M P Diabetes-Care. 1992 August; 15(8): 1031-3 0149-5992

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Vitamin C and hyperglycemia in the European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk) study: a population-based study. Author(s): Department of Community Medicine, University of Cambridge, Institute of Public Health, UK. [email protected] Source: Sargeant, L A Wareham, N J Bingham, S Day, N E Luben, R N Oakes, S Welch, A Khaw, K T Diabetes-Care. 2000 June; 23(6): 726-32 0149-5992

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

Agonist-dependent failure of neutrophil function in diabetes correlates with extent of hyperglycemia. Author(s): Department of Pathology, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA. [email protected] Source: McManus, L M Bloodworth, R C Prihoda, T J Blodgett, J L Pinckard, R N JLeukoc-Biol. 2001 September; 70(3): 395-404 0741-5400

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Beneficial effects of L-arginine supplementation in experimental hyperlipemiahyperglycemia in the hamster. Author(s): Institute of Cellular Biology and Pathology N. Simionescu, 8 BP Hasdeu Street, Bucharest 79691, Romania. [email protected] Source: Popov, Doina Costache, Gabriela Georgescu, Adriana Enache, Mirela CellTissue-Res. 2002 April; 308(1): 109-20 0302-766X

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Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats. Author(s): Department of Internal Medicine I, School of Medicine, Oita Medical University, Oita, 879-5593 Japan. Source: Hidaka, Shuji Yoshimatsu, Hironobu Kondou, Seiya Tsuruta, Yoshio Oka, Kyoko Noguchi, Hitoshi Okamoto, Kenjirou Sakino, Hiroshi Teshima, Yasushi Okeda, Toshimitsu Sakata, Toshiie FASEB-J. 2002 April; 16(6): 509-18 1530-6860

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Dual-test monitoring of hyperglycemia using daily glucose and weekly fructosamine values. Author(s): Cosentino Service Co., Kansas City, MO, USA. [email protected] Source: Carter, A W Borchardt, N Cooney, M Greene, D Diabetes-Technol-Ther. 2001 Fall; 3(3): 399-403 1520-9156

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Effect of hyperglycemia on the polyol pathway in rat kidney during the perinatal period. Source: Freund, N. Prieur, B. Bismuth, J. Delaval, E. Eur-j-biochem. Berlin : SpringerVerlag Berlin. November 1996. volume 242 (1) page 86-89. 0014-2956

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Effect of petroleum ether extract of guar gum in streptozotocin-induced hyperglycemic rats. Source: Bhandari, U. Sharma, J.N. Pharm-biol. Lisse, the Netherlands : Swets & Zeitlinger, c1998-. July 1999. volume 37 (3) page 248-250. 1388-0209

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Effect of posttraumatic hyperglycemia on contusion volume and neutrophil accumulation after moderate fluid-percussion brain injury in rats. Author(s): Department of Neurological Surgery, University of Miami School of Medicine, Miami, Florida 33101, USA. Source: Kinoshita, K Kraydieh, S Alonso, O Hayashi, N Dietrich, W D J-Neurotrauma. 2002 June; 19(6): 681-92 0897-7151

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Effects of hyperglycemia and protein kinase C on connexin43 expression in cultured rat retinal pigment epithelial cells. Author(s): Laboratory of Physiology, KULeuven, Campus Gasthuisberg O/N, Herestraat 49 B-3000 Leuven, Belgium. Source: Malfait, M Gomez, P van Veen, T A Parys, J B De Smedt, H Vereecke, J Himpens, B J-Membr-Biol. 2001 May 1; 181(1): 31-40 0022-2631

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Effects of selected minerals on leptin secretion in streptozotocin-induced hyperglycemic mice. Author(s): Department of Medical Laboratories, Taichung Veterans General Hospital, 160 Taichung-Kang Road, Section 3, Taichung 40705, Taiwan. Source: Chen, M D Yang, V C Alexander, P S Lin, P Y Song, Y M Exp-Biol-Med(Maywood). 2001 October; 226(9): 836-40 1535-3702

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Efficient synthesis of antihyperglycemic (S)-alpha-aryloxy-beta-phenylpropionic acid using a bifunctional asymmetric catalyst. Author(s): Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd, [email protected] Source: Takamura, M Yanagisawa, H Kanai, M Shibasaki, M Chem-Pharm-Bull-(Tokyo). 2002 August; 50(8): 1118-21 0009-2363

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Enhancement of hyperglycemia-induced acidification of human melanoma xenografts with inhibitors of respiration and ion transport. Author(s): Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA. Source: Zhou, R Bansal, N Leeper, D B Pickup, S Glickson, J D Acad-Radiol. 2001 July; 8(7): 571-82 1076-6332

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Hyperglycemia and hypertriglyceridemia secondary to olanzapine. Author(s): Department of Psychiatry, University of Arkansas for Medical Sciences, Little Rock, USA. [email protected] Source: Domon, S E Webber, J C J-Child-Adolesc-Psychopharmacol. 2001 Fall; 11(3): 2858 1044-5463

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Hyperglycemia impairs antro-pyloric coordination and delays gastric emptying in conscious rats. Author(s): Department of Internal Medicine, Wakayama Medical College, Japan. Source: Ishiguchi, Tadashi Tada, Hitoshi Nakagawa, Kazuhiko Yamamura, Takehira Takahashi, Toku Auton-Neurosci. 2002 January 10; 95(1-2): 112-20 1566-0702

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Hyperglycemic effect of leaves of Mimosa pudica Linn. Author(s): Entomology Research Institute, Loyola College, Chennai-600 034, India. Source: Amalraj, T Ignacimuthu, S Fitoterapia. 2002 July; 73(4): 351-2 0367-326X

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Hypoglycemic and antihyperglycemic activity of Syzygium alternifolium (Wt.) Walp. seed extracts in normal and diabetic rats. Source: Kameswara Rao, B. Appa Rao, C. Phytomedicine. Stuttgart; New York : G. Fischer, c1994-. March 2001. volume 8 (2) page 88-93. 0944-7113

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Hypoglycemic effect of Hibiscus rosa sinensis L. leaf extract in glucose and streptozotocin induced hyperglycemic rats. Author(s): Department of Chemistry, Faculty of Science, Dayalbagh Educational Institute, Agra, India. Source: Sachdewa, A Nigam, R Khemani, L D Indian-J-Exp-Biol. 2001 March; 39(3): 2846 0019-5189

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Interactive dysmorphogenic effects of toxaphene or toxaphene congeners and hyperglycemia on cultured whole rat embryos during organogenesis. Author(s): School of Dietetics and Human Nutrition, MacDonald Campus of McGill University, 21, 111 Lakeshore Road, Ste.-Anne-de-Bellevue, Quebec, Canada H9X 3V9. Source: Calciu, Cristina Kubow, Stan Chan, Hing Man Toxicology. 2002 June 14; 175(13): 153-65 0300-483X

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Lipid hydroperoxide induced corneal neovascularization in hyperglycemic rabbits. Author(s): Department of Ophthalmology, Showa University School of Medicine, Tokyo, Japan. Source: Higa, A Nakanishi Ueda, T Arai, Y Tsuchiya, T Ueda, T Fukuda, S Watanabe, K Kan, K Yasuhara, H Koide, R Armstrong, D Curr-Eye-Res. 2002 July; 25(1): 49-53 02713683

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Mechanical hyperalgesia in rats with chronic perfusion of lumbar dorsal root ganglion with hyperglycemic solution. Author(s): Department of Pharmacology and Toxicology, Slot 611, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR 72205-7101, USA. [email protected] Source: Dobretsov, M Hastings, S L Stimers, J R Zhang, J M J-Neurosci-Methods. 2001 September 30; 110(1-2): 9-15 0165-0270

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Oral therapies for diabetic hyperglycemia. Author(s): Department of Medicine, State University of New York Health Science Center at Brooklyn, Brooklyn, New York, USA. Source: Lebovitz, H E Endocrinol-Metab-Clin-North-Am. 2001 December; 30(4): 909-33 0889-8529

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Pancreatic beta-cells from obese-hyperglycemic mice are characterized by excessive firing of cytoplasmic Ca2+ transients. Author(s): Department of Medical Cell Biology, Uppsala University, Sweden. Source: Ahmed, M Grapengiesser, E Endocrine. 2001 June; 15(1): 73-8 0969-711X

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Region-specific pathophysiological alterations occurring in calf lenses in vitro during hyperglycemia. Author(s): Department of Chemistry, and Biochemistry, Medical Institute, Plovdiv, Bulgaria. [email protected] Source: Argirova, M D Argirov, O K Graefes-Arch-Clin-Exp-Ophthalmol. 2002 February; 240(2): 126-30 0721-832X

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Sequential hypoglycemia, hyperglycemia, and the carcinoid syndrome arising from a plurihormonal neuroendocrine neoplasm. Author(s): Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA. Source: Mitzner, L D Nohria, A Chacho, M Inzucchi, S E Endocr-Pract. 2000 SepOctober; 6(5): 370-4 1530-891X

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Sustained hyperglycemia and insulin resistance induced by dietary restriction. Author(s): Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Yada, Japan. [email protected] Source: Maeda, T Sakita, R Kaihatsu, T Miwa, M Biol-Pharm-Bull. 2001 August; 24(8): 950-3 0918-6158

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The antihyperglycemic effect of estrone sulfate in genetically obese-diabetic (ob/ob) mice is associated with reduced hepatic glucose-6-phosphatase. Author(s): Department of Obstetrics & Gynecology, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK. Source: Borthwick, E B Houston, M P Coughtrie, M W Burchell, A Horm-Metab-Res. 2001 December; 33(12): 721-6 0018-5043

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The effect of chromium supplementation on the glucose tolerance of hypoglycemic, marginally hyperglycemic and normal subjects. Source: Anderson, R.A. Polansky, M.M. Bryden, N.A. Kozlovsky, A.S. Trace elements in man and animals : TEMA 5 : proceedings of the fifth International Symposium on Trace Elements in Man and Animals / editors C.F. Mills, I. Bremner, & J.K. Chesters. Farnham Royal, Slough : Commonwealth Agricultural Bureaux, c1985. page 811-814. ISBN: 085198553X

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Thiamine reverses hyperglycemia-induced dysfunction in cultured endothelial cells. Author(s): Division of Vascular Surgery, Maimonides Medical Center, Brooklyn, NY 11219, USA. Source: Ascher, E Gade, P V Hingorani, A Puthukkeril, S Kallakuri, S Scheinman, M Jacob, T Surgery. 2001 November; 130(5): 851-8 0039-6060

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Thirty-six cases of hyperglycemia treated by promoting blood circulation to remove stasis. Author(s): AIR CHINA, Capital International Airport, Beijing 100621. Source: Song, F J-Tradit-Chin-Med. 2001 September; 21(3): 187-8 0254-6272

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The following is a specific Web list relating to hyperglycemia; 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: •

Minerals Biotin Source: Prima Communications, Inc.www.personalhealthzone.com Chromium Source: Integrative Medicine Communications; www.drkoop.com

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Food and Diet Diabetes Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. DISSERTATIONS ON HYPERGLYCEMIA Overview In this chapter, we will give you a bibliography on recent dissertations relating to hyperglycemia. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “hyperglycemia” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on hyperglycemia, we have not necessarily excluded non-medical dissertations in this bibliography.

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

Hyperglycemia and Capacitative Calcium Entry in the Heart by Pang, Yi; PhD from The University of Alabama at Birmingham, 2003, 130 pages http://wwwlib.umi.com/dissertations/fullcit/3101483

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Polytherapeutic Approaches to the Control of Hyperglycemia in Non-insulin Dependent Diabetics in Korea by Gang, G-Hyon, PhD from University of Florida, 1995, 267 pages http://wwwlib.umi.com/dissertations/fullcit/9607370

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Risk Factors for Hyperglycemia in Children, a Precursor of Type 2 Diabetes by Stone, Sarah Lind; MS from The Texas A&M University System Health Science Center, 2003, 53 pages http://wwwlib.umi.com/dissertations/fullcit/1414184

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

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CHAPTER 4. CLINICAL TRIALS AND HYPERGLYCEMIA Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning hyperglycemia.

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

Gluconeogenesis in Very Low Birth Weight Infants Who Are Receiving Nutrition By Intravenous Infusion Condition(s): Infant, Low Birth Weight; Hyperglycemia Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Baylor College of Medicine Purpose - Excerpt: RATIONALE: Very low birth weight infants have problems maintaining normal blood sugar levels. Gluconeogenesis is the production of sugar from amino acids and fats. The best combination of amino acids, fat, and sugar to help very low birth weigh infants maintain normal blood sugar levels is not yet known. PURPOSE: Clinical trial to study how very low birth weight infants break down amino acids, fat, and sugar given by intravenous infusion, and the effect of different combinations of nutrients on the infants' ability to maintain normal blood sugar levels. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005889

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Study of Recombinant Human Insulin-Like Growth Factor I in Patients with Severe Insulin Resistance Condition(s): Insulin Resistance; Hyperglycemia

8

These are listed at www.ClinicalTrials.gov.

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Study Status: This study is currently recruiting patients. Sponsor(s): FDA Office of Orphan Products Development; Beth Israel Deaconess Medical Center Purpose - Excerpt: Objectives: I. Determine the efficacy and toxic effects of recombinant human insulin-like growth factor I (rhIGF-I) on carbohydrate tolerance, insulin action, insulin secretion, hyperandrogenism, and hyperlipidemia in patients with severe insulin resistance who have failed other therapies. II. Determine the dose and time response of rhIGF-I on carbohydrate homeostasis and secondary abnormalities in this patient population. III. Determine the effect of rhIGF-I on insulin clearance, the regulation of insulin-like growth factor binding protein 1, the regulation of sex hormone binding globulin, and hypothalamic pituitary gonadal axis in this patient population. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004419 •

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

Infections;

Hypercholesterolemia;

Hypertriglyceridemia;

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

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “hyperglycemia” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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CHAPTER 5. PATENTS ON HYPERGLYCEMIA Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “hyperglycemia” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on hyperglycemia, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Hyperglycemia By performing a patent search focusing on hyperglycemia, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 9Adapted

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

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

Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders Inventor(s): Boueres; Julia K. (Piscataway, NJ), Desai; Ranjit C. (Kendall Park, NJ), Koyama; Hiroo (Hoboken, NJ), Miller; Daniel J. (Edison, NJ), Sahoo; Soumya P. (Old Bridge, NJ) Assignee(s): Merck & Co., Inc. (rahway, Nj) Patent Number: 6,645,997 Date filed: September 24, 2001 Abstract: A class of benzopyrancarboxylic acid derivatives comprises compounds that are potent agonists of PPAR alpha and/or gamma, and are therefore useful in the treatment, control or prevention of non-insulin dependent diabetes mellitus (NIDDM), hyperglycemia, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, obesity, vascular restenosis, inflammation, and other PPAR alpha and/or gamma mediated diseases, disorders and conditions. Excerpt(s): The instant invention is concerned with benzopyrancarboxylic acids and related heterocyclic compounds and pharmaceutically acceptable salts and prodrugs thereof which are useful as therapeutic compounds, particularly in the treatment and prevention of Type 2 diabetes mellitus, often referred to as non-insulin dependent diabetes (NIDDM), of conditions that are often associated with this disease, and of lipid disorders. Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus. There are two generally recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulinsensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance. Web site: http://www.delphion.com/details?pn=US06645997__

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Composition and method for maintaining blood glucose level Inventor(s): Dhawan; Sanju (Chandigarh, IN), Singla; Anil Kumar (Chandigarh, IN) Assignee(s): Council of Scientific & Industrial Research (new Delhi, In) Patent Number: 6,703,045 Date filed: August 21, 2001 Abstract: A composition useful for reducing serum glucose levels by an oral controlled release system and a method for treating diabetes in a human being by controlling the blood glucose level (BGL) and reducing the complications associated with diabetic hyperglycemia and also the long term management of Non-Insulin Dependent Diabetes Mellitus (NIDDM) by avoiding the problems associated with the tight control of BGL, i.e., hypoglycemia tolerance and seizures. The composition is directed to a solid, hydrophilic matrix controlled release oral dosage form where the dosage form contains a therapeutically effective amount of antidiabetic drug in the matrix ensuring complete bioavailability of the drug from the matrix of the tablet. The formulation undergoes substantially or approaches zero order release of active drug and the concentration of the excepients and the water swellable polymers is chosen in such a way that the erosion or dissolution rate of the polymer is equal to the swelling rate of the polymer to get a constant release. Also, the concentration is chosen in such a way that the tablet will be fully dissolved at the same time the last of the drug is released and in addition a bioadhesive polymer may also be added to increase the residence time of the dosage form in the g.i.t. and at high concentration of the polymer, beta cyclodextrin may also be added to improve the release kinetics. Excerpt(s): (1) American Diabetes Association. Diabetes 1996 Vital Statistics. Rockville, Md.: American Diabetes Association, 1996. (2) Harris, M. I., Cowie, C. C., Stern, M. P. eds. Diabetes in America, 2nd. ed. National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases. NIH Publication No. 95-1468, 1995. (3) Clark, C. M., Vinicor, F. Introduction: Risks and benefits of intensive management in non-insulin-dependent diabetes mellitus. The Fifth Regensrief Conference. Ann Intern Med, 124(1, pt 2), 81-85, 1996. Web site: http://www.delphion.com/details?pn=US06703045__

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Hypoglycemic and hypolipidemic compounds Inventor(s): Dominianni; Samuel James (Indianapolis, IN), Faul; Margaret Mary (Zionsville, IN), Stucky; Russell Dean (Indianapolis, IN), Winneroski, Jr.; Leonard Larry (Greenwood, IN) Assignee(s): Eli Lilly and Company (indianapolis, In) Patent Number: 6,541,497 Date filed: March 3, 2000 Abstract: This invention provides compounds and their pharmaceutically-acceptable salts, pharmaceutical formulations of said compounds, and methods for treating hyperglycemia associated with non-insulin dependent diabetes and for treating hyperlipidemia. Excerpt(s): The disease, diabetes mellitus, is recognized in two forms. Type I diabetes requires exogenous insulin for control of the disease because it appears that endogenous production of insulin by the Isles of Langerhans in the pancreas is extremely poor or

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non-existent. Type I diabetes is often referred to as insulin-dependent diabetes mellitus (IDDM). Type II, non-insulin-dependent diabetes mellitus (NIDDM), is characterized by defects of insulin sensitivity in peripheral tissues such as adipose tissue and muscle, as described by J. E. Gerich in New Engl. J. Med., 321, 1231-1245 (1989). Hyperlipidemia is often observed in diabetics (Diabetes Care, 18, Supplement 1, 86-93, 1995). The combination of hyperlipidemia and hyperglycemia greatly increases the risk of cardiovascular diseases in diabetics. Successful treatment of hyperlipidemia and hyperglycemia in diabetics is needed urgently. Blank reviewed hypoglycemic agents (Burger's Medicinal Chemistry, 4th Ed., Part II, John Wiley and Sons, N.Y., 1979, 10571080). Newer hypoglycemic agents were reviewed by Hulin in Progress in Medicinal Chemistry, 31, ed. G. P. Ellis and D. K. Luscombe, Elsevier Publishing Co., 1993. Web site: http://www.delphion.com/details?pn=US06541497__ •

Method for treating diabetes mellitus Inventor(s): Weinstein; Allan M. (9205 Pegasus Ct., Potomac, MD 20854), Weinstein; Robert E. (177 Commonwealth Ave., Boston, MA 02116) Assignee(s): None Reported Patent Number: 6,652,838 Date filed: April 4, 2002 Abstract: A method for treating postprandial hyperglycemia in diabetes mellitus in a human which employs a combination of an aerosolizable topical insulin and a shortacting oral hypoglycemic agent as a regimen taken adjacent to mealtime. Excerpt(s): The present invention relates generally to the treatment of diabetes. Particularly, the present invention relates to the treatment of diabetes without the use of insulin injections. Diabetes mellitus is a chronic illness caused by a lack of an effective amount of insulin. It is manifested by the elevation of blood sugar. Diabetes mellitus is the fourth leading cause of death by disease in the United States and the leading cause of irreversible blindness and chronic renal failure. Treatment for diabetes is directed to lowering blood sugar, particularly after meals, and to preventing long term complications that include neuropathy, accelerated atherosclerosis, myocardial infarction, gangrene of the lower extremities, retinopathy and nephropathy. Diabetic individuals are typically required to comply with treatments over very long periods of time to avoid these complications. The two pharmacological modalities presently used to lower blood sugar are oral hypoglycemic (anti-diabetic) agents and insulin. Insulin replacement is presently accomplished by injection and is based upon the lack of insulin or limitation of its action in diabetes mellitus. Oral anti-diabetic agents are not chemically akin to insulin and their sugar-lowering mechanism differs from the action of direct insulin replacement. Oral hypoglycemic agents and insulin are, at present, therapeutically utilized alone or in concert with each other, according to the needs of the diabetic individual. Some individuals are best treated with more than one oral agent, with, or without insulin. Web site: http://www.delphion.com/details?pn=US06652838__

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Naphthylsulfonic acids and related compounds as glucose uptake agonists Inventor(s): Kozlowski; Michael R. (Palo Alto, CA), Lum; Robert T. (Palo Alto, CA), Manchem; Prasad V. V. S. V. (South San Francisco, CA), Park; Jeong Weon (Emeryville, CA), Robinson; Louise (San Carlos, CA), Schow; Steven R. (Redwood Shores, CA), Shi; Songyuan (Fremont, CA), Spevak; Wayne R. (Albany, CA) Assignee(s): Telik, Inc. (palo Alto, Ca) Patent Number: 6,653,321 Date filed: July 28, 2000 Abstract: Methods for treating conditions associated with hyperglycemia, especially Type II diabetes, with novel naphthylsulfonic acids and related compounds. These compounds, as single stereoisomers or mixtures of stereoisomers, or their pharmaceutically acceptable salts, are useful in methods of stimulating the kinase activity of the insulin receptor, enhancing the activation of the insulin receptor by insulin, and stimulating the uptake of glucose into cells. A variety of antidiabetic compounds and pharmaceutical compositions comprising the antidiabetic compounds are also disclosed. Excerpt(s): The present invention relates to methods, pharmaceutical compositions, and compounds for enhancing insulin-dependent glucose uptake. The compounds of the invention activate the insulin receptor kinase, leading to an increased sensitivity to insulin and an increase in glucose uptake. The invention relates in particular to the use of the compounds in methods for the treatment of humans with hyperglycemia, and especially for the treatment of Type II diabetes. Among the many functions performed by peptide and protein hormones in metabolism is the ability to interact with receptors with high specificity. The insulin receptor is present on virtually all cells and at high concentrations on the cells for the liver, skeletal muscles, and adipose tissue. Stimulation of the insulin receptor with insulin is an essential element in carbohydrate metabolism and storage. Diabetics either lack sufficient endogenous secretion of the insulin hormone (Type I) or have an insulin receptor-mediated signaling pathway that is resistant to endogenous or exogenous insulin (Type II, or non-insulin-dependent diabetes mellitus (NIDDM)). Type II diabetes is the most common form of diabetes, affecting about 5% of individuals in the industrialized nations. In Type II diabetics, major insulin-responsive tissues such as liver, skeletal muscle and fat exhibit the insulin resistance (Haring and Mehnert, Diabetologia 36:176-182 (1993); Haring et al., Diabetologia, 37 Suppl 2:S149-54 (1994)). The resistance to insulin in Type II diabetes is complex and likely multifactorial but appears to be caused by an impaired signal from the insulin receptor to the glucose transport system and to glycogen synthase. Impairment of the insulin receptor kinase has been implicated in the pathogenesis of this signaling defect. Insulin resistance is also found in many non-diabetic individuals, and may be an underlying etiologic factor in the development of the disease (Reaven, Diabetes, 37:1595-1607 (1988)). Web site: http://www.delphion.com/details?pn=US06653321__

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Synergistic effect of a sulfonylurea and/or non-sulfonylurea K+ATP channel blocker, and a phosphodiesterase 3 type inhibitor Inventor(s): Fryburg; David A. (East Lyme, CT), Parker; Janice C. (Ledyard, CT) Assignee(s): Pfizer Inc. (new York, Ny) Patent Number: 6,610,746 Date filed: April 10, 2001 Abstract: The present invention provides methods of treating non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the methods comprising the step of administering to a patient having or at risk of having non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance a synergistic amount of:1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also provides kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also relates to kits and pharmaceutical compositions that comprise 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; 2) a cAMP phosphodiesterase type 3 inhibitor; and 3) an additional compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance. Excerpt(s): The present invention relates to methods of treating non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the methods comprising the step of administering to a patient having or at risk of having non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also relates to kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also relates to kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; 2) a cAMP phosphodiesterase type 3 inhibitor; and 3) an additional compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance. In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery

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of and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes can be improved. A group of compounds that stimulate insulin secretion and stimulate de novo synthesis of insulin are the cAMP phosphodiesterase type 3 inhibitors. It is believed that cAMP phosphodiesterase type 3 inhibitors act to increase insulin secretion by increasing intracellular levels of cAMP in pancreatic.beta.-cells in the islet of Langerhans. In contrast, sulfonylureas act on the K.sup.+ ATP channels of pancreatic.beta.-cells in the islet of Langerhans. Moreover, cAMP phosphodiesterase type 3 is known to exist in two forms: type A and type B. Type A cAMP phosphodiesterase 3 is associated with cardiac tissue and with platelets, and type B is associated with liver and adipose tissue, and.beta.-cells in the pancreas. Web site: http://www.delphion.com/details?pn=US06610746__

Patent Applications on Hyperglycemia As of December 2000, U.S. patent applications are open to public viewing.10 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 hyperglycemia: •

11-BETA-HYDROXYSTEROID DEHYDROGENASE 1 INHIBITORS USEFUL FOR THE TREATMENT OF DIABETES, OBESITY AND DYSLIPIDEMIA Inventor(s): Balkovec, James M.; (Martinsville, NJ), Olson, Steven H.; (Metuchen, NJ), Zhu, Yuping; (Scotch Plains, NJ) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20040048912 Date filed: June 9, 2003 Abstract: Compounds having Formula I, including pharmaceutically acceptable salts, hydrates and solvates thereof: 1are selective inhibitors of the 11.beta.-HSD1 enzyme. The compounds are useful for the treatment of diabetes, such as noninsulin-dependent diabetes (NIDDM), hyperglycemia, obesity, insulin resistance, dylsipidemia, hyperlipidemia, hypertension, Syndrome X, and other symptoms associated with NIDDM. Excerpt(s): The present invention is related to U.S. provisional application Serial No. 60/387,385, filed Jun. 10, 2002, the contents of which are hereby incorporated by reference. The present invention relates to inhibitors of the enzyme 11-betahydroxysteroid dehydrogenase Type I (11.beta.-HSD-1 or HSD-1), and methods of treatment using such compounds. The compounds are useful for the treatment of diabetes, such as non-insulin dependent type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, lipid disorders and other diseases and conditions. Diabetes is caused by multiple factors and is most simply characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state. There are two generally recognized forms of diabetes: type I diabetes, or insulin-dependent diabetes mellitus (IDDM), in which patients produce little or no insulin, the hormone which regulates glucose utilization, and type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), wherein

10

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

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patients produce insulin and even exhibit hyperinsulinemia (plasma insulin levels that are the same or even elevated in comparison with non-diabetic subjects), while at the same time demonstrating hyperglycemia. Type 1 diabetes is typically treated with exogenous insulin administered via injection. However, type 2 diabetics often develop "insulin resistance", such that the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, namely, muscle, liver and adipose tissues, is diminished. Patients who are insulin resistant but not diabetic have elevated insulin levels that compensate for their insulin resistance, so that serum glucose levels are not elevated. In patients with NIDDM, the plasma insulin levels, even when they are elevated, are insufficient to overcome the pronounced insulin resistance, resulting in hyperglycemia. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

2-methylpropionic acid derivatives and pharmaceutical compositions comprising the same Inventor(s): Akahane, Masuo; (Nagano, JP), Hirabayashi, Akihito; (Nagano, JP), Mukaiyama, Harunobu; (Nagano, JP), Muranaka, Hideyuki; (Nagano, JP), Sato, Masaaki; (Nagano, JP), Tamai, Tetsuro; (Nagano, JP), Tanaka, Nobuyuki; (Nagano, JP) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, NW; Washington; DC; 20037-3213; US Patent Application Number: 20030166719 Date filed: February 5, 2003 Abstract: The present invention provides novel 2-methylpropionic acid derivatives represented by the general formula: 1(wherein R.sup.1 represents a hydroxy group, a lower alkoxy group or an aralkyl group; R.sup.2 represents a hydroxy group, a lower alkyl group or a halogen atom; A represents an oxygen atom or an imino group; the carbon atom marked with (R) represents a carbon atom in R configuration; and the carbon atom marked with (S) represents a carbon atom in S configuration) and pharmaceutically acceptable salts thereof, which have excellent.beta.sub.3-adrenoceptor stimulating effects and are useful as agents for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract. Excerpt(s): The present invention relates to novel 2-methylpropionic acid derivatives and pharmaceutically acceptable salts thereof which are useful as medicaments. It is known that three subtypes of sympathetic.beta.-adrenoceptor, which have been classified as.beta.sub.1,.beta.sub.2 and.beta.sub.3, are present and that each receptor subtype is distributed in specified organs in living body and has specific function. For example,.beta.sub.1-adrenoceptor is mainly present in the heart and the stimulation ofthis receptor leads to increment of heart rate and cardiac contractility.beta.sub.2Adrenoceptor is mainly present in smooth muscle of blood vessels, the trachea and uterus. The stimulation of this receptor leads to vasodilation, bronchodilation and inhibition of uterine contraction.beta.sub.3-Adrenoceptor is mainly present in adipocytes, the gallbladder and intestinal tract. It is known that.beta.sub.3-adrenoceptor is also present in the brain, liver, stomach and prostate. It is reported that the stimulation of this receptor leads to increment of lipolysis, inhibition of intestinal tract motility, increment of glucose uptake, anti-depression and so on (Drugs of the Future, Vol.18, No.6, pp.529-549 (1993); Molecular Brain Research, Vol.29, pp.369-375 (1995);

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European Journal of Pharmacology, Vol.289, pp.223-228 (1995); Pharmacology, Vol.51, pp.288-297 (1995)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Adenoviral library assay for adipogenesis genes and methods and compositions for screening compounds Inventor(s): Bout, Abraham; (Moerkapelle, NL), Schouten, Govert; (Leidenderp, NL), van Es, Helmuth; (Hoofddorp, NL), Van Rompaey, Luc; (Keerbergen, BE), Vogels, Ronald; (Linschoten, NL) Correspondence: Synnestvedt & Lechner, Llp; 2600 Aramark Tower; 1101 Market Street; Philadelphia; PA; 191072950 Patent Application Number: 20030170633 Date filed: February 13, 2002 Abstract: Methods, and compositions for use therein, for directly, rapidly, and unambiguously identifying, in a high throughput setting, unique nucleic acids involved in the process of lipid vacuole formation in cells and/or the cell differentiation process of adipogenesis, using an adenoviral vector library system. The method identifies unique nucleic acids capable of inducing lipid droplet formation in a cell, and determines whether the expression product of such a nucleic acid is secreted. Drug candidate compounds useful in the treatment of disease states such as obesity, type II diabetes and hyperglycemia are identified by the screening of compounds that either increase or decrease the formation of lipid droplets, or mRNA expression in host cells. Pharmaceutical compositions and methods of treatment comprising the polypeptides or polynucleotides identified by the methods of the present invention are disclosed. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 10/036,949, filed on Dec. 21, 2001, which is a divisional of U.S. patent application Ser. No. 09/358,036, filed on Jul. 21, 1999, now U.S. Pat. No. 6,340,595, which is a continuation-in-part of pending U.S. patent application Ser. No. 09/097,239, filed on Jun. 12, 1998. The invention relates to high throughput methods for identifying the function of sample nucleic acids and their products. The ultimate goal of the Human Genome Project is to sequence the entire human genome. The expected outcome of this effort is a precise map of the 70,000-100,000 genes that are expressed in man. Since the early 1980s, a large number of Expressed Sequence Tags (ESTs), which are partial DNA sequences read from the ends of complementary DNA (cDNA) molecules, have been obtained by both government and private research organizations. A hallmark of these endeavors, carried out by a collaboration between Washington University Genome Sequencing Center and members of the IMAGE (Integrated Molecular Analysis of Gene Expression) consortium (http:/www-bio.llnl.gov/bbrp/image/image.html), has been the rapid deposition of the sequences into the public domain and the concomitant availability of the sequence-tagged cDNA clones from several distributors (Marra, et al. (1998) Trends Genet. 14(1):4-7). At present, the collection of cDNAs is believed to represent approximately 50,000 different human genes expressed in a variety of tissues including liver, brain, spleen, B-cells, kidney, muscle, heart, alimentary tract, retina, and hypothalamus, and the number is growing daily. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Antidiabetic agents Inventor(s): Gammill, Ronald B.; (East Lyme, CT) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030199553 Date filed: February 19, 2003 Abstract: A compound of the formula 1wherein n, m, Z, R.sup.1, R.sup.5, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are as defined above, useful in the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia. Excerpt(s): The present invention relates to substituted 1H-(indole-2-carboxamides and 6H-thieno[2,3-b]pyrrole-5-carboxamides which are antidiabetic agents and as such are useful in the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia. This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to the pharmaceutical compositions useful therefor. In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidinediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Bicyclic pyrrolyl amides as glycogen phosphorylase inhibitors Inventor(s): Du Bois, Daisy Joe; (Palo Alto, CA) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030195361 Date filed: February 14, 2003 Abstract: This invention relates to compounds of Formula I 1or stereoisomers, pharmaceutically acceptable salts or prod rugs thereof or a pharmaceutically acceptable salts of the prodrugs. This invention also relates to pharmaceutical compositions comprising a compound of Formula I, and to methods of treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia. Excerpt(s): This invention relates to bicyclic pyrrolyl amides and pharmaceutical compositions comprising bicyclic pyrrolyl amides. This invention also relates to the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia, using the bicyclic pyrrolyl amides. In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later

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discovery of and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin requires multiple daily doses, usually by self injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycemic agents, e.g., thiazolidenediones, and in more severe cases, insulin. However, the clinically available hypoglycemic agents can have side effects that limit their use, or an agent may not be effective with a particular patient. In the case of insulin dependent diabetes mellitus (Type I), insulin is usually the primary course of therapy. Hypoglycemic agents that have fewer side effects or succeed where others fail are needed. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Combinations Inventor(s): Cohen, David Saul; (New Providence, NJ) Correspondence: Thomas Hoxie; Novartis, Patent And Trademark Department; One Health Plaza 430/2; East Hanover; NJ; 07936-1080; US Patent Application Number: 20030114469 Date filed: August 28, 2002 Abstract: The present invention relates to a pharmaceutical composition, comprising(a) a phosphodiesterase 5 inhibitor or a pharmaceutically acceptable salt thereof and(b) at least one of the active ingredients selected from the group consisting of(i) an antidiabetic agent;(ii) HMG-Co-A reductase inhibitors;(iii) an anti-hypertensive agent; and(iv) a serotonin reuptake inhibitor (SSRI) or, in each case, or a pharmaceutically acceptable salt thereof; anda pharmaceutically acceptable carrier. The pharmaceutical composition may be employed for the treatment of sexual dysfunction, hyperglycemia, hyperinsulinaemia, hyperlipidaemia, hypertriglyceridemia, diabetes, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, obesity, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, syndrome X, erectile dysfunction, coronary heart disease, hypertension, especially ISH, angina pectoris, myocardial infarction, stroke, vascular restenosis, endothelial dysfunction, impaired vascular compliance, congestive heart failure. Excerpt(s): a pharmaceutically acceptable carrier. Anti-diabetic agents include insulin secretion enhancers which are active ingredients that have the property to promote the secretion of insulin from pancreatic.beta.-cells. Examples of insulin secretion enhancers are a biguanide derivative, for example, metformin or, if appropriate, a pharmaceutically acceptable salt thereof, especially the hydrochloride thereof. Other insulin secretion enhancers include sulfonylureas (SU), especially those which promote the secretion of insulin from pancreatic.beta.-cells by transmitting signals of insulin secretion via SU receptors in the cell membrane including, but are not limited to, tolbutamide; chlorpropamide; tolazamide; acetohexamide; 4-chloro-N-[(1pyrolidinylamino)carbonyl]-benzensulfonamide (glycopyramide); glibenclamide (glyburide); gliclazide; 1-butyl-3-metanilylurea; carbutamide; glibonuride; glipizide; gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide; glymidine; glypinamide;

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phenbutamide; and tolylcyclamide, or pharmaceutically acceptable salts thereof. and repaglinide [(S)-2-ethoxy-4-{2-[[3-methyl-1-[2-(1-piperidinyl)p- henyl]butyl]amino]-2oxoethyl}benzoic acid]. Repaglinide is disclosed in EP 589874, EP 147850 A2, in particular Example 11 on page 61, and EP 207331 A1. It can be administered in the form as it is marketed, e.g., under the trademark NovoNorm.TM.; calcium (2S)-2-benzyl-3(cis-hexahydro-- 2-isoindolinlycarbonyl)-propionate dihydrate (mitiglinide--cf. EP 507534); furthermore representatives of the new generation of SUs such as glimepiride (cf. EP 31058); in free or pharmaceutically acceptable salt form. The term nateglinide likewise comprises crystal modifications such as disclosed in EP 0526171 B1 or U.S. Pat. No. 5,488,510, respectively, the subject matter of which, especially with respect to the identification, manufacture and characterization of crystal modifications, is herewith incorporated by reference to this application, especially the subject matter of claims 8-10 of said U.S. patent (referring to H-form crystal modification) as well as the corresponding references to the B-type crystal modification in EP 196222 B1 the subject matter of which, especially with respect to the identification, manufacture and characterization of the B-form crystal modification. Preferably, in the present invention, the B- or H-type, more preferably the H-type, is used. Nateglinide can be administered in the form as it is marketed, e.g., under the trademark STARLIX.TM. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Composition and method for maintaining blood glucose level by employing the hydrophilic matrix based oral controlled release antidiabetic composition Inventor(s): Dhawan, Sanju; (Chandigarh, IN), Singla, Anil Kumar; (Chandigarh, IN) Correspondence: John P. O'banion; O'banion & Ritchey Llp; Suite 1550; 400 Capitol Mall; Sacramento; CA; 95814; US Patent Application Number: 20030113371 Date filed: August 21, 2001 Abstract: A composition useful for reducing serum glucose levels by an oral controlled release system and a method for treating diabetes in a human being by controlling the blood glucose level (BGL) and reducing the complications associated with diabetic hyperglycemia and also the long term management of Non-Insulin Dependent Diabetes Mellitus (NIDDM) by avoiding the problems associated with the tight control of BGL, i.e., hypoglycemia tolerance and seizures. The composition is directed to a solid, hydrophilic matrix controlled release oral dosage form where the dosage form contains a therapeutically effective amount of antidiabetic drug in the matrix ensuring complete bioavailability of the drug from the matrix of the tablet. The formulation undergoes substantially or approaches zero order release of active drug and the concentration of the excepients and the water swellable polymers is chosen in such a way that the erosion or dissolution rate of the polymer is equal to the swelling rate of the polymer to get a constant release. Also, the concentration is chosen in such a way that the tablet will be fully dissolved at the same time the last of the drug is released and in addition a bioadhesive polymer may also be added to increase the residence time of the dosage form in the g.i.t. and at high concentration of the polymer, beta cyclodextrin may also be added to improve the release kinetics. Excerpt(s): (1) American Diabetes Association. Diabetes 1996 Vital Statistics. Rockville, Md.: American Diabetes Association, 1996. (2) Harris, M. I., Cowie, C. C., Stern, M. P. eds. Diabetes in America, 2nd. ed. National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases. NIH Publication No.95-1468, 1995. (3)

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Clark, C. M., Vinicor, F. Introduction: Risks and benefits of intensive management in non-insulin-dependent diabetes mellitus. The Fifth Regensrief Conference. Ann Intern Med, 124(1, pt 2), 81-85, 1996. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions containing a substituted indolealkanoic acid and an angiotensin converting enzyme inhibitor Inventor(s): Sredy, Janet; (Milford, CT), Zandt, Michael C. Van; (Guilford, CT) Correspondence: Steven J. Sarussi; Mcdonnell Boehnen Hulbert & Berghoff; 32nd Floor; 300 S. Wacker Drive; Chicago; IL; 60606; US Patent Application Number: 20030171405 Date filed: February 18, 2003 Abstract: Disclosed are methods of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis, the methods comprising administration of substituted indolealkanoic acids to patients in need of such treatment. Also disclosed are such compounds useful in the treatment of angiogenesis, hyperglycemia, hyperlipidemia and chronic complications arising from diabetes mellitus. Also disclosed are pharmaceutical compositions containing the compounds. Further, disclosed are combinations of an angiotensin converting enzyme inhibitor and a substituted indole acetic acid. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/186,511, filed Mar. 2, 2000. The present invention relates to pharmaceutical compositions, and in particular to pharmaceutical compositions containing an aldose reductase inhibitor (ARI) and an angiotensin converting enzyme (ACE) inhibitor, is useful in the prevention and treatment of the complications of diabetes mellitus. In particular, the invention relates to combinations of an ACE with substituted indole acetic acids. The use of aldose reductase inhibitors (ARIs) for the treatment of diabetic complications is well known. The complications arise from elevated levels of glucose in tissues such as the nerve, kidney, retina and lens that enters the polyol pathway and is converted to sorbitol via aldose reductase. Because sorbitol does not easily cross cell membranes, it accumulates inside certain cells resulting in changes in osmotic pressure, alterations in the redox state of pyridine nucleotides (i.e. increased NADH/NAD.sup.+ ratio) and depleted intracellular levels of myoinositol. These biochemical changes, which have been linked to diabetic complications, can be controlled by inhibitors of aldose reductase. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Compounds that modulate PPAR activity and methods for their preparation Inventor(s): Auerbach, Bruce J.; (Ann Arbor, MI), Bratton, Larry D.; (Whitmore Lake, MI), Filzen, Gary F.; (Ann Arbor, MI), Geyer, Andrew G.; (Novi, MI), Trivedi, Bharat K.; (Farmington Hills, MI), Unangst, Paul C.; (Ann Arbor, MI) Correspondence: Warner-lambert Company; 2800 Plymouth RD; Ann Arbor; MI; 48105; US Patent Application Number: 20030225158 Date filed: January 22, 2003

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Abstract: This invention discloses compounds that alter PPAR activity. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds or their salts, and methods of using them as therapeutic agents for treating or preventing disipidemia, hypercholesteremia, obesity, eating disorders, hyperglycemia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia and diabetes in a mammal as well as methods of supressing appetite and modulating leptin levels in a mammal. The present invention also discloses methods for making the disclosed compounds. Excerpt(s): This application claims priority to U.S. Provisional Applications Serial No. 60/370,508, filed Apr. 5, 2002 and No. 60/386,026, filed Jun. 5, 2002. The present invention relates to compounds and pharmaceutical formulations that can be used to treat conditions mediated by nuclear hormone receptors, more specifically, to compounds and pharmaceutical formulations that modulate Peroxisome Proliferator Activation Receptor (PPAR) activity. Hypercholesterolemia, dyslipidemia, diabetes, and obesity are well-recognized risk factors in the onset of atherosclerosis and coronary heart disease. The diseases are characterized by high levels of cholesterol and lipids in the blood. The blood cholesterol pool is generally dependent on dietary uptake of cholesterol from the intestine, and from the biosynthesis of cholesterol throughout the body, especially the liver. The majority of cholesterol in plasma is carried on apolipoprotein B-containing lipoproteins, such as low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL). The risk of coronary artery disease in man increases when LDL and VLDL levels increase. Conversely, high levels of cholesterol carried in high-density lipoproteins (HDL) is protective against coronary artery disease (Am. J. Med., 1977;62:707-714). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Furans, benzofurans, and thiophenes useful in the treatment of insulin resistance and hyperglycemia Inventor(s): Adebayo, Folake O.; (Cranbury, NJ), Dollings, Paul J.; (Newtown, PA), McDevitt, Robert E.; (Somerset, NJ) Correspondence: Michael R. Nagy; 5 Giralda Farms; Madison; NJ; 07940; US Patent Application Number: 20030073709 Date filed: August 8, 2002 Abstract: This invention provides compounds of Formula I having the structure 1whereinR.sup.1 and R.sup.2 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, halogen, pertluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, phenyl or phenyl substituted with trifluoromethyl, chloro, methoxy, or trifluoromethoxy;R.sup.3 and R.sup.4 are each, independently, hydrogen, carboxyl, hydroxyl, hydoxyalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, perfluoroalkanoyloxy of 2-7 carbon atoms, arylalkoxy of 7-15 carbon atoms, aryloxy of 6-12 carbon atoms, aroyloxy of 6-12 carbon atoms, aryloxycarbonyl of 7-13 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, perfluoroalkoxycarbonyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamnino of 16 carbon atoms per alkyl group, tetrazolyl, mercapto, nitrile, nitro, amino, -NHSO.sub.2CF.sub.3, carbamoyl, carboxyaldehyde, halogen, acylamino, 3-hydroxycyclobut-3-ene-4-yl-1,2-dione, pyridyl, isoxazolyl, pyrimidyl or pyrimidyl substituted with mercapto, or tetronic acid;R.sup.5 is hydrogen, alkyl of 1-6 carbon atoms,

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perfluoroalkyl of 1-6 carbon atoms, naphthalenylmethyl, benzyl or benzyl substituted with halogen,R.sup.6 and R.sup.7 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or perfluoroalkyl of 1-6 carbon atoms, or R.sup.6 and R.sup.7 may be taken together as a diene unit having the structure --CH.dbd.CH--CH.dbd.CH--;W is S or O,X is --NR.sup.8CH.sub.2--, --NR.sup.8--, or O;R.sup.8 is hydrogen or alkyl;Y is carbonyl, methylene, ethyl, or --NHCH.sub.2--;Z is phenyl, pyridyl, naphthyl, thienyl, furyl, pyrrolyl, pyrazolyl, isoxazolyl, or isothiazolyl;or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia. Excerpt(s): The prevalence of insulin resistance in glucose intolerant subjects has long been recognized. Reaven et al (American Journal of Medicine 1976, 60, 80) used a continuous infusion of glucose and insulin (insulin/glucose clamp technique) and oral glucose tolerance tests to demonstrate that insulin resistance existed in a diverse group of nonobese, nonketotic subjects. These subjects ranged from borderline glucose tolerant to overt, fasting hyperglyceriaa. The diabetic groups in these studies included both insulin dependent (EDDM) and noninsulin dependent (NIEDDM) subjects. Coincident with sustained insulin resistance is the more easily determined hyperinsulinemia, which can be measured by accurate determination of circulating plasma insulin concentration in the plasma of subjects. Hyperinsulinemia can be present as a result of insulin resistance, such as is in obese and/or diabetic (NIDDM) subjects and/or glucose intolerant subjects, or in IDDM subjects, as a consequence of over injection of insulin compared with normal physiological release of the hormone by the endocrine pancreas. The association of hyperinsulinemia with obesity and with ischernic diseases of the large blood vessels (e.g. atherosclerosis) has been well established by numerous experimental, clinical and epidemiological studies (summarized by Stout, Metabolism 1985, 34, 7, and in more detail by Pyorala et al, Diabetes/Metabolism Reviews 1987, 3, 463). Statistically significant plasma insulin elevations at 1 and 2 hours after oral glucose load correlates with an increased risk of coronary heart disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Glucagon antagonists/inverse agonists Inventor(s): Behrens, Carsten; (Kobenhavn N, DK), Lau, Jesper; (Farum, DK), Madsen, Peter; (Bagsvaerd, DK) Correspondence: Reza Green, ESQ.; Novo Nordisk OF North America, INC.; Suite 6400; 405 Lexington Avenue; New York; NY; 10174-6400; US Patent Application Number: 20030203946 Date filed: May 17, 2002 Abstract: A novel class of compounds, which act to antagonize the action of the glucagon hormone on the glucagon receptor. Owing to their antagonizing effect of the glucagon receptor the compounds may be suitable for the treatment and/or prevention of any diseases and disorders, wherein a glucagon antagonistic action is beneficial, such as hyperglycemia, Type 1 diabetes, Type 2 diabetes, disorders of the lipid metabolism and obesity. Excerpt(s): The present invention relates to agents that act to antagonize the action of the glucagon peptide hormone on the glucagon receptor. More particularly, it relates to glucagon antagonists or inverse agonists. Glucagon is a key hormonal agent that, in cooperation with insulin, mediates homeostatic regulation of the amount of glucose in the

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blood. Glucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of glucagon is opposite to that of insulin, which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones. Glucagon is produced in the alpha islet cells of the pancreas and insulin in the beta islet cells. Diabetes mellitus is a common disorder of glucose metabolism. The disease is characterized by hyperglycemia and may be classified as Type 1 diabetes, the insulin-dependent form, or Type 2 diabetes, which is non-insulin-dependent in character. Subjects with Type 1 diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin. However, in some patients with Type 1 or Type 2 diabetes, absolute or relative elevated glucagon levels have been shown to contribute to the hyperglycemic state. Both in healthy control animals as well as in animal models of Type 1 and Type 2 diabetes, removal of circulating glucagon with selective and specific antibodies has resulted in reduction of the glycemic level (Brand et al., Diabetologia 37, 985 (1994); Diabetes 43, [suppl 1], 172A (1994); Am. J. Physiol. 269, E469-E477 (1995); Diabetes 44 [suppl 1], 134A (1995); Diabetes 45, 1076 (1996)). These studies suggest that glucagon suppression or an action that antagonizes glucagon could be a useful adjunct to conventional treatment of hyperglycemia in diabetic patients. The action of glucagon can be suppressed by providing an antagonist or an inverse agonist, ie substances that inhibit or prevent glucagon-induced responses. The antagonist can be peptidic or non-peptidic in nature. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Glucopyranosyloxybenzylbenzene containing the same

derivatives

and

medicinal

compositions

Inventor(s): Fujikura, Hideki; (Nagano, JP), Fushimi, Nobuhiko; (Nagano, JP), Isaji, Masayuki; (Nagano, JP), Nishimura, Toshihiro; (Nagano, JP), Tatani, Kazuya; (Nagano, JP) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, N.W.; Washington; DC; 20037; US Patent Application Number: 20040018998 Date filed: July 29, 2003 Abstract: The present invention relates to glucopyranosyloxybenzylbenzene derivatives represented by the general formula: 1wherein P represents a group forming a prodrug; and R represents a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxy-substituted (lower alkyl) group, a lower alkoxy-substituted (lower alkoxy) group or a lower alkoxy-substituted (lower alkylthio) group, which have an improved oral absorption and can exert an excellent inhibitory activity in human SGLT2 in vivo and which are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, diabetic complications or obesity, and pharmaceutical compositions comprising the same. Excerpt(s): The present invention relates to glucopyranosyloxybenzylbenzene derivatives which are useful as medicaments and pharmaceutical compositions comprising the same. wherein R represents a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxy-substituted (lower alkyl) group, a lower alkoxysubstituted (lower alkoxy) group or a lower alkoxy-substituted (lower alkylthio) group, are active forms, and relates to pharmaceutical compositions comprising the same. Diabetes is one of lifestyle-related diseases with the background of change of eating

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habit and lack of exercise. Hence, diet and exercise therapies are performed in patients with diabetes. Furthermore, when its sufficient control and continuous performance are difficult, drug treatment is simultaneously performed. At present, biguamides, sulfonylureas and agents for reducing insulin resistance have been employed as antidiabetic agents. However, biguamides and sulfonylureas show occasionally adverse effects such as lactic acidosis and hypoglysemia, respectively. In case of using agents for reducing insulin resistance, adverse effects such as edema occasionally are observed, and it is also concerned for advancing obesity. Therefore, in order to solve these problems, it has been desired to develop antidiabetic agents having a new mechanism. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 Inventor(s): Barf, Tjeerd; (Uppsala, SE), Nilsson, Marianne; (Rimbo, SE), Vallgarda, Jerk; (Uppsala, SE) Correspondence: Jeffrey D Hsi; Fish & Richardson; 225 Franklin Street; Boston; MA; 02110-2804; US Patent Application Number: 20030199501 Date filed: March 18, 2003 Abstract: The present invention relates to using a compound having the formula (I) wherein T is I) thienyl, which optionally is substituted with halogen, or II) phenyl optionally substituted with halogen and/or C.sub.1-6-alkyl; E is a bond, --CH.sub.2-- or --CO--; L is a bond, --CH.sub.2--, --CHR.sup.4-- or --NR.sup.3--; R.sup.3 is H, C.sub.1-6alkyl, C.sub.1-6-acyl or --COR.sup.4; R.sup.4 is morpholino or C.sub.1-6-amido; R.sup.6 and R.sup.7 are independently hydrogen or C.sub.1-6-alkyl; and R.sup.8 and R.sup.9 are independently hydrogen or C.sub.1-6-alkyl, as well as pharmaceutically acceptable salts, hydrates and solvates thereof, in the manufacture of a medicament for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, dementia, depression, virus diseases and inflammatory disorders. Excerpt(s): The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-.beta.-hydroxysteroid dehydrogenase type 1 enzyme (11.beta.HSD1). It has been known for more than half a century that glucocorticoids have a central role in diabetes, e.g. the removal of the pituitary or the adrenal gland from a diabetic animal alleviates the most severe symptoms of diabetes and lowers the concentration of glucose in the blood (Long, C. D. and F. D. W. Leunins (1936) J. Exp. Med. 63:465-490; Houssay, B. A. (1942) Endocrinology 30:884-892). It is also well established that glucocorticoids enable the effect of glucagon on the liver. The role of 11.beta.HSD1 as an important regulator of local glucocorticoids effect and thus of hepatic glucose production is well substantiated (see e.g. Jamieson et al. (2000) J. Endocrinol. 165: p. 685-692). The hepatic insulin sensitivity was improved in healthy human volunteers treated with the non-specific 11.beta.HSD1 inhibitor carbenoxolone (Walker, B. R et al. (1995) J. Clin. Endocrinol. Metab. 80:3155-3159). Furthermore, the expected mechanism has been established by different experiments with mice and rats. These studies showed that the MRNA levels and activities of two key enzymes in hepatic glucose production were reduced, namely: the rate-limiting enzyme gluconeogenesis, phosphoenolpyrnvate carboxykinase (PEPCK), and glucose-6-

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phosphatase (G6Pase) catalyzing the last common step of gluconeogenesis and glycogenolysis. Finally, the blood glucose level and hepatic glucose production is reduced in mice having the 11.beta.HSD1 gene knocked-out. Data from this model also confirm that inhibition of 11.beta.HSD1 will not cause hypoglycemia, as predicted since the basal levels of PEPCK and G6Pase are regulated independently of glucocorticoids (Kotelevtsev, Y. et al., (1997) Proc. Natl. Acad. Sci. USA 94:14924-14929). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Insoluble compositions for controlling blood glucose Inventor(s): Brader, Mark Laurence; (Indianapolis, IN) Correspondence: Eli Lilly And Company; Patent Division; P.O. Box 6288; Indianapolis; IN; 46206-6288; US Patent Application Number: 20030144181 Date filed: January 7, 2003 Abstract: The present invention relates to insoluble compositions comprising a protein selected from the group consisting of insulin, insulin analogs, and proinsulins; a derivatized protein selected from the group consisting of derivatized insulin, derivatized insulin analog, and derivatized proinsulin; a complexing compound; a hexamer-stabilizing compound; and a divalent metal cation. Formulations of the insoluble composition are suitable for both parenteral and non-parenteral delivery for treating hyperglycemia and diabetes. Microcrystal forms of the insoluble precipitate are pharmaceutically analogous to the neutral protamine Hagedorn (NPH) insulin crystal form. Surprisingly, it has been discovered that suspension formulations of such insoluble compositions possess unique and controllable dissolution properties that provide therapeutically advantageous glucodynamics compared with insulin NPH formulations. Excerpt(s): This invention is in the field of human medicine. More particularly, this invention is in the field of pharmaceutical treatment of the diseases of diabetes and hyperglycemia. It has long been a goal of insulin therapy to mimic the pattern of endogenous insulin secretion in normal individuals. The daily physiological demand for insulin fluctuates and can be separated into two phases: (a) the absorptive phase requiring a pulse of insulin to dispose of the meal-related blood glucose surge, and (b) the post-absorptive phase requiring a sustained delivery of insulin to regulate hepatic glucose output for maintaining optimal fasting blood glucose. Accordingly, effective therapy for people with diabetes generally involves the combined use of two types of exogenous insulin formulations: a rapid acting meal time insulin provided by bolus injections and a long-acting, so-called, basal insulin, administered by injection once or twice daily to control blood glucose levels between meals. An ideal basal insulin will provide an extended and "flat" time action--that is, it will control blood glucose levels for at least 12 hours, and preferably for 24 hours or more, without significant risk of hypoglycemia. Furthermore, an ideal basal insulin should be mixable with a soluble meal-time insulin, and should not cause irritation or reaction at the site of administration. Finally, basal insulin preparations that are suspension formulations should be able to be readily, and uniformly resuspended by the patient prior to administration. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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•

Liposome-encapsulated insulin formulations Inventor(s): Margalit, Rimona; (Givatayim, IL) Correspondence: Bozicevic, Field & Francis Llp; 200 Middlefield RD; Suite 200; Menlo Park; CA; 94025; US Patent Application Number: 20040033256 Date filed: August 15, 2003 Abstract: The present invention provides formulations of insulin or insulin analogs encapsulated in a liposome, and methods of producing such formulations. The invention further provides methods of treating hyperglycemia and related disorders by administering a formulation of the invention. Excerpt(s): This invention relates generally to liposomal insulin formulations, and methods of treating hyperglycemia and related conditions using the formulations. There are several metabolic diseases of human and animal glucose metabolism, eg., hyperglycemia, insulin dependent diabetes mellitus, impaired glucose tolerance, hyperinsulinemia, and insulin insensitivity, such as in non-insulin dependent diabetes mellitus (NIDDM). Hyperglycemia is a condition where the blood glucose level is above the normal level in the fasting state, following ingestion of a meal or during a glucose tolerance test. It can occur in NIDDM as well as in obesity. Hyperglycemia can occur without a diagnosis of NIDDM. This condition is called impaired glucose tolerance or pre-diabetes. Impaired glucose tolerance occurs when the rate of metabolic clearance of glucose from the blood is less than that commonly occurring in the general population after a standard dose of glucose has been orally or parenterally administered. It can occur in NIDDM as well as obesity, pre-diabetes and gestational diabetes. Hyperinsulinemia is defined as having a blood insulin level that is above normal level in fasting state or following ingestion of a meal. It can be associated with or causative of hypertension or atherosclerosis. Insulin insensitivity, or insulin resistance occurs when the insulin-dependent glucose clearance rate is less than that commonly occurring in the general population during diagnostic procedures. Diabetes mellitus is a disease affecting approximately 150 million persons worldwide. Of the 7.5 million diagnosed diabetics in the United States, approximately one-third are treated using insulin replacement therapy. Those patients receiving insulin typically self-administer one or more doses of the drug per day by subcutaneous injection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Liquid formulation of metformin Inventor(s): Chandran, Ravi; (Bolton Landing, NY), Gogia, Ashish; (New Delhi, IN) Correspondence: Jayadeep R. Deshmukh, ESQ.; Ranbaxy Pharmaceuticals INC.; Suite 2100; 600 College Road East; Princeton; NJ; 08540; US Patent Application Number: 20030149111 Date filed: March 6, 2003 Abstract: The present invention is directed to a liquid formulation of metformin or its pharmaceutically acceptable salts thereof. The liquid pharmaceutical composition comprises a therapeutically effective amount of metformin or its pharmaceutically acceptable salt, in a liquid carrier, which may also include a sweetener that does not increase the blood glucose level of a subject after ingestion thereof. In one embodiment,

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it may also include alkyl hydroxyethylcellulose, and/or a polyhydroxy alcohol. In another embodiment, the carrier may contain a sweetener, mineral acid, and bicarbonate salt maintained at a pH of 4.0 to 9.0. It is useful for treating hyperglycemia and diabetes. Excerpt(s): This application is claiming benefit of U.S. Provisional Application Serial No. 60/223,391, filed on Aug. 7, 2000. The present invention relates to a liquid formulation of metformin and salts thereof and to the use thereof in treating hyperglycemia and/or diabetes. Diabetes Mellitus is the most common of the serious metabolic diseases affecting humans. It has been estimated that there are over 200 million people that have diabetes in the world. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Malto-oligosaccharide derivatives and use thereof Inventor(s): Nasu, Ayako; (Chiba, JP), Uchida, Riichiro; (Chiba, JP) Correspondence: Banner & Witcoff; 1001 G Street N W; Suite 1100; Washington; DC; 20001; US Patent Application Number: 20040006046 Date filed: December 6, 2002 Abstract: The present invention provides a substance which strongly inhibits human.alpha.-amylase and is effective for the prevention and treatment of hyperglycemia, for example, diabetes and the diseases caused thereby, and an.alpha.amylase inhibitor and a prophylactic or therapeutic agent for hyperglycemia containing the said substance as active principle.Maltoligosaccharide derivatives represented by the following formula: 1(wherein n is an integer of 0 to 2; m is an integer of 0 to 2; and X represents a hydrogen atom or a hydrophobic group) or their hydrates or physiologically acceptable salts are provided, and they are contained as active principle to prepare an.alpha.-amylase inhibitor and a prophylactic or therapeutic agent for hyperglycemia such as diabetes. Excerpt(s): The present invention relates to maltoligosaccharide derivatives having a specific structure, and their uses. More particularly, it relates to an.alpha.-amylase inhibitor and medicinal preparations useful for the prevention or treatment of hyperglycemia, for example diabetes and its complications, which contain the said derivatives as an active component. Carbohydrates ingested by a mammal are initially digested (hydrolyzed) to some extent with salivary.alpha.-amylase in the mouth and stomach, and then digested wholly with pancreatic.alpha.-amylase in the duodenum and jejunum into an oligosaccharide or disaccharide. There are further hydrolyzed by glucoside-hydrases such as glucoamylase and maltase to finally become a monosaccharide such as glucose, which is absorbed up through the villi on the intestinal tract membranes. Thus, after ingestion of carbohydrates, there takes place a temporary rise of blood glucose level, or so-called hyperglycemia, due to the absorption of glucose. Normally, however, this temporarily elevated blood glucose level is adjusted to stay in a normal range by the homeostasis maintenance system in the living body to recover from hyperglycemia. However, abnormalities of carbohydrate metabolism, such as long-time continuance of alimentary hyperglycemic symptoms or occurrence of an abnormally high blood glucose level, may lead to a disease called hyperglycemia, causing such cases as obesity and diabetes. This obesity is caused as secretion of a large volume of insulin is promoted by a hyperglycemic symptom induced by overeating, provoking an increase of synthesis of fat and a decrease of its decomposition to accumulate fat in the

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body. On the other hand, diabetes is caused as secretion of a large volume of insulin is promoted by a hyperglycemic symptom induced by overeating to provoke a reduction of sensitivity of insulin receptors or exhaustion of.beta. cells of the islet of Langerhans in the pancreas. It is also known that obesity and diabetes tend to trigger many serious complications such as hyperlipidemia, hypertension, arteriosclerosis, autonomic troubles and cataract. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Metformin salts of lipophilic acids Inventor(s): Kessler, Dean; (Edmonds, WA), Lal, Manjari; (Bellevue, WA), Palepu, Nagesh; (Mill Creek, WA) Correspondence: Christensen, O'connor, Johnson, Kindness, Pllc; 1420 Fifth Avenue; Suite 2800; Seattle; WA; 98101-2347; US Patent Application Number: 20030220301 Date filed: February 14, 2003 Abstract: Metformin salts of lipophilic acids, their pharmaceutical formulations, and methods of administrating the metformin salts for the treatment of hyperglycemia. Excerpt(s): The present application claims the benefit of U.S. Provisional Patent Application No. 60/357,196, filed Feb. 14, 2002, which is incorporated herein by reference in its entirety. The present invention relates to metformin salts of lipophilic acids, formulations including metformin salts of lipophilic acids, and methods for administering metformin salts of lipophilic acids. Metformin is a biguanide, antihyperglycemic agent currently marketed in the United States in the form of its hydrochloride salt (GLUCOPHAGE, Bristol-Myers Squibb Company). The oral medication is designed to help control elevated blood sugar levels in NIDDM (noninsulin-dependent diabetes mellitus) or Type II diabetes. Current metformin therapy has proven less than optimal as it is associated with a high incidence of gastrointestinal side effects. Further, the drug is commonly administered at high doses (as oral tablets) 2 or 3 times per day to achieve effective glucose-lowering treatment. Anonymous, "Glucophage Prescription Information," Bristol-Myers Squibb Company, Princeton, N.J., 1999. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Method of regulating glucose metabolism, and reagents related thereto Inventor(s): Bachovchin, William W.; (Melrose, MA), Drucker, Daniel; (Toronto, CA), Plaut, Andrew G.; (Lexington, MA) Correspondence: Matthew P. Vincent; Patent Group; Foley, Hoag & Eliot Llp; One Post Office Square; Boston; MA; 02109; US Patent Application Number: 20030153509 Date filed: July 3, 2002 Abstract: The present invention provides methods and compositions for modification and regulation of glucose and lipid metabolism, generally to reduce insulin resistance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoprotein-emia (such as chylomicrons, VLDL and LDL), and to regulate body fat and more generally

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lipid stores, and, more generally, for the improvement of metabolism disorders, especially those associated with diabetes, obesity and/or atherosclerosis. Excerpt(s): Diabetes adversely affects the way the body uses sugars and starches which, during digestion, are converted into glucose. Insulin, a hormone produced by the pancreas, makes the glucose available to the body's cells for energy. In muscle, adipose (fat) and connective tissues, insulin facilitates the entry of glucose into the cells by an action on the cell membranes. The ingested glucose is normally converted in the liver to CO.sub.2 and H.sub.2O (50%); to glycogen (5%); and to fat (30-40%), the latter being stored in fat depots. Fatty acids from the adipose tissues are circulated, returned to the liver for re-synthesis of triacylglycerol and metabolized to ketone bodies for utilization by the tissues. The fatty acids are also metabolized by other organs. Fat formation is a major pathway for carbohydrate utilization. The net effect of insulin is to promote the storage and use of carbohydrates, protein and fat. Insulin deficiency is a common and serious pathologic condition in man. In insulin-dependent (IDDM or Type I) diabetes the pancreas produces little or no insulin, and insulin must be injected daily for the survival of the diabetic. In noninsulin-dependent (NIDDM or Type II) diabetes the pancreas retains the ability to produce insulin and in fact may produce higher than normal amounts of insulin, but the amount of insulin is relatively insufficient, or less than fully effective, due to cellular resistance to insulin. Diabetes mellitus (DM) is a major chronic illness found in humans with many consequences. Some complications arising from long-standing diabetes are blindness, kidney failure, and limb amputations. Insulin-dependent diabetes mellitus (IDDM) accounts for 10 to 15% of all cases of diabetes mellitus. The action of IDDM is to cause hyperglycemia (elevated blood glucose concentration) and a tendency towards diabetic ketoacidosis (DKA). Currently treatment requires chronic administration of insulin. Non-insulin dependent diabetes mellitus (NIDDM) is marked by hyperglycemia that is not linked with DKA. Sporadic or persistent incidence of hyperglycemia can be controlled by administering insulin. Uncontrolled hyperglycemia can damage the cells of the pancreas which produce insulin (the.beta.-islet cells) and in the long term create greater insulin deficiencies. Currently, oral sulfonylureas and insulin are the only two therapeutic agents available in the United States. for treatment of Diabetes mellitus. Both agents have the potential for producing hypoglycemia as a side effect, reducing the blood glucose concentration to dangerous levels. There is no generally applicable and consistently effective means of maintaining an essentially normal fluctuation in glucose levels in DM. The resultant treatment attempts to minimize the risks of hypoglycemia while keeping the glucose levels below a target value. The drug regimen is combined with control of dietary intake of carbohydrates to keep glucose levels in control. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method, system, and computer program product for the evaluation of glycemic control in diabetes from self-monitoring data Inventor(s): Cox, Daniel J.; (Charlottesville, VA), Kovatchev, Boris P.; (Amherst, VA) Correspondence: Robert J Decker; University OF Virginia Patent Foundation; 1224 West Main Street Suite 1 110; Charlottesville; VA; 22903; US Patent Application Number: 20030212317 Date filed: September 26, 2002 Abstract: A method, system, and computer program product related to the diagnosis of diabetes, and is directed to predicting the long term risk of hyperglycemia, and the

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long-term and short-term risks of severe hypoglycemia in diabetics, based on blood glucose readings collected by a self-monitoring blood glucose device. The method, system, and computer program product pertain directly to the enhancement of existing home blood glucose monitoring devices, by introducing an intelligent data interpretation component capable of predicting both HbA.sub.1c and periods of increased risk of hypoglycemia, and to the enhancement of emerging continuous monitoring devices by the same features. With these predictions the diabetic can take steps to prevent the adverse consequences associated with hyperglycemia and hypoglycemia. Excerpt(s): The present invention claims priority from U.S. Provisional Patent Application Serial No. 60/193,037 filed Mar. 29, 2000, entitled "Algorithm for the Evaluation of Glycemic Control in Diabetes From Self-Monitoring Data" the entire disclosure of which is hereby incorporated by reference herein. The present system relates generally to Glycemic Control of individuals with diabetes, and more particularly to a computer-based system and method for evaluation of predicting glycosylated hemoglobin (HbA.sub.1c and HbA.sub.1) and risk of incurring hypoglycemia. Extensive studies, including the Diabetes Control and Complications Trial (DCCT) (See DCCT Research Group: The Effect Of Intensive Treatment Of Diabetes On The Development And Progression Of Long-Term Complications Of Insulin-Dependent Diabetes Mellitus. New England Journal of Medicine, 329: 978-986, 1993), the Stockholm Diabetes Intervention Study (See Reichard P, Phil M: Mortality and Treatment Side Effects During Long-term Intensified Conventional Insulin Treatment in the Stockholm Diabetes Intervention Study. Diabetes, 43: 313-317, 1994), and the United Kingdom Prospective Diabetes Study (See UK Prospective Diabetes Study Group: Effect of Intensive Blood Glucose Control With Metformin On Complications In Patients With Type 2 Diabetes (UKPDS 34). Lancet, 352: 837-853, 1998), have repeatedly demonstrated that the most effective way to prevent the long term complications of diabetes is by strictly maintaining blood glucose (BG) levels within a normal range using intensive insulin therapy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods and systems for assessing glycemic control using predetermined pattern label analysis of blood glucose readings Inventor(s): Armbrecht, Eric Stephen; (St. Louis, MO), Bortz, Jonathan David; (St. Louis, MO) Correspondence: Michael T. Marrah; Sonnenschein Nath & Rosenthal; Wacker Drive Station, Sears Tower; P.O. Box #061080; Chicago; IL; 60606-1080; US Patent Application Number: 20030216628 Date filed: January 28, 2002 Abstract: Methods and systems for analyzing blood glucose readings comprising the steps of obtaining a plurality of blood glucose readings taken within a predetermined time category and time period, performing first calculations on said readings based on a predetermined normal range of glycemia in a first analysis and selecting and applying a pattern label having predetermined criteria to the plurality of blood glucose readings by comparing the results of the first calculations to the pattern label criteria. The invention may also include the steps of performing second calculations on said readings based on predetermined thresholds for severe hyperglycemia and severe hypoglycemia and selecting and appending a severity suffix having predetermined severity criteria to said

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pattern label by comparing the results of the second calculations to the severity criteria as well as performing third calculations on said readings based on a predetermined normal range of glycemia and selecting and appending a minor comment having minor comment criteria to said pattern label by comparing the results of the third calculations to the comment criteria. Excerpt(s): The present invention is in the field of chemical arts, specifically, the field of blood glucose level analysis. Proper analysis of blood glucose levels is crucial to providing optimal care to diabetic patients. However, proper analysis of blood glucose levels for even a single patient requires the analysis of mountains of individual readings from various time categories taken over various spans to determine the clinical significance of the individual readings and any information shown by groups of readings. Such analysis is time-consuming and tedious for medical professionals to perform on any significant scale. Moreover, the lack of generally accepted analytical terms for analyzing the raw blood glucose reading data increases the complexity of the analysis and burdens the exchange of analysis data between medical professionals. This makes it more difficult for medical professionals to correlate a given series of readings with the proper course of medical intervention. Of course, it also makes educating patients about their own condition and treatment options difficult. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods fo treating conditions associated with insulin resistance with aicar, (5amino-4-imidazole carboxamide riboside) and related compounds Inventor(s): Ido, Yasuo; (Brookline, MA), Kraegen, Edward W; (Sydney, AU), Ruderman, Neil; (Newton, MA) Correspondence: Weingarten, Schurgin, Gagnebin & Lebovici Llp; Ten Post Office Square; Boston; MA; 02109; US Patent Application Number: 20030212014 Date filed: March 12, 2003 Abstract: The long-term usage of AICR (5-aminio, 4-imidazole carboxamide riboside) to produce sustained metabolic and biological changes in mammals that overcome insulin resistance, i.e., increase insulin sensitivity, and result in benefits in diseases and conditions such as diabetes, hypertension, atherosclerosis, polycystic ovary syndrome and gallstones is described long-term usage of AICAR, particularly intermittent administration, e.g., three days per week, appears to have some of the positive effects of exercise, having an impact on the amount Of food consumed by a subject and resulting in reduced fat build-up and increase in muscle mass. Therefore, AICAR administration has a positive impact in reducing obesity. AICAR can also Prove useful in preventing or treating vascular diseases associated with hyperglycemia, high plasma levels of free fatty acids (FFA) and triglyceride, and insulin resistance by virtue of the fact that this agent activates fatty acid oxidation. Animal tests have Shown that chronic intermittent treatment with AICAR has not resulted in any noticeable toxic effects. AICAR and related compounds are activators of AMP-activated protein kinase (AMPK) and, furthermore, are effective at decreasing malonyl CoA levels in the animal. Excerpt(s): This application claims the priority of the following applications: U.S. Provisional Application No. 60/222,131, filed Jul. 31, 2000 entitled, USE OF AICAR (5AMINO-4-IMIDAZOLE CARBOXAMIDE RIBOSIDE) AND RELATED COMPOUNDS TO TREAT INSULIN RESISTANCE; International Application No. PCT/US00/40607,

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filed Aug. 9, 2000 entitled, METHOD OF MAINTAINING VASCULAR INTEGRITY USING AICAR (5-AMINO-4-IMIDAZOLE CARBOXAMIDE RIBOSIDE) AND RELATED COMPOUNDS; and International Application No. PCT/US01/18467 filed Jun. 6, 2001 entitled, USE OF AICAR (5-AMINO-4-IMIDAZOLE CARBOXAMIDE RIBOSIDE) AND RELATED COMPOUNDS FOR THE PREVENTION AND TREATMENT OF OBESITY, the whole of which are hereby incorporated by reference herein. AMP-activated protein kinase (AMPK) is a cytoplasmic enzyme that has been shown to exist in both the liver and skeletal muscle. As its name indicates, AMPK is activated by increasing levels of AMP and, secondarily, by an increase in the ratio of AMP to ATP in the cell. AMP levels rise in the cell as ATP is hydrolyzed to ADP and Pi. Two molecules of ADP, through the action of myokinase, also known as adenylate kinase, produce one molecule of ATP and one molecule of AMP. In addition to its activation by AMP, AMPK is activated through phosphorylation by an upstream kinase called AMPK kinase (AMPKK). AMP also allosterically activates AMPKK. Phosphorylation of AMPK by AMPKK makes it a poor substrate for phosphatases. All these factors combined together make AMPK very sensitive to minimal fluctuations in cellular AMP levels. AMPK has several known substrates, specifically enzymes that it can phosphorylate and modulate. In the liver, AMPK has been shown to phosphorylate hydroxymethyl glutaryl CoA (HMGCOA) reductase and acetyl CoA carboxylase (ACC), inhibiting the actions of both enzymes. Reducing HMGCOA reductase activity inhibits cholesterol synthesis, and reducing ACC activity decreases the generation of malonyl CoA, an intermediate in fatty acid synthesis. In skeletal muscle, AMPK also is an inhibitor of carnitine palmitoyl transferase I, which regulates the uptake of fatty acids into mitochondria where they are oxidized. In addition, AMPK has been shown to increase glucose transport into the muscle. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods for affecting various diseases utilizing LXR compounds Inventor(s): Bischoff, Eric D.; (San Diego, CA), Schulman, Ira G.; (San Diego, CA), Tangirala, Rajendra K.; (San Diego, CA) Correspondence: Morrison & Foerster Llp; 3811 Valley Centre Drive; Suite 500; San Diego; CA; 92130-2332; US Patent Application Number: 20030073614 Date filed: October 17, 2001 Abstract: The present invention relates to methods for elevating high density lipoprotein (HDL) plasma levels, decreasing the absorption of dietary cholesterol in the intestine, decreasing the plasma level of low density lipoprotein (LDL), and increasing the conversion of cholesterol to bile acids, utilizing LXR.beta. selective agonists, usually without elevating the plasma levels of triglycerides. Also provided are methods of using such agonists to treat metabolic diseases alone or in combination with other active agents. Also provided are methods for decreasing hyperglycemia and insulin resistance methods for treating type II diabetes, and methods for treating type II diabetes and reducing the cardiovascular complications of type II diabetes, utilizing an LXR agonist. Further provided are methods for treating obesity and methods for treating the complications of obesity including type II diabetes, cardiovascular disease, hyperlipidemia, and hypertension, administering an LXR.alpha.-selective antagonist. Excerpt(s): The present invention relates to LXR.beta.-selective agonists and their use in increasing reverse cholesterol transport, elevating the plasma level of high density

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lipoprotein (HDL) in a mammal, and in treating metabolic disorders including, but not restricted to, cardiovascular disease, diabetes, obesity, gallstone disease, syndrome X, hypertension, hypercholesterolemia, cholesterol absorption or transport disease, HDL deficiencies, and hyperlipidemia. Also provided by the present invention are methods for decreasing hyperglycemia and insulin resistance, and methods for treating type II diabetes and reducing the cardiovascular complications of type II diabetes, said methods comprising administering to said mammal, a therapeutically-effective amount of an LXR agonist. Further provided are methods for treating obesity, and methods for treating the complications of obesity including type II diabetes, cardiovascular disease, hyperlipidemia, and hypertension, said methods comprising administering a therapeutically-effective amount of an LXR.alpha.-selective antagonist. Also included in the present invention are methods of identifying said agonists and antagonists. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods for the treatment of diabetes, the reduction of body fat, improvement of insulin sensitivity, reduction of hyperglycemia, and reduction of hypercholesterolemia with chromium complexes, conjugated fatty acids, and/or conjugated fatty alcohols Inventor(s): Greenberg, Danielle; (Waccabuc, NY), Katz, David P.; (Dobbs Ferry, NY), Komorowski, James R.; (Trumbull, CT) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20030091654 Date filed: December 12, 2002 Abstract: A composition for treating insulin-dependent diabetes, reducing body fat, improving insulin sensitivity, reducing hyperglycemia, and reducing hypercholesterolemia with at least one chromium complex and a conjugated fatty acid or conjugated fatty alcohol is disclosed. A method of treating a subject suffering from insulin-dependent diabetes by administering a composition that includes at least one chromium complex and a conjugated fatty acid or conjugated fatty alcohol is similarly provided. The administration of a composition containing an effective dose of at least one chromium complex and a conjugated fatty acid or conjugated fatty alcohol for the treatment of obesity is likewise provided. Excerpt(s): This application is a divisional of prior application Ser. No. 09/957,876, filed Sep. 20, 2001, which claims priority to provisional application filed Sep. 21, 2000 having application No. 60/234,474, and provisional application filed Jun. 6, 2001 having application No. 60/296,688, each of which is hereby incorporated by reference. The disclosed invention related to compositions and methods for the treatment of type 1 diabetes, reduction of body fat, improvement of insulin sensitivity, reduction of hyperglycemia, and reduction of hypercholesterolemia. Specifically, compositions comprising chromium complexes in combination with conjugated compounds such as isomers of conjugated fatty acids or conjugated fatty alcohols. Diabetes is a chronic metabolic disorder which afflicts 16 million people in the United States, over one and one half million of whom have its most severe form, childhood diabetes (also called juvenile, type 1 or insulin-dependent diabetes). Insulin-dependent diabetes appears suddenly, most often in children and young adults, and progresses rapidly. In this form, the pancreas ceases to manufacture insulin, a hormone necessary to convert the food we eat into energy for the body. In the United States, diabetes is the fourth leading cause of

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death, killing more than 162,000 people each year. Notably, the mortality rate of patients with insulin-dependent diabetes increases dramatically after 15 years of disease duration. In addition, virtually every major organ system in the body is damaged by diabetes. Complications can include blindness, kidney failure, heart disease, stroke, amputation of extremities, loss of nerve sensation, early loss of teeth, high-risk pregnancies and babies born with birth defects. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods of monitoring glucose levels in a subject and uses thereof Inventor(s): Ackerman, Neil; (San Carlos, CA) Correspondence: Barbara G. Mcclung; Cygnus INC.; Intellectual Property DEPT.; 400 Penobscot Drive; Redwood City; CA; 94063; US Patent Application Number: 20030208114 Date filed: April 23, 2003 Abstract: Methods of frequently monitoring glucose amounts and/or concentrations in a subject who is at risk for hypoglycemia, hyperglycemia, and/or glucose level fluctuations that put the subject at risk are provided. Also provided are methods of monitoring the effects of one or more pharmaceutical compositions on the levels of glucose in a subject. Excerpt(s): This application is related to U.S. Provisional Patent Application Serial No. 60/228,617, filed Aug. 28, 2000, from which priority is claimed under 35 USC.sctn.119(e)(1), and which application is incorporated herein by reference in its entirety. The present invention is in the field of medical devices and methods of use thereof. More particularly it relates to methods of using glucose monitoring devices to monitoring glucose amounts and/or concentrations in a subject who is at risk for hypoglycemia, hyperglycemia, or fluctuations toward hypoglycemia and/or hyperglycemia. The methods also include methods of monitoring the effects of one or more pharmaceutical compositions on the levels of glucose in a subject. The level, presence, and/or absence of glucose in a subject can have a number of consequences. For example, fluctuations of blood glucose levels can result in one of two physiological states, hypoglycemia and hyperglycemia. Hypoglycemia is defined as plasma glucose levels below normal. Hypoglycemia can be symptomatic or asymptomatic. For example, subjects suffering from postprandial hypoglycemia generally have symptoms of adrenergic stimulation including diaphoresis, anxiety, irritability, palpitations, tremor, and hunger. Such symptoms typically occur from about 2 to 4 hours postprandially and tend to occur suddenly with symptoms generally subsiding in about 15 to 20 minutes. Hypoglycemia can be caused by release of adrenergic and cholinergic hormones. Postprandial hypoglycemia is often idiopathic, however, it can be caused by early diabetes, alcohol intake, renal failure, and drug treatments. In addition, a category of hypoglycemia exists which is designated as fasting hypoglycemia. Clinically, this form of hypoglycemia may have symptoms of neuroglycopenia including headache, fatigue, and mental dullness. In more severe cases, hypoglycemia can progress to confusion, blurring of vision, seizure, and ultimately loss of consciousness or seizure. Fasting hypoglycemia can occur with a fast of greater than 4 hours, and further can be caused by insulinoma (resulting from self-administered insulin or intake of other hypoglycemic agents, alcohol abuse, liver disease (e.g., decreased gluconeogenesis), pituitary insufficiency, or adrenal insufficiency).

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Modified and stabilized GDF propeptides and uses thereof Inventor(s): Khor, Soo-Peang; (Winchester, MA), Wolfman, Neil M.; (Dover, MA) Correspondence: C/o Rebecca M. Mcneill; Finnegan, Henderson, Farabow,; Garrett & Dunner, L.L.P.; 1300 I Street, N.W.; Washington; DC; 20005-3315; US Patent Application Number: 20030104406 Date filed: February 8, 2002 Abstract: Modified and stabilized propeptides of Growth Differentiation Factor proteins, such as GDF-8 and Bone Morphogenetic Protein-11, are disclosed. Also disclosed are methods for making and using the modified propeptides to prevent or treat human or animal disorders in which an increase in muscle tissue would be therapeutically beneficial. Such disorders include muscle or neuromuscular disorders (such as amyotrophic lateral sclerosis, muscular dystrophy, muscle atrophy, congestive obstructive pulmonary disease, muscle wasting syndrome, sarcopenia, or cachexia), metabolic diseases or disorders (such as such as type 2 diabetes, noninsulin-dependent diabetes mellitus, hyperglycemia, or obesity), adipose tissue disorders (such as obesity), and bone degenerative diseases (such as osteoporosis). Excerpt(s): This application claims the benefit of provisional application serial No. 60/267,509, filed on Feb. 8, 2001, the entire disclosure of which is hereby incorporated by reference. This invention relates to inhibitors of Growth Differentiation Factor-8 (GDF-8) proteins and methods for their use. More particularly, the invention provides modified and stabilized propeptides of GDF-8 proteins which inhibit the activity of GDF-8. The invention is particularly useful for preventing or treating human or animal disorders in which an increase in skeletal muscle tissue would be therapeutically beneficial. Such disorders include muscle or neuromuscular disorders (such as amyotrophic lateral sclerosis, muscular dystrophy, muscle atrophy, congestive obstructive pulmonary disease, muscle wasting syndrome, sarcopenia, or cachexia), metabolic diseases or disorders (such as type 2 diabetes, noninsulin-dependent diabetes mellitus, hyperglycemia, or obesity), adipose tissue disorders (such as obesity), or bone degenerative diseases (such as osteoporosis). Growth and Differentiation Factor-8 (GDF8), also known as myostatin, is a member of the Transforming Growth Factor-beta (TGF.beta.) superfamily of structurally related growth factors, all of which possess important growth-regulatory and morphogenetic properties (Kingsley et al. (1994) Genes Dev. 8:133-46; Hoodless et al. (1998) Curr. Topics Microbiol. Immunol. 228:235-72). GDF-8 is a negative regulator of skeletal muscle mass, and there is considerable interest in identifying factors which regulate its biological activity. For example, GDF-8 is highly expressed in the developing and adult skeletal muscle. The GDF-8 null mutation in transgenic mice is characterized by a marked hypertrophy and hyperplasia of the skeletal muscle (McPherron et al. (1997) Nature 387:83-90). Similar increases in skeletal muscle mass are evident in naturally occurring mutations of GDF-8 in cattle (Ashmore et al. (1974) Growth 38:501-507; Swatland and Kieffer (1994) J. Anim. Sci. 38:752-757; McPherron and Lee (1997) Proc. Natl. Acad. Sci. U.S.A. 94:12457-12461; and Kambadur et al. (1997) Genome Res. 7:910-915). Recent studies have also shown that muscle wasting associated with HIV-infection in humans is accompanied by increases in GDF-8 protein expression (Gonzalez-Cadavid et al. (1998) PNAS 95:14938-43). In addition, GDF-8 can modulate the production of muscle-specific enzymes (e.g., creatine kinase) and modulate myoblast cell proliferation (WO 00/43781).

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Mouse model for rheumatoid arthritis Inventor(s): Faustman, Denise L.; (Weston, MA), Hayashi, Takuma; (Malden, MA) Correspondence: Leon R Yankwich; Yankwich & Associates; 201 Broadway; Cambridge; MA; 02139; US Patent Application Number: 20040031066 Date filed: July 16, 2002 Abstract: Nonobese Diabetic Mice (NOD mice) that do not develop diabetes may be bred to produce F.sub.1 offspring that develop a condition that closely mimics rheumatoid arthritis (RA) in humans. The RA-like disease in the F.sub.1 mice, designated NOD-RA mice, is similar to human RA in clinical, radiological, histological and serological characteristics. The parents (F.sub.0) and their progeny (F.sub.1) are not diabetic and never develop hyperglycemia, and the parental mice (F.sub.0) do not themselves exhibit any symptoms of the RA-like condition that afflicts some of their progeny. The incidence, penetrance, gender domination, progression, and lifelong exacerbation of symptoms after pregnancy shown in the RA-like condition afflicting NOD-RA mice are all comparable to phenomena observed in the human disease. The NOD-RA mice provide a new spontaneous model of human RA that will be useful for studying rheumatoid arthristis and testing new drugs and reagents for treating or diagnosing the disease. Excerpt(s): The present invention pertains to the field of medical research, particularly to the development of mammalian models of human rheumatoid arthritis. Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint swelling, deformation and, ultimately, destruction, culminating in severe physical disability. De Graaf et al., in The Epidemiolog of Chronic Rheumatism, Dellgren and Ball, eds. (Blackwell, Oxford, 1963), pp. 446-56; Meenam et al., Arthritis Rheum., 24:544-50 (1981); Gabriel et al., J. Rheumatol, 26:1269-74 (1999); James, Clin Exp. Rheumatol, 17:392-93 (1999). RA is a progressive condition with well-recognized symptoms including symmetrical peripheral joint swelling and synovial inflammation while sparing the axial skeleton; the presence of rheumatoid factor (RF) autoantibodies; increased concentrations of interleukin-6 (IL-6), interleukin-1.beta. (IL-1.beta.), and granulocyte/macrophage colony-stimulating factor (GM-CSF) in serum and synovial fluid; low concentrations of interleukin-ra (IL-ra); and pregnancy-induced disease remission followed by severe postpartum flares, that is, while women with RA commonly undergo remission during pregnancy, the disease returns and may be even more severe and show a new onset or more accelerated course after delivery. See, Turgen, in Immunology and Serology in Laboratory Medicine. 2.sup.nd edition, Shanahan ed. (Mosby Year Book, St. Louis, 1996), pp. 387-98; Hirano et al., Eur. J. Immunol, 18:1797-1801 (1988); Wilder et al., Ann. N. Y. Acad. Sci., 876:14-31 (1999); Iijima et al., J. Rheumatol, 26:755-56 (1999); Ostensen, Ann. N.Y Acad. Sci., 876:13143 (1999). In medical research directed to understanding, diagnosing and treating RA, several animal models of the disease have been described, but no spontaneous animal model that closely mimics all the features of the human disease has been discovered (See, for example, Hang et al., 1982. J. Exp. Med., 155:1690-1701; and Kouskoff et al., 1996. Cell, 87:811-822). Kouskoffet al. report a RA mouse model that exhibits aggressive arthritis, produced by mating a T cell receptor (TCR) transgenic mouse strain with a NOD strain. This RA mouse model is strictly dependent on the presence of the KRN

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transgene and is characterized by several inherent symptomological features of RA that distinguish it from human RA (hRA), however, including: 100% penetrance, early (i.e., 25-35 days) onset of disease, attack of the distal interphalangeal joints, inflammation of the spine, large excess of myeloid cells over T lymphocytes and plasma cells in the synovial membrane, a total absence of rheumatoid factor (RF) autoantibodies, and a coating of IgG deposits on internal organs. These features result in a more aggressive RA than the RA typically found in humans. Human RA has preferential disease expression in middle-aged females, peripheral disease sparing of the DIP joints, rheumatoid factor autoantibodies, similar peripheral and joint cytokine derangements, etc. The mechanism of development of arhritis-like disease in NOD/TCR mice differs dramatically from that of natural RA expression in humans, limiting the utility of this RA mouse as a model for hRA. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel naphthalene ureas as glucose uptake enhancers Inventor(s): Kozlowski, Michael R.; (Palo Alto, CA), Lum, Robert T.; (Palo Alto, CA), Manchem, Prasad V.V.S.V.; (South San Francisco, CA), Schow, Steven R.; (Redwood Shores, CA), Shi, Songyuan; (Fremont, CA), Spevak, Wayne R.; (Albany, CA) Correspondence: Heller Ehrman White & Mcauliffe Llp; 275 Middlefield Road; Menlo Park; CA; 94025-3506; US Patent Application Number: 20030135063 Date filed: September 6, 2002 Abstract: Compounds of formula I are useful for treating conditions associated with hyperglycemia, especially Type II diabetes. These compounds are useful in stimulating the kinase activity of the insulin receptor, activating the insulin receptor, and stimulating the uptake of glucose. Pharmaceutical compositions comprising the antidiabetic compounds are also disclosed. Excerpt(s): This application claims the priority under 35 USC 119(e) of Provisional Application No. 60/136,128, filed May 26, 1999. The invention relates to a means to enhance insulin-dependent glucose uptake. Specifically, the invention concerns compounds that activate the insulin receptor kinase leading to increased glucose uptake. The invention also concerns methods for treating hyperglycemia in humans, and especially methods for treating Type II diabetes. Among the many functions performed by peptide and protein hormones in metabolism is the ability to interact with receptors with high specificity. The insulin receptor is present on virtually all cells and at high concentrations on the cells for the liver, skeletal muscles, and adipose tissue. Stimulation of the insulin receptor with insulin is an essential element in carbohydrate metabolism and storage. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Novel substituted benzimidazol-2-ones as vasopressin receptor antagonists and neuropeptide Y modulators Inventor(s): Demarest, Keith T.; (Flemington, NJ), Gunnet, Joseph W. JR.; (Flemington, NJ), Urbanski, Maud J.; (Flemington, NJ) Correspondence: Audley A. Ciamporcero JR.; Johnson & Johnson; One Johnson & Johnson Plaza; New Brunswick; NJ; 08933-7003; US Patent Application Number: 20030073842 Date filed: October 23, 2001 Abstract: The invention is directed to substituted benzimidazol-2-ones of Formula I, 1wherein A, X, Y, m, n, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are as described in the specification, which are useful as vasopressin receptor antagonists or Neuropeptide Y Modulators for treating conditions such as aggression, obsessive-compulsive disorders, hypertension, dysmenorrhea, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, edema, ischemia, stroke, thrombosis, water retention, nephrotic syndrome, central nervous injuries, obesity, anorexia, hyperglycemia, diabetes, anxiety, depression, asthma, memory loss, sexual dysfunction, disorders of sleep and other circadian rhythms, and Cushing's disease. Excerpt(s): This application claims priority from U.S. Ser. No. 60/243,817, filed Oct. 27, 2000. This invention relates to novel substituted benzimidazol-2-ones. More particularly, the compounds of the present invention modulate the binding of the peptide hormone vasopressin and neuropeptide Y to their respective receptors and are therefore useful for treating conditions involving increased vascular resistance, cardiac insufficiency, and disorders of energy metabolism. Vasopressin is a nonapeptide hormone that is secreted primarily from the posterior pituitary gland. The hormone effects its actions through the vascular V-1 and renal V-2 receptor subtypes. The functions of vasopressin include contraction of uterine, bladder, and smooth muscle; stimulation of glycogen breakdown in the liver; induction of platelet aggregation; release of corticotropin from the anterior pituitary and stimulation of renal water reabsorption. As a neurotransmitter within the central nervous system (CNS), vasopressin can affect aggressive behavior, sexual behavior, the stress response, social behavior and memory. The V-1a receptor mediates central nervous system effects, contraction of smooth muscle and hepatic glycogenolytic effects of vasopressin, while the V-1b receptor mediates anterior pituitary effects of vasopressin. The V-2 receptor, presumably found only in the kidney, effects the antidiuretic actions of vasopressin via stimulation of adenylate cyclase. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Novel uses of Gugulipid: as cognition enhancer, anti-hyperglycemic and for dermal conditions Inventor(s): Asthana, Onkar Prasad; (Lucknow, IN), Murthy, Puvvada Sri Ramachandra; (Lucknow, IN), Nand, Nitya; (Lucknow, IN), Nath, Chandeshwar; (Lucknow, IN), Pal, Raghwendra; (Lucknow, IN), Pratap, Ram; (Lucknow, IN), Raina, Depak; (Lucknow, IN), Rastogi, Anil Kumar; (Lucknow, IN), Shankar, Girja; (Lucknow, IN), Singh, Hemant Kumar; (Lucknow, IN), Singh, Narendra; (Lucknow, IN), Singh, Satyawan; (Lucknow, IN), Srivastava, Arwind Kumar; (Lucknow, IN), Srivastava, Sudhir; (Lucknow, IN) Correspondence: Piper Rudnick Llp; Supervisor, Patent Prosecution Services; 1200 Nineteenth Street, N.W.; Washington; DC; 20036-2412; US Patent Application Number: 20030099729 Date filed: December 20, 2002 Abstract: The present invention provides new uses of Gugulipid, an ethyl acetate extract of the resin of the plant Comiphora wighitii, for controlling or preventing cognitive dysfunction, hyperglycemia and some infective conditions of the skin and a method of preparing Gugulipid by agitating the resin in shake flask assembly or sonicating assembly and preparing a solid or a creamy dosage forms. Excerpt(s): The present invention claims some new uses of Gugulipid, an ethyl acetate extract of the resin of the plant Comiphora wighitii, commonly called gum guggulu. These include modifications of the extraction methods and methods for controlling or preventing cognitive dysfunction, hyperglycemia and some infective conditions of the skin. Ayurveda takes a holistic view of human disease. It views any disease as a dysfunction of the whole body rather than of a single organ or physiological process. Most of the Ayurvedic drugs therefore are likely to act on a number of dysfunctions of the body involving a number of organs and functions. Gugulipid, an ethylacetate soluble fraction of gum guggul, was developed as a hypolipidemic agent, based on the reference to the lipid lowering effect of guggul resin in Charak Samhita, a classic text of Ayurveda. Chemopharmacological investigation of this extract resulted in the characterization of guggulsterone [cis-and trans-4, 17 (20)-pregnadiene-3, 16-dione] as the major constituent. Apart from guggulsterone, other chemical constituents in the ethyl acetate soluble fraction added to and modulated the total activity. This fraction rather than pure guggulsterone was developed as a hypolipidemic drug and named gugulipid. As a follow up of the holistic view of Ayurveda of human disease, gugulipid was tested for other related and unrelated conditions/dysfunction and found to possess cognitive and anti-hyperglycemic activities and also improved in general dermal dysfunctions. These novel uses of gugulipid are now claimed. Guggul, highly valued in Indian system of medicine Ayurveda, is the gum resin exudate of a small tree Commiphora wighitii belonging to the family Burseraceae. It is specially recommended for the treatment of obesity, lipid disorders and rheumatoid arthritis (Ayurvedic treatise: Sushruta, Vagabhatta). In Tibetan medicine, the plant (C. Wighitii) mixed with other herbs is used for skin diseases, anemia, edema, salivation and heaviness of stomach [Lama, S. and Santra, S. C., Sci. Cult. 45, 262 (1979)]. Modern0 pharmacological studies on the crude drug and some of its fractions have supported the claims of Ayurveda. The anti-arthritis and anti-inflammatory activities were confirmed by Gujral and co-workers [Gujral, M. L., Sareen, K., Tangri, K. K., Amma, M. K. P. and Roy, A. K. Ind. J. Physiol. Pharmacol. 4, 267 (1960)]. The hypolipidemic and anti-atherosclerotic activities reported by Dwarakanath and Satyawati. [Dwarakanath, C., and Satyawati, G. V. Ayurveda Pradeepika (Ceylon), 1, 69 (1970)]; Satyawati, G. V. in "Effect of an indigenous drug and disorders of lipid metabolism with special reference to

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atherosclerosis and obesity (Medoroga)", M. D. Thesis (Doctor of Ayurvedic Medicine), Banaras Hindu University, Varanasi, (1966)]. Later on, its ethyl acetate extract was developed by joint efforts of Malti-Chem Research Center, Baroda and Central Drug Research Institute, Lucknow as hypolipidemic drug [A process for obtaining hypolipidemic and anti-platelet aggregation fraction from guggul resin. Indian Patent No. 148265 dated Jun. 4, 1979, N. K. Kapoor., Sukh Dev and S. Nityanand]. A mixed type of mechanism has been implicated for lipid lowering effect of gugulipid. The stimulation of plasma LCAT, hepatic lipases, receptor mediated catabolism of LDL and increased faecal bile acid excretion as well as suppression of hepatic cholesterol biosynthesis are the mechanisms responsible for lipid lowering effect of gugulipid [S. Nityanand and N. K. Kapoor, Ind. J. Exp. Biol. 11, 395 (1973); N. K. Kapoor and S. Nityanand, Ind. J. Heart Res. Supp-1) 22 (1988)]. With the discovery of hypolipidemic activity of the gum resin, systematic chemical investigations were carried out to characterize compounds of the gum resin responsible for hypolipidemic activity. Mc Cook et al. have recently claimed alcoholic extract of gum guggul for controlling or preventing sebum secretion from sebocytes which is associated with a shiny, undesirable appearance and a disagreeable tactile sensation [J. P. Mc Cook et. al. U.S. Pat. No. 5,690,948 (1997). Antisebum and antioxidant compositions containing gugulipid and alcoholic fractions thereof]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Pharmaceutical composition Inventor(s): Ikeda, Hitoshi; (Higashiosaka, JP), Odaka, Hiroyuki; (Kobe, JP), Sohda, Takashi; (Takatsuki, JP) Correspondence: Wenderoth, Lind & Ponack, L.L.P.; 2033 K Street N. W.; Suite 800; Washington; DC; 20006-1021; US Patent Application Number: 20030216443 Date filed: June 17, 2003 Abstract: Pharmaceutical composition which comprises an insulin sensitivity enhancer in combination with other antidiabetics differing from the enhancer in the mechanism of action, which shows a potent depressive effect on diabetic hyperglycemia and is useful for prophylaxis and treatment of diabetes. Excerpt(s): The present invention relates to a pharmaceutical composition comprising an insulin sensitivity enhancer in combination with one or more other antidiabetics differing from said enhancer in the mechanism of action. Recent years, the pathology of diabetes has become more and more understood and, in parallel, drugs specific for the respective pathologic states have been developed. Accordingly a variety of drugs having new mechanisms of action have appeared one after another. Insulin sensitivity enhancers are also known as insulin resistance deblockers because they have the action to normalize the impaired insulin receptor function, and are gathering much attention in these years. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Processes and intermediates for preparing glycogen phosphorylase inhibitors Inventor(s): Barrila, Mark T.; (East Lyme, CT), Busch, Frank R.; (Gales Ferry, CT), Couturier, Michel A.; (Pawcatuck, CT), Orrill, Susan L.; (Gales Ferry, CT), Rose, Peter R.; (Ledyard, CT), Tickner, Derek L.; (Waterford, CT), Tobiassen, Harry O; (Ledyard, CT), Withbroe, Gregory J.; (Gales Ferry, CT) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030187051 Date filed: January 16, 2003 Abstract: The instant invention provides novel processes and intermediates useful in the preparation of certain N-(indole-2-carbonyl)-.beta.-alaninamide compounds, which compounds are glycogen phosphorylase inhibitors useful in the treatment of diseases such as hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis, diabetes, diabetic cardiomyopathy, infection, tissue ischemia, myocardial ischemia, and in inhibiting tumor growth. Excerpt(s): The instant invention provides novel processes and intermediates useful in the preparation of certain N-(indole-2-carbonyl)-.beta.-alanina- mide compounds, which compounds are glycogen phosphorylase inhibitors useful in the treatment of diseases such as hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis, diabetes, diabetic cardiomyopathy, infection, tissue ischemia, myocardial ischemia, and in inhibiting tumor growth. Despite the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of, and use of, sulfonylureas (e.g. Chlorpropamide.TM. (Pfizer), Tolbutamide.TM. (Upjohn), Acetohexamide.TM. (E. I. Lilly), Tolazamide.TM. (Upjohn), and biguanides (e.g. Phenformin.TM. (Ciba Geigy), and Mefformin.TM. (G. D. Searle)) as oral hypoglycemic agents, therapeutic regimens for the treatment of diabetes remain less than satisfactory. The use of insulin, necessary in about 10% of diabetic patients in which synthetic hypoglycemic agents are not effective (Type 1 diabetes, insulin dependent diabetes mellitus), requires multiple daily doses, usually by self-injection. Determination of the proper dosage of insulin requires frequent estimations of sugar levels in the urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type 2 diabetes) usually consists of a combination of diet, exercise, oral agents, e.g., sulfonylureas, and, in more severe cases, insulin. However, clinically available hypoglycemic agents can have other side effects that limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. A continuing need for hypoglycemic agents, which may have fewer side effects or succeed where others fail, is clearly evident. Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerotic development and occlusive heart disease is well known. The earliest stage in this sequence is the formation of "fatty streaks" in the carotid, coronary, and cerebral arteries, and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. It is further postulated that most of the cholesterol found within the fatty streaks, in turn, gives rise to development of the socalled "fibrous plaque", which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin, and proteoglycans. These cells, plus matrix, form a fibrous cap that covers a deeper deposit

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of cell debris and more extra cellular lipid, which comprises primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the so-called "complicated lesion" which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm that characterize advanced atherosclerosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

PTTG knockout rodent as a model to study mechanisms for various physiological phenomena, including diabetes Inventor(s): Melmed, Shlomo; (Los Angeles, CA), Wang, Zhiyong; (Los Angeles, CA) Correspondence: Edward G. Poplawski, ESQ.; Sidley Austin Brown & Wood; 555 West Fifth Street; Los Angeles; CA; 90013-1010; US Patent Application Number: 20030106080 Date filed: October 15, 2001 Abstract: Disclosed is a null mutant (or knockout) rodent comprising in its germ cells an artificially induced PTTG null mutation. In some embodiments, the null mutant rodent can be generated by way of homologous recombination in an embryonic stem cell or germ cell. The inventive null mutant rodent can be used to study mammalian physiology at the cellular, tissue, and/or organismal level with respect to various phenotypes, including hyperglycemia, hypoinsulinaemia, hypoleptinemia, diabetes, chromosomal aneuploidy, premature centromere division, chromosomal damage, aberrant mitotic cellular division, thrombocytopenia, thymic hyperplasia, splenic hypoplasia, testicular hypoplasia, and female subfertility. Also disclosed is an animal model for diabetes. Also disclosed is a somatic or germ cell obtained from the null mutant rodent. Also disclosed is a cell line derived from a cell obtained from the null mutant rodent. Excerpt(s): Throughout the application, various publications are referenced in parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in the application in order to more fully describe the state of the art to which this invention pertains. The present invention is related to the biomedical arts, in particular to genetics. The particular gene that is the subject of the present invention is PTTG, which is believed to have a role in proper cell cycle progression. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Therapeutic/edible compositions comprising herbal ingredients and methods for treating hyperglycemia Inventor(s): Chalasani, Kishore Babu; (Hyderabad, IN), Chary, Govardhana Maroju; (Hyderabad, IN), Chauhan, Abhay Singh; (Hyderabad, IN), Diwan, Prakash Vamanrao; (Hyderabad, IN), Kataram, Rajasekhar; (Hyderabad, IN), Raghavan, Kondapuram Vijaya; (Hyderabad, IN), Surapanini, Sridevi; (Hyderabad, IN), Yandrapu, Sharath Kumar; (Hyderabad, IN) Correspondence: Ladas & Parry; 26 West 61 Street; New York; NY; 10023; US Patent Application Number: 20030180399 Date filed: March 19, 2002 Abstract: A therapeutic or an edible composition comprising at least three of the five herbs selected from Prunus amygdales, Ocimum sanctum, Azadirachta indica, Aegle marelose and Vitus vinefera, is provided for the treatment of hyperglycemia, especially for non-insulin dependent diabetic subjects, and the herbal composition has significantly reduced the blood glucose levels in both diabetic and non-diabetic experimental subjects having elevated blood glucose levels. Excerpt(s): The present invention relates to an edible or medicinal herbal composition consisting of five different herbs and use of as hypoglycemic agent for lowering the blood glucose levels in mammals, especially humans, suffering from diabetic mellitus. Diabetes mellitus is an insidious medical condition for which there is no permanent cure. Across the globe many humans are suffering with this disease and with its implications such as heart attacks, strokes, loss of eyesight, difficulty in wound healing, more susceptible to disorders of aging and such conditions worsening to death. The onset of diabetes can occur in early age of life although many people are getting in much later part of life. The medical condition of diabetes characterized by the inability of the pancreas gland to secrete "insulin". Insulin is produced in the body by the beta cells of pancreas gland and helps in the metabolism of glucose to produce the energy required by the humans. In the diabetic patients the pancreas gland deteriorates and the beta cells are too small and insufficiently numerous to produce a proper amount of insulin. Hence the sugar is not properly metabolized to produce energy. As a result, diabetic patient experience an elevated levels of sugar in the blood. The diabetes can be broadly categorized into IDDM and NIDDM. Roughly "IDDM" refers to insulin dependent diabetes mellitus or type I wherein, anti-bodies destroy.beta.-cells of islets of Langerhans which produce insulin and hence very low and no insulin levels in the circulation. In NIDDM there is no loss or moderate reduction in.beta.-cell mass and is due to abnormality in gluco-receptor of.beta.-cells, reduced sensitivity of peripheral tissues to insulin. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of CNTF (ciliary neurotrophic factor) receptor activators for the treatment of obesity Inventor(s): Ciliberto, Gennaro; (Rome, IT), Cortese, Riccardo; (Rome, IT), Demartis, Anna; (Rome, IT), Di Marco, Annalise; (Rome, IT), Gloaguen, Isabelle; (Scoppito L'Aquila, IT), Laufer, Ralph; (Rome, IT) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20030176346 Date filed: January 31, 2003 Abstract: The present invention refers to the use of hCNTF (human ciliary neurotrophic factor), mutants thereof or other molecules that activate the CNTF receptor, for the preparation of drugs for the treatment of obesity and associated diseases, for example hyperglycemia. FIG. 1 shows the anti-obesity effect of hCNTF and leptin on body weight (left panels) and on food intake (right panels) in genetically obese mice and in mice with diet-induced obesity (DIO). Excerpt(s): The subject of the present invention is the use of molecules that activate the CNTF (ciliary neurotrophic factor) receptor--such as hCNTF (human CNTF) or mutants of hCNTF--as active principles in the formulation of pharmaceutical compositions suitable for the treatment of obesity and of related diseases. The term hCNTF mutant is intended to mean an amino acid sequence that can in theory be derived from hCNTF by substitution of one or more amino acids. Obesity, which affects >30% of the adult population in the industrial world, is a major public health problem, since it is associated with type II diabetes, hypertension, hyperlipidemia and increased mortality rate. Obesity is the result of a positive energy balance, as a consequence of an increased ratio of caloric intake to energy expenditure. Treatment is generally unsuccessful due to the operation of mechanisms that restore adipose mass after both intentional or unintentional changes (1). The lipostasis theory postulates that the size of the body fat depot is regulated by a feedback loop, constituted by adipocyte-derived circulating molecules that act on the hypothalamus to decrease appetite and increase energy expenditure (2). The recently identified 16-kilodalton plasma protein leptin (3) fulfills many of the criteria expected from such a lipostatic hormone. It is expressed in adipose tissue, and its plasma levels are highly correlated with body mass index in rodents and humans (4). The absence of leptin in obese (ob/ob) mutant mice leads to a massive increase in body fat, which can be reversed by systemic administration of the recombinant protein (5, 6, 7). However, human obesity does not appear to be due to deficient expression of leptin, since leptin mRNA and plasma protein levels were shown to be increased in obese versus lean subjects (4). Thus, obese humans may be insensitive to the lipostatic effect of leptin, possibly due to a defect at the level of leptin transport, leptin receptor activity, or post-receptorial signalling mechanisms (8). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of integrin-linked kinase inhibitors for treating insulin resistance, hyperglycemia and diabetes Inventor(s): Bhanot, Sanjay; (Carlsbad, CA) Correspondence: Jane Massey Licata; Licata & Tyrrell P.C.; 66 E. Main Street; Marlton; NJ; 08053; US Patent Application Number: 20040006005 Date filed: July 2, 2002 Abstract: The present invention features methods for treating conditions of insulin resistance, hyperglycemia and/or diabetes. In a broad embodiment, the methods comprise the step of administering to a mammal in need of treatment a therapeutically effective amount of an ILK inhibitor. ILK inhibitors in accordance with the present invention includes small molecules, antibodies, peptides, and antisense compounds. In one embodiment, antisense compounds in accordance with the present invention comprise antisense oligomers. Excerpt(s): Insulin resistance is a metabolic abnormality that may lead to impaired glucose tolerance and diabetes mellitus. Cellular manifestations of insulin resistance include impaired insulin-stimulated glucose uptake by peripheral tissues and impaired glucose disposal. In the liver, there is increased conversion of substrates to glucose in the presence of insulin. This hepatic insulin resistance is associated with decreased activity of glucokinase, and increased activity of gluconeogenic enzymes. Many patients have insulin resistance and impaired glucose tolerance for several years before progressing to diabetes mellitus. Diabetes mellitus is a syndrome characterized by abnormal insulin secretion associated with hyperglycemia and decreased glucose tolerance. A National Diabetes Data Group (NDDG) of the National Institutes of Health distinguishes several subclasses of diabetes. These include insulin-dependent diabetes mellitus (Type I), a ketosis-prone type of diabetes associated with histocompatibility antigens on chromosome 6 and with islet cell antibodies, and non-insulin-dependent diabetes mellitus (Type II), a non-ketosis-prone type of diabetes not secondary to other diseases or conditions. Type II diabetes is characterized by tissue insensitivity or resistance to insulin and impaired pancreatic B cell response to glucose. (Karam, J. H., in Basic Clinical Pharmacology, 5th Ed., B. G. Katzung, ed, Appleton & Lange, Norwalk, Conn., 1992, pp. 586-601). Current therapy for treatment of insulin resistance is injection of high doses of insulin to provide greater availability to insulin receptors in the tissues. Very high doses of insulin may ultimately be required, and the resulting high circulating levels of insulin cause some of the side effects such as diabetic nephropathy. This "therapy" may in fact worsen the disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with hyperglycemia, 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 “hyperglycemia”

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(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 hyperglycemia. You can also use this procedure to view pending patent applications concerning hyperglycemia. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 6. BOOKS ON HYPERGLYCEMIA Overview This chapter provides bibliographic book references relating to hyperglycemia. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on hyperglycemia 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 “hyperglycemia” (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 hyperglycemia: •

Outsmarting Diabetes: A Dynamic Approach for Reducing the Effects of InsulinDependent Diabetes Source: Minneapolis, MN: Chronimed Publishing. 1994. 247 p. Contact: Available from Chronimed Publishing. P.O. Box 59032, Minnetonka, MN 55459-9686. (800) 848-2793 or (612) 541-0239. Fax (800) 395-3344 or (612) 541-0210. PRICE: $14.95. ISBN: 1565610512. Available from Joslin Publications. One Joslin Place, Boston, MA 02215. (800) 344-4501. Fax (617) 732-2562. PRICE: $14.95. Summary: Based on the results of the Diabetes Control and Complications Trial (DCCT) and the expertise of the Joslin Diabetes Center in Boston, this book explains to readers the benefits of careful diabetes control. Designed to help people with diabetes reduce their risks for complications, the book's 11 chapters address whether or not complications can truly be prevented; intensive insulin management; designing an

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individualized plan; getting started; maintenance on an intensive plan; meal planning; using multiple daily insulin injections; using insulin pumps; exercise and the intensive plan; pregnancy and intensive diabetes therapy; psychological concerns; and handling problems. Numerous appendices provide information on intensified conventional treatment programs; Ultralenta programs; the use of premeal regular plus bedtime intermediate insulin; the insulin pump; calculating daily volume for insulin pump therapy; exercise guidelines; hyperglycemia; hypoglycemia; products and foods for hypoglycemic reactions; and a sample record book. A brief subject index concludes the volume. •

Getting the Most Out of Diabetes Camp: A Guide for Parents and Kids Source: Alexandria, VA: American Diabetes Association. 2002. 106 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $14.95 plus shipping and handling. ISBN: 1580401422. Summary: For many children, attending a diabetes camp is a life-changing experience. These camps provide a safe place where kids are surrounded by people with diabetes, where everyone else is doing the same things to manage their illness and have a good quality of life. This book helps youngsters with diabetes and their parents learn about diabetes camps, decide whether to go, and then to choose the right diabetes camp. The book offers nine chapters: why choose diabetes camp over other types of camps, how to determine if a child is ready for camp, selecting the most appropriate camp, the application process, packing tips, what to expect at camp, homesickness, traditional camps, and how to evaluate a camp experience after it is over. The authors include numerous quotes from children and parents, and practical suggestions in each chapter. The book includes four appendices: a list of diabetes camps, a sample application packet, a sample scholarship application, and the warning signs of hypoglycemia (low blood glucose) and hyperglycemia (high blood glucose). A subject index concludes the book.

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Practical Insulin: A Handbook for Prescribers Source: Alexandria, VA: American Diabetes Association. 2002. 60 p. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. E-mail: [email protected]. Fax: (770) 4429742. Website: www.diabetes.org. PRICE: $7.95; plus shipping and handling. ISBN: 580401538. Summary: Insulin therapy is a medical necessity for all patients with type 1 diabetes and the many patients with type 2 diabetes who cannot reach their glycemic goals without insulin therapy. This pocket handbook to prescribing insulin is designed to help primary care providers handle ever-increasing numbers of patients with diabetes. The handbook covers patient selection, insulin choices, insulin character, insulin absorption, mixing insulins, insulin regimens, insulin for type 1 patients, insulin for type 2 patients, troubleshooting (patient resistance to starting insulin, weight gain, fasting hyperglycemia, hypoglycemia, and hypoglycemia unawareness), patient SMBG (self monitoring of blood glucose) records, and patient education. Lengthy appendices cover endogenous insulin action, insulin storage, insulin potency, additives, insulin delivery, insulin pumps, and determining insulin to carbohydrate ratio. The handbook concludes

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with a brief description of the American Diabetes Association and its contact information (www.diabetes.org). •

Diabetes Annual/6 Source: New York, NY: Elsevier Science Publishing Company, Inc. 1991. 685 p. Contact: Available from Elsevier Science Publishing Company, Inc. P.O. Box 882, Madison Square Station, New York, NY 10159. (212) 989-5800. PRICE: $240. ISBN: 0444892516. Summary: This annual publication reviews recent developments in all the major areas of diabetes research. Synthesized by experts in the field, each review focuses on a specific topic, including the epidemiology of diabetes mellitus and related disorders; the immunology of insulin-dependent diabetes mellitus (IDDM); the etiology of noninsulindependent diabetes mellitus (NIDDM); diabetes in tropical developing countries; the molecular genetics of diabetes; trends in the dietary management of diabetes mellitus; the sulfonylureas; insulin injection therapy; diabetes and exercise; diabetes education; computers in diabetes care; pregnancy; pancreatic transplantation; the development of implantable amperometric glucose sensors; diabetic nephropathy; autonomic neuropathy; obesity, insulin resistance and diabetes; non-enzymatic glycosylation; hyperglycemic emergencies; proinsulin; plasma lipids and lipoproteins; macroangiopathy; insulin secretion in vitro; insulin infusion devices; hyperglycemia in IDDM; growth hormone and insulin-like growth factor I in experimental and human diabetes; glucose transport in muscle and fat; ketone body metabolism; and progress in the understanding of diabetes through study of its pathogenesis in animal models. 3272 references.

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My Sister Rose Has Diabetes Source: Santa Fe, NM: Health Press. 1997. 32 p. Contact: Available from Health Press. P.O. Box 1388, Santa Fe, NM 87504. (800) 6432665. Fax (505) 983-1733. E-mail: [email protected]. Website: www.healthpress.com. PRICE: $8.95 (paperback). ISBN: 09291732779. Summary: This book addresses many of the difficult issues facing children who have diabetes and their families. It demonstrates how manageable the disease can be and reduces the devastation of those concerned. The book is written from the perspectives of both Rose, a ten year old girl who has diabetes, and her twelve year old brother. Rose's parents were surprised that she was diagnosed with diabetes; in fact, the book notes that 90 percent of children with diabetes do not have a family history of the disease. Topics include coping, self-monitoring blood glucose, injecting insulin, meal planning, hypoglycemia and hyperglycemia symptoms, sick days, working with a patient care team, and recordkeeping. Rose points out that the three things that she needs to balance are food, insulin, and exercise. Drawings painted with watercolor are included on nearly every page. A glossary explains terms of anatomy, diabetes, and treatment in children's wording. (AA-M).

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Living a Healthy Life With Chronic Conditions: Self-Management of Heart Disease, Arthritis, Stroke, Diabetes, Asthma, Bronchitis, Emphysema and Others Source: Palo Alto, CA: Bull Publishing Company. 1994. 296 p.

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Contact: Available from Bull Publishing Company. P.O. Box 208, Palo Alto, CA 943020208. (800) 676-2855 or (415) 322-2855. Fax (415) 327-3300. E-mail: [email protected]. PRICE: $14.95. ISBN: 0923521283. Summary: This book is a complete self-management guide for people with chronic diseases. The authors focus on day-to-day living skills, in the context of the specific chronic diseases, including heart disease, arthritis, stroke, diabetes, asthma, bronchitis, and emphysema. General topics include the psychological aspects to self-management; finding resources; smoking and quitting; understanding common symptoms; using one's mind to manage symptoms; exercising for fun and fitness; exercising for flexibility and strength; exercising for endurance; exercising tips for people with specific chronic diseases; the importance of communication; durable powers of attorney for health care; eating well; and managing medications. The chapter on diabetes covers diabetes and its causes; maintaining an appropriate blood glucose level; symptoms of hyperglycemia and hypoglycemia; dietary management; exercise; insulin injections; oral medications; emotions; self-monitoring of blood glucose and urine; the complications of diabetes; and diabetes resources. Each chapter includes limited references and a subject index concludes the volume. •

Diabetes Problem Solver Source: Alexandria, VA: American Diabetes Association. 1999. 511 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $19.95 for members; plus shipping and handling. ISBN: 1570400091. Summary: This book is a reference guide that helps people who have diabetes identify and prevent the most common diabetes-related problems they encounter on a daily basis. The book is divided into two major sections. The first section consists of a series of flowcharts to help readers decide what they need to do about a particular condition or symptom. Flowcharts focus on arm and hand pain, back pain, blurry vision, chest pain, confusion, convulsions or seizures, difficulty breathing, dizziness, dry skin, eating disorders, emotional problems, emotional changes in women, feeling tired, fever, foot problems, headache, hyperglycemia, hypoglycemia, injection site problems, and intestinal problems. Other flowcharts deal with leg and foot pain, loss of consciousness, muscular weakness, nausea, numbness and tingling, pain or discomfort in women, palpitations, problems with the mouth, problems with blood glucose in women, sexual problems in men and women, skin discoloration, skin lesions, skin rashes and itchy skin, sleeping problems, stomach pain, sweating, swelling, thickening of the skin, urinary problems, vision problems, and vomiting. The second section provides more detailed information about many of the problems people who have diabetes face. Solutions are provided for monitoring and testing problems; hypoglycemia and hyperglycemia problems; insulin delivery and oral medication problems; circulation, neuropathy, kidney, vision, gastrointestinal, infection, foot, and skin problems; men's, women's, and children's problems; eating, exercise, and weight problems; lifestyle problems; coping problems; discrimination and insurance problems; and other medical problems. Each section provides the reader with information on the symptoms of the condition, who is at risk and what risk the particular condition poses for the reader, what the reader's immediate course of action should be, treatment in a medical setting, and how to prevent the condition from developing. The reader may use the book in two ways. If the reader knows he or she has a particular condition or wants more information, he or she can go straight to the second section and look up the condition. The reader may use the

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book as a guide to possible conditions that may be causing symptoms by referring to the flowcharts in the first section. The book also includes a glossary, resources, and an index. 6 figures. 5 tables. •

Core Curriculum for Diabetes Education. 4th ed.: (Volume 1) Diabetes and Complications Source: Chicago, IL: American Association of Diabetes Educators (AADE). 2001. 245 p. Contact: Available from American Association of Diabetes Educators. AADE Member Service Center, 100 W. Monroe Street, Suite 400, Chicago, IL 60603. (800) 338-3633. Fax (312) 424-2427. Website: www.diabeteseducator.org. PRICE: Individual volume $45.00 for members and $60.00 for nonmembers; complete 4-volume set $149.95 for members and $199.95 for nonmembers; plus shipping and handling. ISBN: 1881876055 (Volume 1); 1881876098 (4-volume set). Summary: This book is one in a series of four texts that make up a Core Curriculum, designed primarily to help educators prepare for the Certified Diabetes Educator (CDE) exam. In addition, these books can be used as a diabetes educator's reference source for diabetes education and management. This first volume, on diabetes and its complications, covers the pathophysiology of the diabetes disease state, hyperglycemia (high blood glucose levels), an overview of chronic complications of diabetes, diabetes foot care and education, skin and dental care, macrovascular disease, eye disease and adaptive diabetes education for visually impaired persons, nephropathy (kidney disease) , and diabetic neuropathy (nerve disease). Each chapter lists the learning objectives for that chapter, presents information in outline and bulleted format, summarizes the key educational considerations, offers self review questions and questions for discussion, presents an illustrative case report, and concludes with a list of references. A post-test and the answers to the post-test questions are appended to each chapter. The volume concludes with a subject index.

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American Diabetes Association Guide to Raising a Child with Diabetes. 2nd ed Source: Alexandria, VA: American Diabetes Association. 2000. 165 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $16.95 plus shipping and handling. ISBN: 1580400272. Summary: This book presents up to date information on diabetes to help parents and other family members care for a child who has diabetes. The book begins with a chapter that explains the causes of type 1 diabetes, identifies the signs and symptoms of diabetes, and discusses the management of blood glucose levels. The next chapter focuses on caring for the child who has diabetes. Topics include new thinking about treating children with diabetes, the role of health care providers, and ways to keep a child's best interests a top priority. Chapter three discusses the use of insulin to manage diabetes, focusing on insulin types, insulin dosages, insulin administration, site rotation, insulin delivery devices, needle disposal, insulin adjustment, and self injection. This is followed by a chapter that explains blood glucose testing. Topics include determining the number of times per day to test blood glucose, recording blood glucose test results, making sure a blood glucose meter is accurate, testing urine for glucose and ketones, helping a child test regularly, and understanding the glycated hemoglobin test. The fifth chapter deals with meal planning, focusing on planning balanced meals; using exchanges and carbohydrate counting to plan meals; helping a child accept meal

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planning; coping with schedule changes, holidays, and parties; and eating out. The next chapter offers guidelines for playing games and sports safely. This is followed by a chapter that explains how to prevent and treat hypoglycemia, hyperglycemia, and ketoacidosis and how to handle sick days and infections. Chapter eight deals with diabetes care during various stages of development, focusing on care of infants, preschoolers, school age children, and adolescents. The final chapter offers advice for living with diabetes, focusing on budgeting, traveling, solving the day to day challenges of diabetes, coping with diabetes, and asking for help. The book provides problem solving examples and easy to read tables throughout. In addition, the book includes a glossary, a list of resources, and an index. 44 figures. 2 tables. •

Diabetes Sourcebook. 3rd ed Source: Detroit, MI: Omnigraphics. 2003. 621 p. Contact: Available from Omnigraphics. 615 Griswold Street, Detroit, MI 48226. (800) 234-1340. Fax (800) 875-1340. Website: www.omnigraphics.com. ISBN: 780806298. Summary: This book provides information for people seeking to understand the risk factors, complications, and management of type 1 diabetes, type 2 diabetes, and gestational diabetes. The book offers 67 chapters in seven sections: diabetes types and diagnosis; lifestyle and related diabetes management concerns; exercise and nutrition for diabetes management; medication management of diabetes; complications of diabetes; treatment of end stage renal disease (ESRD); and diabetes-related research and statistics. Specific topics include risk factors, impaired glucose tolerance (IGT), insulin resistance, HbA1c (glycosylated hemoglobin) testing, blood glucose testing, urine testing, SMBG (self monitoring of blood glucose), non-invasive blood glucose monitors, preventing complications, how stress affect diabetes, alternative therapies for diabetes, exercise, exchange lists, carbohydrate counting, eating at restaurants, insulin administration and dosage, oral medications, amputation, kidney disease (diabetic nephropathy), diabetic retinopathy (eye disease), diabetic neuropathy (nerve disease), gastroparesis (reduced motility of stomach contents), hypoglycemia (low blood glucose levels), hyperglycemia (high blood glucose levels), erectile dysfunction (ED formerly called impotence), research advances in diabetes, and diabetes in ethnic and racial groups. The book includes a glossary of related terms, information about locating financial help for diabetes care, and a list of resources, including organizations, recipes and cookbooks.

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Core Curriculum for Diabetes Education. 3rd ed Source: Chicago, IL: American Association of Diabetes Educators. 1998. 901 p. Contact: Available from American Association of Diabetes Educators. 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (800) 338-3633 or (312) 424-2426. Fax (312) 4242427. PRICE: $95.00 for AADE members; $135.00 for nonmembers. ISBN: 1881876047. Summary: This book provides the most up-to-date information for diabetes educators so that they can help people with diabetes to become effective decision makers for their own diabetes care. The first section addresses the issue of education, focusing on the program design and educational methods used to help patients learn about diabetes. The next section examines psychosocial issues, including psychological assessment, behavior changes, and psychological disorders. The third section explains the pathophysiology of the diabetes disease state. The following section describes therapies that will help people with diabetes make self directed behavior changes to improve their overall diabetes management or nutritional status. Topics include nutrition, exercise,

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pharmacologic therapies, self-monitoring of blood glucose, and monitoring of metabolic control by the health care team. The fifth section examines blood glucose management, focusing on pattern management; hyperglycemia; hypoglycemia; illness and surgery; and skin, foot, and dental care. The sixth section discusses the impact of diabetes during each stage of the life cycle, focusing on diabetes in children, adolescents, pregnant women, and the elderly. This is followed by a section on the complications of diabetes, including eye disease, neuropathy, nephropathy, and macrovascular disease. The final section discusses the importance of research and outcomes. Chapters include case studies, self-review questions, and lists of suggested readings. The book concludes with continuing education post-test questions for each chapter and an index. 41 figures. Numerous tables. Numerous references. •

Family and Friends' Guide to Diabetes: Everything You Need to Know Source: New York, NY: John Wiley and Sons, Inc. 2000. 282 p. Contact: Available from John Wiley and Sons, Inc. Distribution Center, 1 Wiley Drive, Somerset, NJ 08875-1272. (800) 225-5945 or (732) 469-4400. Fax (732) 302-2300. E-mail: [email protected]. Website: www.wiley.com. PRICE: $14.95 plus shipping and handling. ISBN 0471348015. Summary: This book uses a question and answer format to provide the family and friends of people who have diabetes with information on the disease so that they can be understanding and supportive to those who have diabetes. Chapter one presents facts about diabetes. The chapter explains what diabetes is and what a normal blood glucose level is; describes type 1, type 2, and gestational diabetes; and discusses the causes of these types of diabetes. Other topics include diagnosing and treating diabetes, monitoring blood glucose levels, and understanding complications. In addition, the chapter dispels common myths about diabetes. The second chapter focuses on the management of low blood glucose. Topics include the causes, symptoms, and treatment of hypoglycemia. The next chapter deals with meal planning. The chapter teaches readers what people who have diabetes are advised to eat, what exchanges and carbohydrate counting are, and how to modify meals to make them lower in fat and sodium. In addition, readers learn how to plan menus and identify the different types of sugar found naturally in foods. Chapter four reviews the effect illness has on diabetes. The chapter describes the causes, symptoms, and treatment of hyperglycemia and diabetic ketoacidosis and offers tips on how to help people who have diabetes during an illness. This is followed by a chapter that focuses on planning special occasions. The chapter provides tips and ideas on how to make holidays and celebrations fun and healthy for everyone. Other topics include simple courtesies to keep in mind to make special times less stressful for those who have diabetes or others who are watching what they eat. Chapter six offers guidelines for creating a work environment that supports healthy lifestyle habits and is diabetes friendly. The chapter helps readers assess their workplace and organizational culture to identify any barriers that could create diabetes self care challenges and discusses the creation of an emergency plan for hypoglycemia. In addition, the chapter explains why diabetes is a legal disability and how current laws prevent workplace discrimination. This is followed by a chapter that helps readers assess the impact of diabetes on their lives, teaches them positive coping skills, and suggests ways to create a supportive environment for them and the person who has diabetes. Chapter eight focuses on promoting healthy habits at home. The chapter helps readers learn how change occurs and to plan for it, assess readiness to change an unhealthy behavior, and help someone trying to change or break an unhealthy habit.

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The final chapter offers guidelines for building positive relationships and friendships. 4 appendices. Numerous references. •

Surveying and Preventing the Complications of Diabetes in Nova Scotia Source: Halifax, Nova Scotia: Diabetes Care Program of Nova Scotia. 1997. (book and flipchart). Contact: Available from Diabetes Care Program of Nova Scotia. P.O. Box 9000, 1278 Tower Road, Bethune Building, Suite 577, Halifax, Nova Scotia B3H 2Y9. (902) 473-3219. Fax (902) 473-3911. E-mail: [email protected]. PRICE: $27.50. Summary: This book, which is accompanied by a quick reference guide flipchart, presents papers that provide information on diabetes control and complications. The book serves as a resource for health professionals involved in the care and education of people who have diabetes in Nova Scotia. The first paper discusses targets for good metabolic control in diabetes. Topics include the health benefits of lowering hyperglycemia, low density lipoprotein cholesterol, and blood pressure; quitting smoking; eating healthy; and exercising. The remaining papers focus on macrovascular disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, and foot problems. Each complication is discussed in terms of its features, magnitude, and risk factors. Each paper also describes methods of screening for the complication and guidelines for prevention and management. The papers include a flow chart for the assessment and treatment of each complication. The quick reference flipchart presents a brief selection of text and an algorithm for the surveillance, prevention, and management of these complications. 4 appendices. 6 figures. Numerous references.

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My Doctor Says I Have a Little Diabetes Source: Garden City Park, NY: Avery Publishing Group. 1997. 138 p. Contact: Available from Avery Publishing Group. 120 Old Broadway, Garden City Park, NY 11040. (800) 548-5757 or (516) 741-2155. Fax (516) 742-1892. E-mail: [email protected]. Website: www.averypublishing.com. PRICE: $9.95 plus shipping and handling. ISBN: 0895298600. Summary: This book, which is written in easy to understand language, serves as a guide to understanding and controlling type 2 diabetes. The book begins with a chapter that provides basic information on diabetes and diabetes care. Topics include the symptoms of diabetes, the types of diabetes, risk factors for diabetes, diagnostic tests for diabetes, common misconceptions about diabetes, and the management of the emotional aspects of diabetes. Each of the remaining chapters examines a specific aspect of diabetes care, including monitoring blood levels, following an appropriate diet, exercising, using medications, managing high and low blood glucose levels, preventing complications, and handling special situations. The chapter on glucose monitoring offers guidelines for selecting a monitor and checking blood glucose levels. The chapter on diet presents the latest goals and guidelines for the nutritional management of type 2 diabetes; explains how protein, carbohydrates, fats, and other nutrients affect diabetes; provides meal planning options that will make eating an enjoyable experience; and offers tips for handling special situations. The chapter on exercise discusses some of the advantages of following a program of regular exercise, helps readers choose a program suited to their needs, and offers advice about how to begin an exercise program. The chapter on medication discusses the different diabetes medications, medication interactions and precautions, and the effects that many prescription and over the counter medications have on diabetes. The chapter also presents information about mixing and injecting

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various types of insulin. The chapter on dealing with high and low blood glucose levels presents the causes, symptoms, and associated problems of hyperglycemia and hypoglycemia. Guidelines for treating these problems are also provided. The chapter on the prevention of complications reviews symptoms and prevention of the complications associated with diabetes, including high blood pressure; atherosclerosis; eye disorders; kidney disease; and foot and lower leg, autonomic nervous system, skin, and sexual problems. The final chapter on special situations covers the special care needed on sick days and when traveling. The book also includes a list of resources and provides tables for converting glucose, cholesterol, and triglyceride levels from milligram per deciliter to millimoles per liter. 3 figures. 8 tables. 28 references. •

Diabetes Is Not a Piece of Cake Source: Lake Oswego, OR: Lincoln Publishing Incorporated. 1994. 281 p. Contact: Available from Lincoln Publishing, Inc. P.O. Box 1499, Lake Oswego, OR 97035. (800) BOOKS-4-U or (503) 699-1000. Fax (503) 699-2000. PRICE: $14.95 plus $1.80 shipping and handling (as of 1995). ISBN: 1884929753. Summary: This book, written for the family, friends, colleagues and classmates of people with diabetes, provides easily understandable, comprehensive information about diabetes and how it is managed. Written primarily in a question and answer format, the book covers the history of diabetes; how diabetes affects the body physically; different types of diabetes treatments; the costs of managing diabetes; diabetes complications; hypoglycemia and its treatment; hyperglycemia and its prevention; the diabetes diet; cooking for people with diabetes; dining out with someone with diabetes; exercise; pregnancy in women with diabetes; diabetes in children and adolescents; and the psychosocial and emotional factors that diabetes can generate. The book also provides 24 pages of recipes, a glossary of terms, removable poster pages on dealing with emergencies, a list of resources, and a subject index. The book is illustrated throughout with humorous cartoon figures.

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Do Your Level Best: Start Controlling Your Blood Sugar Today Source: Bethesda, MD: National Diabetes Outreach Program (NDOP), National Diabetes Information Clearinghouse (NDIC). September 1995. 60 p. Contact: Available from National Diabetes Information Clearinghouse (NDIC). 1 Information Way, Bethesda, MD 20892-3560. (800) 860-8747 or (301) 654-3327. Fax (301) 634-0716. E-mail: [email protected]. Also available at http://www.niddk.nih.gov/. PRICE: Single copy free; bulk orders available to health professionals; contact NDIC for current availability status. Also available at http://www.niddk.nih.gov/. Summary: This booklet helps people with newly diagnosed diabetes learn how to take care of their diabetes and how to prevent complications of the disease. Topics include an introduction to how diabetes affects the body and the types of diabetes; regular diabetes care, including proper food, nutrition, medications, monitoring (blood glucose testing), and recordkeeping; what to do when blood glucose levels are high (hyperglycemia) or low (hypoglycemia); the impact diabetes can have on the heart and blood vessels, the eyes, the kidneys, the nervous system, the gums and teeth, and the feet; taking care of diabetes in special circumstances, including sick days, travel, and during pregnancy; and where to get additional information and help. The booklet features a back pocket with various brochures, including those on diabetes and periodontal disease, diabetic

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eye disease, and diabetes research, and a recordkeeping form for readers to keep track of their diabetes management activities. •

Living with Type 2 Diabetes Source: Hamilton, Ontario, Canada: Hamilton Civic Hospitals. 1997. 43 p. Contact: Available from Robert Panchyson, Education Department, 3LN, Hamilton Health Sciences Corp. General Site, 237 Barton Street East, Hamilton, Ontario, Canada, L8L 2X2. (905) 527-4322, ext. 6615. Fax (905) 527-1941. PRICE: Contact directly for current price. Summary: This booklet is written primarily for elderly patients with diabetes. It is written at a grade 4 to 6 reading level. The booklet defines diabetes and blood glucose and covers the impact of foods on blood glucose levels, insulin, how insulin works, type 2 diabetes, weight and meal plans, exercise and activity levels, low blood glucose (hypoglycemia) and its treatment, prevention of hypoglycemia, high blood glucose (hyperglycemia), diabetes medications, alcohol and diabetes medications, and diabetes complications. The booklet presents clear practical suggestions for managing various aspects of diabetes self care, and is illustrated with simple line drawings to help readers comprehend the topics. The 1997 revision of the English-language version (other language versions have not yet been revised) includes additional information about cholesterol, blood pressure and oral medications. The booklet is available in English, Spanish, French, Italian, Polish, or Portuguese. A Hindi version is expected.

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Best for You and Your Baby: Answers About Gestational Diabetes Source: Indianapolis, IN: Boehringer Mannheim Corporation. 1993. 40 p. Contact: Available from Boehringer Mannheim Corporation. Medical Services Department. 9115 Hague Road, Indianapolis, IN 46250. (800) 428-5076. PRICE: Single copy free. Summary: This easy-to-read patient education booklet offers general information about gestational diabetes. Topics include the patient care team and the patient's role in it; a definition of gestational diabetes; the causes of high blood glucose levels; complications to the fetus and the mother caused by hyperglycemia; monitoring fetal health; selfmonitoring of blood glucose (SMBG); meal planning; the use of insulin; the role of exercise; emotional support; labor and delivery; postpartum problems with diabetes; and breastfeeding. Written in clear, basic language, the booklet features charcoal drawing illustrations and sidebars that highlight the important points on each page. The booklet concludes with a glossary of relevant terms. It is also available in Spanish (Lo Mejor para Usted y su Bebe: Respuestas Sobre la Diabetes del Embarazo).

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What You Need to Know About Diabetes: A Short Guide Source: Boston, MA: Joslin Diabetes Center. 1999. 60 p. Contact: Available from Joslin Diabetes Center. One Joslin Place, Boston, MA 02215. (800) 344-4501 or (508) 583-3240. Fax (617) 732-2562. Website: www.joslin.harvard.edu. PRICE: $11.50 each; plus shipping and handling. Order number JDC210. Summary: This guide provides people who have diabetes with information on the basics of diabetes self care. The guide begins with a chapter that explains normal metabolism and the impact of diabetes on body functioning, identifies the short-and long-term risks of high blood sugar, defines low blood sugar, and offers self care tips. This is followed

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by a chapter that explains how to use good nutrition practices to care for diabetes. Topics include eating the right amount and kind of food at the right time; developing a meal plan; and making healthy food choices by limiting fatty foods, consuming high fiber food, using less salt, replacing sugar with artificial sweeteners, and limiting alcohol consumption. The chapter also offers tips for eating out and developing healthy eating habits and provides examples of food choices from various food groups. Chapter three provides guidelines for using exercise to care for diabetes, focusing on starting an exercise plan and preventing a low blood sugar reaction. This is followed by a chapter that focuses on the use of medications to care for diabetes. The chapter provides information on insulin, offers tips for drawing up and injecting a single or mixed dose of insulin, and presents suggestions for taking care of insulin and syringes. In addition, the chapter explains how oral diabetes medications work, presents guidelines for taking oral diabetes medications, and summarizes tips for using oral medications that are currently available. Chapter five focuses on the monitoring of blood glucose. Topics include the steps involved in checking blood for sugar and urine for ketones. The sixth chapter discusses special problems, including hyperglycemia, diabetic ketoacidosis, hyperglycemic hyperosmolar nonketotic state, and hypoglycemia. Remaining chapters outline sick day rules; offer foot care tips; present guidelines for avoiding eye, kidney, nerve, heart and blood vessel, and foot damage; and provide suggestions for living with diabetes. •

Core Curriculum for Diabetes Education. 5th ed.: (Volume 1) Diabetes and Complications Source: Chicago, IL: American Association of Diabetes Educators (AADE). 2003. 232 p. Contact: Available from American Association of Diabetes Educators (AADE). AADE Member Service Center, 100 W. Monroe Street, Suite 400, Chicago, IL 60603. (800) 3383633 or (312) 424-2426. Fax (312) 424-2427. Email: [email protected]. Website: www.aadenet.org. PRICE: Individual volume $55.00 for members and $75.00 for nonmembers: complete 4-volume set $159.95 for members and $229.95 for nonmembers; plus shipping and handling. ISBN: 88187611x (Volume 1); 881876152 (4-volume set). Summary: This guidebook is one in a series of four handbooks in the CORE Curriculum, a project originally planned to help educators prepare for the Certified Diabetes Educators (CDE) exam. However, the use and scope of the CORE Curriculum has expanded; it is both a key reference for the Advanced Diabetes Management credential exam and an authoritative source of information for diabetes education, training, and management. This first volume covers diabetes and complications. Topics include pathophysiology of the diabetes disease state, hyperglycemia, an overview of the chronic complications of diabetes, diabetic foot care and education, skin and dental care, macrovascular disease, eye disease and adaptive diabetes education for visually impaired persons, nephropathy (kidney disease) and diabetic neuropathy (nerve disease). Each chapter includes an introduction, a list of learning objectives, key definitions (glossary), key educational considerations, self review questions, references, and a post-test (including an answer key). The handbook concludes with a subject index.

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Diabetes Mellitus: A Practical Handbook. 6th ed Source: Palo Alto, CA: Bull Publishing. 1995. 200 p. Contact: Available from Bull Publishing. P.O. Box 208, Palo Alto, CA 94302-0208. (415) 322-2855. Fax (415) 327-3300. PRICE: $12.95 plus shipping and handling. ISBN: 0923521313.

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Summary: This handbook explains diabetes in simple language and diagrams. Topics include the etiology of diabetes mellitus; hyperglycemia and hypoglycemia; blood sugar levels; diet and nutrition; self monitoring of blood glucose; urine testing; ketones and ketoacidosis; insulin and insulin storage; injection techniques; oral diabetes medications; laboratory tests; exercise; sick days; personal hygiene, including skin care and foot care; stress and emotions; traveling with diabetes; complications; and research. Additional sections discuss resources and organizations where peole can seek more information; a bibliography; meal planning forms; and a time schedule. •

Therapy for Diabetes Mellitus and Related Disorders. 3rd ed Source: Alexandria, VA: American Diabetes Association. 1998. 487 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $39.95 plus shipping and handling. ISBN: 0945448945. Summary: This handbook focuses on the treatment of problems that are of importance in the management of people with diabetes mellitus. The book attempts to help health professionals apply major advances in health care to their patients. Topics include the diagnosis and classification of diabetes mellitus, genetic counseling for type 1 diabetes, gestational diabetes mellitus, the management of pregnant women who have diabetes, antepartum and intrapartum obstetric care, neonatal problems and their management, type 1 diabetes and diabetic ketoacidosis in children, psychosocial adjustment in children who have type 1 diabetes, psychosocial aspects in adults, diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic syndrome in adults, and lactic acidosis. Other topics include the role of diabetes education in patient management; self monitoring of blood glucose; the rationale for management of hyperglycemia; medical nutrition therapy; pharmacological treatment of obesity; exercise; oral hypoglycemic agents such as sulfonylureas, repaglinide, metformin, alpha glucosidase inhibitors, and thiazolidinediones; insulin treatment; insulin pump therapy; combination therapy for hyperglycemia; and diabetes complications. In addition, the book discusses surgery and anesthesia in people with diabetes, geriatric patient care, hypoglycemia in patients who have type 1 diabetes, insulin allergy and insulin resistance, drugs and hormones that increase blood glucose levels, diabetic dyslipidemia, antihypertensive therapy, cutaneous disorders associated with diabetes mellitus, infections, visual loss, ocular complications, drug induced renal dysfunction, diabetic nephropathy, chronic kidney disease, painful or insensitive lower extremity, mononeuropathy and amyoradiculopathy, gastrointestinal disturbances, and bladder dysfunction. Final topics include erectile dysfunction, female sexual disorders, postural hypotension, sudomotor dysfunction and dark vision, cardiac denervation syndrome, noninvasive cardiac testing, angina and congestive heart failure, myocardial infarction, peripheral vascular disease, and foot ulcers and infections. The book includes an index. Numerous figures. Numerous tables. Numerous references.

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Your Child Has Diabetes: A Parents Guide for Managing Diabetes in Children Source: Atlanta, GA: Pritchett and Hull Associates, Inc. 2002. 40 p. Contact: Available from Pritchett and Hull Associates, Inc. 3440 Oakcliff Road, N.E., Suite 110, Atlanta, GA 30340. (800) 241-4925. Website: www.p-h.com. PRICE: $3.25; plus shipping and handling.

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Summary: This handbook was written to teach parents of children newly diagnosed with diabetes the basics about diabetes and its management. The booklet begins by reminding parents that it may take some time to learn about diabetes and its management, so not to be too discouraged at first. Topics covered include glucose and how the body uses glucose for energy; the two most common types of diabetes; diabetes from the child's perspective; the multi-pronged approach to diabetes care, including food, exercise, insulin, oral medicines, and checking blood glucose levels; the members of the typical patient care team; eating healthy meals and snacks; meal planning, diabetes exchanges, and carbohydrate counting; the food pyramid (slightly modified for diabetes); insulin, including injections, insulin pumps, and self monitoring of blood glucose, or SMBG; coping with blood glucose problems, including hyperglycemia (high blood glucose levels) and hypoglycemia (low blood glucose levels); complications of diabetes; and coping with diabetes in school. The booklet is illustrated with colorful, cartoon drawings and includes spaces for parents to individualize the information with their child's goals, the health care providers' telephone numbers, and management strategies. The booklet concludes with a list of resource organizations through which parents can obtain additional information. •

Insulin-Dependent Diabetes in Children, Adolescents and Adults: How to Become an Expert on Your Own Diabetes Source: Uddevalla, Sweden: Becton Dickinson and Company. 1998. 268 p. Contact: Available from Becton Dickinson and Company. Becton Dickinson Division, 1 Becton Drive, Franklin Lakes, NJ 07417-1884. (201) 847-6800. Fax (201) 847-6692. PRICE: $29.00; plus shipping and handling. ISBN: 9163062615. Also available from www.amazon.com and Piara Publishing. Turkosv 12, S-451 62 Uddevalla, Sweden. +46 522 66 93 66. E-mail: [email protected]. Summary: This illustrated book provides people with the practical information they need to take good care of their diabetes. The book begins by describing the anatomy of the digestive system and explaining how the healthy body works. This is followed by sections that focus on self care; the symptoms and treatment of hypoglycemia and hyperglycemia; insulin treatment; insulin requirements; injection technique; injection aids such as indwelling catheters, automatic injectors, and jet injectors; the insulin pump; the side effects of insulin treatment; the adjustment of insulin doses; temporary and permanent changes to insulin doses; and urine and blood testing. Other sections focus on diet, the use of dietary sweeteners, the consumption of candy and ice cream, weight control, eating disorders, physical exercise, stress, sick days, active and passive smoking, alcohol consumption, pregnancy, social issues, travel, associated diseases, and complications. Several sections focus on research efforts, including research addressing the issue of whether better blood glucose control can lessen the risk of complications and research concerning equipment improvements, the cause of diabetes, and alternative modes of insulin administration. Remaining sections deal with psychological issues, needle phobia, and well known persons who have diabetes. The book includes a glossary, an index, and a reading list. 433 references.

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My Own Type 1 Diabetes Book Source: West Vancouver, BC: Grandma Sandy. 1999. 37 p. Contact: Available from Grandma Sandy. 5742 Westport Court, West Vancouver, BC V7W 2X9. Also available from Amazon.com. PRICE: $10.00 plus shipping and handling. ISBN: 0968667201.

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Summary: This illustrated book serves as a tool and a reference for children who have type 1 diabetes and their families and caregivers. The book uses simple text and visual imagery to demystify type 1 diabetes. The book begins by explaining how people get diabetes and what diabetes is. This is followed by a discussion of the need for people who have diabetes to balance their diet, exercise, and insulin level. Other topics include doing blood glucose checks, eating appropriate foods, injecting insulin, using an insulin pump, exercising, and dealing with hyperglycemia and hypoglycemia. The book includes blank pages for recording notes and reminders, lists reference books for further reading and websites that give additional information, and identifies items for a type 1 diabetes kit. •

Keep Yourself Healthy at Home: A Guide for Adults with Diabetes Source: South Deerfield, MA: Channing L. Bete Co., Inc. 2000. 60 p. Contact: Available from Channing L. Bete, Co., Inc. 200 State Road, South Deerfield, MA 01373-0200. (800) 628-7733. Fax (800) 499-6464. PRICE: $3.50 each; plus shipping and handling; quantity discounts available. Order number 97915. Summary: This illustrated handbook provides adults who have diabetes with information on health care. Section one provides general information about health care, the prevention of health problems, and the use of diabetes and general medications. Section two discusses specific problems and their treatment, focusing on allergies, appendicitis, asthma; back pain; bites and stings; bronchitis; bruises, cuts, and scrapes; burns and sunburns; chest pain; colds, flu, and cough; constipation; diarrhea; dizziness and fainting; fever; foot and leg problems; headaches; heartburn; mouth problems; nausea and vomiting; sexual concerns; sexually transmitted diseases; skin problems; sprains and strains; urinary tract infections; and vaginitis. Section three focuses on conditions of special concern for people who have diabetes, including heart disease and stroke and eye, kidney, and nerve diseases. Section four explains how to deal with hypoglycemia and hyperglycemia and provides space for writing down emergency numbers and other emergency information.

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Children with Diabetes: A Resource Guide for Schools Source: Rensselaer, NY: New York State Health Department. 1999. 100 p. Contact: Available from New York State Health Department. Distribution Center, 11 4th Ave., Rensselaer, NY 12144. Fax (518) 465-0432. E-mail: [email protected]. Website: www.health.state.ny.us. PRICE: Single copy free, also can be found at www.health.state.ny.us/nysdoh/consumer/diabetes/resource/families.htm. Summary: This manual serves as a diabetes resource guide for New York State school personnel. The manual presents an overview of the governor's initiative for people with diabetes. This is followed by an American Diabetes Association (ADA) position statement on the care of children with diabetes in school and day care settings and ADA recommendations for diabetes classification, testing, and diagnosis. The next section provides general information about diabetes. Topics include the symptoms and types of diabetes, nutrition, physical activity, blood glucose monitoring, the symptoms and treatment of hyperglycemia and hypoglycemia, insulin and insulin delivery systems, the care of children with diabetes, and diabetes identification cards and care information. This is followed by sections that present tools and information for parents and school nurses. The section for parents focuses on general information about diabetes, the responsibilities of parents who have a child with diabetes, appropriate

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accommodations for a special needs child under the law, care planning, the age related responsibilities of children, psychosocial aspects of the child with diabetes, factors causing emotional distress for the child, sick day and travel guidelines, and medical identification products. The section for school nurses deals with care planning, training, staff training, appropriate accommodations for a special needs child under the law, sick day guidelines, and answers to questions about roles and responsibilities in relation to nursing procedures. Another section presents tools and information for teachers, administrators, school staff, and bus drivers. In addition, the manual includes an appendix that provides sample forms and letters and identifies numerous resources. 1 appendix. •

Living Well With Diabetes Source: Puyallup, WA: Good Samaritan Hospital. 1992. 63 p. Contact: Available from Good Samaritan Hospital. Diabetes Education Center, 407 14th Avenue SE, Puyallup, WA 98372. (206) 848-6661, ext. 1633. PRICE: $24.94 each, 10 or more $19.95 each; matching overheads $10 per set, plus $4.50 shipping and handling for over 5 manuals. Summary: This manual, intended for use in class instruction, is designed to help people newly-diagnosed with diabetes understand the disease and their role in diabetes management. Topics include a brief definition of diabetes, blood glucose testing, hypoglycemia, hyperglycemia, meal planning, exchange lists, sweeteners, fiber, fat and cholesterol, food labels, dining out, alcohol, cooking tips and cookbooks, exercise, insulin and oral hypoglycemic agents, long-term complications, care during illness (sick days), the psychosocial issues of living with diabetes, and support services. The topics are categorized into five class sessions and a 1-month follow-up meeting. Throughout the manual, charts and diagrams illustrate the material being presented.

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Putting Your Diabetes on the Pump Source: Alexandria, VA: American Diabetes Association. 2001. 59 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $7.95 plus shipping and handling. ISBN: 1580401414. Summary: This pocket sized handbook familiarizes readers with how people with diabetes can use an insulin pump to keep blood glucose (sugar) levels within target ranges. The author notes that by using an insulin pump, the patient can match their insulin needs to their lifestyle, rather than take an insulin injection and match their activities to how the insulin is working. Pumps deliver rapid or short-acting insulin 24 hours a day through a catheter placed under the skin. Insulin doses are separated into basal rates, bolus doses to cover the carbohydrate in meals, and correction or supplemental doses. Basal insulin is delivered continuously over 24 hours and keeps the blood glucose levels in range between meals and at night. When the pump user eats, he or she uses buttons on the pump to give additional insulin called a bolus. The booklet describes the positive and negatives aspects of using an insulin pump, what to know before using the pump, good habits, the practicalities of wearing an insulin pump, infusion sets, equipment and supplies, blood glucose targets, exercise and sports, days off the pump, dealing with hyperglycemia (high levels of blood glucose) and hypoglycemia (low levels of blood glucose), coping with sick days, and skin care. The booklet concludes with some suggestions from others who already use the insulin pump

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for part of their diabetes management, a blank form for recordkeeping, and basic information about the American Diabetes Association. The booklet is illustrated with simple line drawings. 1 figure. 4 tables. •

Diabetes Annual/5 Source: New York, NY: Elsevier Science Publishing Company. 1990. 668 p. Contact: Available from Elsevier Science Publishing Company, Inc. Order Department, 655 Avenue of the Americas, New York, NY 10010. (212) 989-5800. PRICE: $217.25. ISBN: 0444812075. Summary: This serial, published annually, presents current research and thinking on a variety of diabetes-related topics. Thirty chapters, authored by international experts in the field of diabetes mellitus, cover topics including: the epidemiology and etiology of diabetes; current trends in the dietary management of diabetes; sulfonylurea therapy; insulin injection therapy; new oral hypoglycemic agents; diabetes and exercise; patient education; the role of computer technology; islet transplantation; diabetic retinopathy; diabetic neuropathy; diabetic kidney disease; obesity and diabetes; hypertension and diabetes; hyperglycemia; lipids and lipoproteins; microangiopathy; insulin action and metabolism; glucose transport in muscle and fat; and growth hormone, insulin-like growth factors and diabetes. Each chapter includes extensive references. A brief subject index is appended.

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American Diabetes Association Complete Guide to Diabetes: The Ultimate Home Diabetes Reference. 2nd ed Source: Alexandria, VA: American Diabetes Association. 1999. 514 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $23.95 plus shipping and handling. ISBN: 1580400388. Summary: This sourcebook provides people who have diabetes with expert advice, written in clear, easy to understand language, on every aspect of type 1, type 2, and gestational diabetes. The book begins with a chapter that provides an overview of type 1, type 2, and gestational diabetes. This is followed by a chapter that offers guidelines for designing a diabetes plan and describes options for treating diabetes, including insulin therapy, pancreas and islet transplantation, diet therapy, and oral diabetes medications. The third chapter provides suggestions for selecting a diabetes care team and answers questions about the glycated hemoglobin test. The next chapter describes types of insulin; explains how to buy, store, and administer insulin; and discusses various insulin plans. This is followed by a chapter that focuses on achieving glucose control. Topics include the impact of food, insulin, exercise, stress, and illness on blood glucose; self monitoring of blood glucose; and the causes and treatment of hypoglycemia and hyperglycemia. Chapter six provides information on diabetes tools, including blood glucose meters, test strips, lancets, and miscellaneous supplies. The focus of chapter seven is on intensive diabetes management. Topics include standard diabetes control versus tight control, goals for type 1 and type 2 diabetes, and intensive management techniques. Chapter eight discusses healthy eating in terms of creating a healthy meal plan using the food pyramid and using medical nutrition therapy. The next chapter offers suggestions for beginning an exercise program, exercising safely, and finding a desirable exercise. Other topics include the impact of exercise on blood glucose levels and exercise during pregnancy. Chapter 10 examines diabetes complications and

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their prevention and treatment. Complications include cardiovascular disease, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and infections. Other chapters discuss the impact of diabetes on sexual health and pregnancy, the psychological impact of diabetes, and the effect of diabetes on other family members. Remaining chapters examine diabetes in the workplace, in the military, and at school and offer advice for working with the health care system. The book includes a glossary, an index, and lists of resources and helpful websites. 1 appendix. 9 figures. •

Rufus Comes Home Source: Plainview, NY: JayJo Books. 1998. 34 p. Contact: Available from JayJo Books. 135 Dupont Street, P.O. Box 760, Plainview, NY 11803-0760. (800) 999-6884. Fax (800) 262-1886. E-mail: [email protected]. Website: www.JayJo.com. PRICE: $11.95 plus shipping and handling. Order number: BK190H170024. ISBN: 891383027. Summary: This story book was written for children who have recently been diagnosed with type 1 diabetes. The book follows the story of a young boy, Brian, and his parents, as they go through the process of diabetes diagnosis and learning how to manage the disease. Topics include the symptoms of diabetes, testing for blood glucose, complications of diabetes, the physiology of insulin and blood glucose levels, the use of insulin injections, the role of meal planning and nutrition, hyperglycemia (high blood glucose levels) and hypoglycemia (low blood glucose levels), and the emotions of being diagnosed with diabetes. The story tells the tale of a stuffed bear, Rufus, being used to help the child with diabetes not feel so alone; the bear has diabetes too, and special patches where blood glucose testing and insulin shots could be pretended. The book ends with information telling readers how they can purchase a Rufus bear. The book is filled with colorful illustrations.

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Endocrinology. 4th ed Source: Philadelphia, PA: Harcourt Health Sciences. 2001. 3 v., 3048 p. Contact: Available from W.B. Saunders. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452 or (314) 453-7010. Fax (800) 568-5136 or (314) 453-7095. E-mail: [email protected]. Website: customerservice.wbsaunders.com. PRICE: $495.00 plus shipping and handling. ISBN: 0721678408 (three volume set). Summary: This three volume set of books provides a complete, authoritative, up to date analysis of endocrine disease and basic endocrine physiology. This edition consists of 194 chapters that cover every aspect of endocrinology in detail by an authority in the field. About one third of the chapters are new, and the remainder have been rewritten and updated. Topics covered in volume one include the principles of hormone action; neuroendocrinology and the pituitary gland; growth and maturation; immunology and endocrinology; obesity, anorexia nervosa, and nutrition in endocrinology; and diabetes mellitus, carbohydrate metabolism, and lipid disorders. Chapters on diabetes mellitus focus on anatomy and physiology, classification, etiology, diagnosis, and treatment. Specific clinical disorders discussed include syndromes of insulin resistance, oculopathy, neuropathy, nephropathy, diabetic foot complications, ketoacidosis, hyperosmolar coma, lactic acidosis, hypoglycemia, atherosclerosis, syndrome X, and hyperglycemia. Volume two includes information on the parathyroid gland, calciotropic hormones, bone metabolism, the thyroid gland, the adrenal gland, and glucocorticoids. Topics covered in volume three include endocrine hypertension and mineralocorticoids, reproductive endocrinology and sexual development, female

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reproduction, endocrinology of the breast, male reproduction, endocrinology and pregnancy, endocrine tumor syndromes, and endocrine testing and treatment. Numerous figures. Numerous tables. Numerous references. •

Managing Your Diabetes: A Comprehensive Study Guide for Patients and Their Health Care Professionals Source: Indianapolis, IN: Eli Lilly and Company. 1994. 107 p. Contact: Available from Eli Lilly and Company. Lilly Corporate Center, Indianapolis, IN 46285. (800) 545-5979 or (317) 276-2000. PRICE: Single copy free. Summary: This workbook provides an overview of diabetes and information on ways to control it. Designed primarily for people newly diagnosed, the workbook has 14 chapters. Topics include a definition of diabetes, its symptoms, and causes; the importance of the team approach to diabetes care; meal planning; exercise; insulin; oral hypoglycemic agents; blood glucose testing; ketone testing; pattern management; hypoglycemia; hyperglycemia; ketoacidosis; long-term complications; and general health care tips, including skin and foot care, sick days, and travel. Many of these sections have blanks to be filled in with the help of a doctor, nurse, pharmacist, or diabetes educator. Full-color photographs and colorful charts illustrate the material presented. The book concludes with a glossary of terms. The booklet is also available in Chinese, Spanish, Turkish, and Italian.

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Strength and Compassion in Kidney Failure Source: Norwell, MA: Kluwer Academic Publishers. 1998. 221 p. Contact: Available from American Association of Kidney Patients (AAKP). 100 South Ashley Drive, Suite 280, Tampa, FL 33602. (800) 749-2257 or (813) 223-7099. Fax (813) 223-0001. E-mail: [email protected]. PRICE: $25.00 plus shipping and handling. ISBN: 079235236X. Summary: Written to celebrate life rather than lament chronic illness, this book offers a collection of medical columns, short stories, and letters that recount an upbeat tale of coping, surviving, and prevailing. The author, a medical technician, wife, and mother, faced progressive loss of sight and ambulation due to kidney failure, diabetes, and Addison's disease. The author includes hints for managing the necessities of diet therapy, handling time changes during travel, and adjusting insulin treatment to adapt to different levels of activity. Other topics covered include drug therapy, medical ethics, holidays, family interactions and relationships, depression and other emotions, skin problems, the physical side of diabetes, coping with constant adaptation to changes in one's body, the Diabetes Control and Complications Trial (DCCT), systemic joint and bone disease in diabetes, insulin therapy, hyperglycemia and hypoglycemia, hemodialysis, end stage renal disease, and kidney transplantation. Each item is briefly introduced by the editor, who is the author's husband. The author died in 1997 at the age of 61 of complications of type 1 diabetes.

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

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

Hyperglycemia, Diabetes, and Vascular Disease (Clinical Physiology Series) by Neil Ruderman (Editor), et al; ISBN: 0195067738; http://www.amazon.com/exec/obidos/ASIN/0195067738/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “hyperglycemia” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:11 •

Normoglycemic glycosuria. The influence of glycosuria and hyperglycemia on glucose tolerance and insulin requirements in diabetes mellitus. Author: Smith, Kendrick Adelbert, 1911-; Year: 1937

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Studies on hyperglycemia in relation to glycosuria. Author: Epstein, Albert Arthur, 1880-; Year: 1916

Chapters on Hyperglycemia In order to find chapters that specifically relate to hyperglycemia, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and hyperglycemia 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 “hyperglycemia” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on hyperglycemia: •

Solving Hyperglycemia Problems Source: in Touchette, N. Diabetes Problem Solver. Alexandria, VA: American Diabetes Association. 1999. p. 105-122.

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In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

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Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $19.95 for members; plus shipping and handling. ISBN: 1570400091. Summary: This chapter deals with solving hyperglycemia problems in people who have diabetes. This condition occurs when there is too much glucose in the blood. People who have diabetes either do not produce enough insulin or their body does not respond to insulin as it should. Without insulin, glucose remains in the blood and the blood glucose level rises too high. Blood glucose levels that remain high for too long can lead to lifethreatening situations. The chapter provides the reader with information on the symptoms of hyperglycemia, who is at risk for this condition, what to do if symptoms of hyperglycemia occur, how hyperglycemia may be treated, and how to prevent this condition from developing. Sometimes people who have diabetes do not know what caused their hyperglycemia, so the chapter discusses unexplained hyperglycemia. Another problem for people who have diabetes is diabetic ketoacidosis (DKA). This lifethreatening condition occurs when there is too little insulin in the blood and too much of the hormones that increase glucose levels in the blood. The chapter provides the reader with information on the symptoms of DKA, who is at risk for this condition, what to do if symptoms of DKA occur, how DKA may be treated, and how to prevent this condition from developing. People who have diabetes, particularly those who have type 2 diabetes, may develop hyperglycemic hyperosmolar state. This condition begins when blood glucose levels rise too high. The body produces more urine to get rid of excess glucose and dehydration occurs. The chapter provides the reader with information on the symptoms of this condition, who is at risk for this condition, what to do if symptoms occur, treatment, and how to prevent this condition from developing. The chapter also provides information on recognizing, handling, and preventing dawn phenomenon and Somogyi effect; recognizing, handling, treating, and preventing brittle diabetes; and recognizing and preventing impaired glucose tolerance. •

Hyperglycemia Source: in Franz, M.J., et al, eds. Core Curriculum for Diabetes Education. 5th ed. (Volume 1) Diabetes and Complications. Chicago, IL: American Association for Diabetes Educators (AADE). 2003. p. 19-42. Contact: Available from American Association of Diabetes Educators (AADE). AADE Member Service Center, 100 W. Monroe Street, Suite 400, Chicago, IL 60603. (800) 3383633 or (312) 424-2426. Fax (312) 424-2427. Email: [email protected]. Website: www.aadenet.org. PRICE: Individual volume $55.00 for members and $75.00 for nonmembers: complete 4-volume set $159.95 for members and $229.95 for nonmembers; plus shipping and handling. ISBN: 88187611x (Volume 1); 881876152 (4-volume set). Summary: This chapter on hyperglycemia (high blood glucose levels) is from the first handbook of the CORE Curriculum, a publication that helps educators prepare for the Certified Diabetes Educators (CDE) exam, serves as a key reference for the Advanced Diabetes Management credential exam, and provides an authoritative source of information for diabetes education, training, and management. This chapter notes that prolonged hyperglycemia can lead to two types of acute metabolic crises: diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). Either of these lifethreatening conditions may result in an altered mental state, loss of consciousness, or possibly death. Topics include the precipitating factors in DKA, the pathophysiology of DKA, the presenting signs and symptoms of DKA, possible variations in initial laboratory values, and goals for the treatment of DKA; the precipitating factors in HHS,

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the pathophysiology of HHS, the presenting signs and symptoms of HHS, and treatment for HHS; and the major differences between laboratory values found in DKA and HHS. The chapter includes an introduction, a list of learning objectives, key definitions (glossary), key educational considerations, self review questions, references, and a post-test (including an answer key). 3 figures. 2 tables. 18 references. •

Endocrine Emergencies: Hypoglycemic and Hyperglycemic Crises Source: in Clark, O.H. and Duh, Q. Textbook of Endocrine Surgery. Philadelphia, PA: W.B. Saunders Company. 1997. p. 651-661. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 545-2522. Fax (800) 874-6418 or (407) 352-3445. PRICE: $155.00. ISBN: 0721658822. Summary: This chapter, from a book on endocrine surgery, provides health professionals with a review of the pathophysiology of hypoglycemic and hyperglycemic crises, which are seen most commonly in patients with diabetes. Such endocrine emergencies can be life-threatening and are encountered with some frequency in the surgical setting. Topics include the physiology of systemic glucose homeostasis, hormonal regulation of glucose metabolism, and management of the surgical patient with diabetes. For both hypoglycemic and hyperglycemic crises, the authors discuss clinical presentation, pathogenesis, and recommended therapy. Hypoglycemic crises may be due to diabetic ketoacidosis or a hyperglycemic hyperosmolar nonketotic state. Hypoglycemic crises are classified as postprandial hypoglycemia or fasting hypoglycemia. In most surgical patients, endocrine crises are due primarily to inadequate or excessive insulin secretion or administration; patients with diabetes are at particular risk. Appropriate monitoring of glucose levels and management with intravenous saline, insulin, and glucose are fundamental to treatment. 3 figures. 1 table. 62 references. (AA-M).

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Approach to Hyperglycemia in the Patient with Diabetes Mellitus Source: Kelley, W.N., ed. Textbook of Internal Medicine. 3rd ed. Vol 2. Philadelphia, PA: Lippincott-Raven Publishers. 1997. p. 2155-2165. Contact: Available from Lippincott-Raven Publishers. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-3030 or (301) 714-2300. Fax (301) 824-7390. PRICE: $125.00 (2 volume edition) or $99.00 (single volume edition). ISBN: 0397515405 (2 volume set); 0397517297 (volume 1); 0397517300 (volume 2); 039751283x (paper). Summary: This chapter, from a textbook on internal medicine, describes for health professionals the therapeutic approach to hyperglycemia in patients with diabetes. The chapter's three sections discuss therapy of hyperglycemia in type 1 diabetes, in type 2 diabetes, and therapy of acute decompensated diabetes (diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma). For type 1 and type 2 hyperglycemic therapy, the author discusses therapeutic objectives, treatment modalities, assessment and monitoring, and special considerations. Information about type 1 therapy includes details about levels of treatment, nutritional plans, exercise, insulin dosage, education and support, and planning for pregnancy. For type 2 therapy, the author provides additional information about nutritional planning, indices of glycemic control, exercise, sulfonylureas, biguanides, other drug therapies, and insulin. The chapter briefly reviews treatment priorities for diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma. 4 figures. 9 tables. 17 references. (AA-M).

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CHAPTER 7. MULTIMEDIA ON HYPERGLYCEMIA Overview In this chapter, we show you how to keep current on multimedia sources of information on hyperglycemia. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Video Recordings An excellent source of multimedia information on hyperglycemia is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “hyperglycemia” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, 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 “Videorecording (videotape, videocassette, etc.).” Type “hyperglycemia” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on hyperglycemia: •

Preventing Long Term Complications of Diabetes Source: Timonium, MD: Milner-Fenwick. 2000. (videocassette). Contact: Available from Milner-Fenwick, Inc. 2125 Greenspring Drive, Timonium, MD 21093-3100. (800) 432-8433. Fax (410) 252-6316. PRICE: $125.00; bulk orders available; plus shipping and handling. Summary: The goal of this video program is to help patients with diabetes understand and prevent the long term complications of their disease. Viewers learn how high blood sugar (hyperglycemia) and the associated damage to blood vessels can possibly lead to heart attack, stroke, loss of vision (diabetic retinopathy), kidney disease (diabetic nephropathy), nerve damage (diabetic neuropathy), and amputation. Information is included about damage to both large and small blood vessels, updated terminology, HbA1c (glycosylated hemoglobin) testing (used to monitor blood glucose levels over time), heart disease risk factors, and erectile dysfunction (impotence). The video stresses that improving blood glucose (sugar) levels can help reduce the patient's risk of

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complications over time. The videotape was produced in cooperation with the American Association of Diabetes Educators (AADE), which defined the content of the video, selected the program consultants, and approved production at each stage of development. The program is closed-captioned. •

Strategies for the Prevention and Treatment of Macrovascular Complications of Type 2 Diabetes Source: Kansas City, MO: American Academy of Family Physicians. 1998. (videocassette). Contact: Available from American Academy of Family Physicians. 8880 Ward Parkway, Kansas City, MO 64114-2797. (800) 274-2237. PRICE: $17.95 for members; $25.00 for nonmembers, plus shipping and handling. Summary: The macrovascular (large blood vessel) complications of diabetes account for the majority of the morbidity (related illness) and mortality (death) associated with the disease. In particular, people with type 2 diabetes are at increased risk for cardiovascular disease, since they exhibit many independent risk factors for heart disease, including obesity, hypertension (high blood pressure), and dyslipidemia (disordered levels of fats in the blood). This continuing education program features a videocassette and study guide that discuss why people with diabetes are at increased risk for macrovascular complications and how to reduce the patient's risk of cardiovascular disease. Topics include hyperglycemia (high blood glucose levels) and cardiovascular disease, insulin resistance and cardiovascular disease, the benefits of improved glycemic control, recommended target glycemic goals, nonpharmacologic therapies for diabetes (diet, exercise, patient education), pharmacologic (drug) therapies for diabetes (insulin secretagogues, insulin sensitizers, alpha-glucosidase inhibitors, and insulin), determining the optimal drug treatment regimen for individual patients, and treating cardiovascular risk factors. The program recommends that patients should be seen quarterly or more often, depending upon the severity of their disease, and target goals for HbA1c (glycosylated hemoglobin, a measurement of blood glucose levels over time) and fasting blood glucose should be established at the initial visit and discussed directly with the patient. Patients should be reminded at every office visit that weight loss and regular exercise are the most important aspects of controlling their diabetes and reducing the risk of macrovascular disease. A sample patient education hand out is included in the study guide. Through this program, users can qualify for one credit hour of Continuing Medical Education (CME) in category 1; the appropriate posttest is provided. 5 figures. 14 tables. 15 references.

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Meeting the Diabetes Challenge in Long Term Care Source: Cypress, CA: Medcom, Inc. 1995. (videocassette). Contact: Available from Medical Audio Visual Communications, Inc. P.O. Box 84548, 2336 Bloor Street West, Toronto, Ontario M6S 1TO Canada. (800) 757-4868 or (905) 6021160. Fax (905) 602-8720. E-mail: [email protected]. PRICE: $235.00 plus shipping and handling. Order number MED307. Summary: This video describes the effects of diabetes on long-term care residents and presents the treatment methods used to manage this disease. Diabetes is widespread among the elderly, and it is easily overlooked because many of its symptoms are the same as those of other diseases. Treating long-term care residents who have diabetes involves balancing nutrition therapy, exercise, and medication. The video identifies the goals of nutrition therapy, discusses meal planning, and highlights the challenges posed

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by nutrition therapy. Other topics include diabetes pathology, exercise therapy, and medication and insulin. The video provides information on the side effects of oral hypoglycemic agents such as sulfonylureas and metformin and identifies the steps involved in monitoring residents who have diabetes. The video also describes the symptoms of acute and long-term complications of diabetes. Acute complications include hyperglycemia, hypoglycemia, ketoacidosis, and hyperosmolar syndrome. Long-term complications include microvascular and macrovascular problems and peripheral neuropathy. The video also offers guidelines on proper leg and foot care. •

Diabetes Road Map: Living with Type 2 Diabetes Source: Tampa, FL: Southern Star. 1999. (videocassette, log book). Contact: Available from Southern Star. P.O. Box 18011, Tampa, FL 33679-8011. (877) 8973276 or (813) 870-0911. Fax (877) 897-3275. Website: www.diabetesroadmap.com. PRICE: $26.95 plus $3.00 shipping and handling. Summary: This videotape serves as a comprehensive resource for people who have type 2 diabetes. The video shows people who have type 2 diabetes how to live with their disease and teaches them step-by-step how to make necessary lifestyle changes for a longer, healthier life. The viewer has virtual consultations with eight doctors, a certified diabetes educator-diabetes clinical nurse specialist, and a certified diabetes dietician. The video consists of 18 different diabetes topic sections so that the viewer can refer to them at any time for answers to specific questions. Section 1 explains what diabetes is; presents the features of type 1 and 2 diabetes, gestational diabetes, and other forms of diabetes; lists risk factors and symptoms; and highlights complications. Section 2 focuses on treatment options, including meal planning, exercise, medications, and lifestyle changes. The third through fifth sections deal with blood glucose, focusing on normal and abnormal blood glucose ranges; self monitoring of blood glucose; and the symptoms, causes, and treatment of hypoglycemia and hyperglycemia. Section 6 identifies types of oral medications, highlights their effects, and describes the features of various forms of insulin. The focus of the next section is meal planning. Topics discussed include carbohydrate counting, the diabetes food pyramid, alcohol consumption, and nutrition labels. Examples of meals are also provided. Section 8 identifies types of exercises and offers tips for effectively exercising. Stress management tips and sick day guidelines are presented in the next two sections. Section 11 discusses the causes of foot problems and provides guidelines for daily food care. Sections 12 through 16 examine the long-term complications of diabetes, including eye problems such as retinopathy, cataracts, and glaucoma; heart disease; kidney diseases; and nerve damage. The next section provides information on preventing and treating dental problems. The final section presents general information on diabetes, including organizations that provide assistance to people who have diabetes. The video is accompanied by a medical emergency card as well as a one-year logbook recorder that helps people keep track of medications and daily monitoring.

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Monitoring Your Blood Sugar: Key Concepts Source: Timonium, MD: Milner-Fenwick, Inc. 1996. (videocassette). Contact: Available from Milner-Fenwick, Inc. 2125 Greenspring Drive, Timonium, MD 21093. (800) 432-8433 or (410) 252-1700. Fax (410) 252-6316. E-mail: [email protected]. Website: www.milner-fenwick.com. PRICE: List price $150; discounts available. Item number DB-32.

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Summary: This videotape, one of a series of patient education videos, provides an overview of the key concepts for monitoring blood glucose levels. The program explains the methods for monitoring diabetes control, including blood glucose testing (SMBG), ketone testing, physician visits, and awareness of symptoms of high and low blood glucose (hyperglycemia and hypoglycemia, respectively). Other topics include recommended blood glucose levels, testing equipment (blood glucose monitors and urine test strips), recordkeeping issues, and testing tips. The program provides guidelines for dealing with hyperglycemia and hypoglycemia, and outlines instructions for handling sick days. The program features a variety of patients and uses both live action and bold graphics to present the concepts. The video series is designed to provide an educational foundation on which patients and diabetes educators can build a practical program of diabetes management. The video reflects current American Association of Diabetes Educators (AADE) guidelines and is coproduced by the association. The video is available in English, Spanish, and closed-captioned versions. (AA-M).

Audio Recordings The Combined Health Information Database contains abstracts on audio productions. To search CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find audio productions, 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 “Sound Recordings.” Type “hyperglycemia” (or synonyms) into the “For these words:” box. The following is a typical result when searching for sound recordings on hyperglycemia: •

Effective Drug Therapy for Diabetes Mellitus Source: Alexandria, VA: American Diabetes Association. 1998. (audiocassette). Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $17.95 for members; $22.95 for nonmembers; plus shipping and handling. ISBN: 1580400213. Summary: These audiocassettes provide information on effective drug therapy for diabetes mellitus. They feature articles first published in 'Clinical Diabetes.' An article on the use of metformin to treat diabetes provides an overview of this agent. Another article describes the use of acarbose to inhibit alpha-glucosidase. This agent decreases postprandial hyperglycemia by delaying carbohydrate digestion and absorption. A third article focuses on the use of lispro insulin, a rapid acting synthetic analog, to treat diabetes. Topics include the molecular structure of lispro insulin, immunologic concerns, and clinical applications and concerns. Another article deals with the use of troglitazone, a thiazolidinedione that improves insulin resistance without stimulating insulin secretion, to treat diabetes and the insulin resistance syndrome. Topics include the pathophysiology of impaired glucose tolerance and type 2 diabetes, the pathophysiological basis of pharmacological therapy, clinical studies, the effects of troglitazone on body weight and lipids, and the safety and adverse effects of the agent. An article on the use of combination oral agent and insulin therapy in patients who have type 2 diabetes includes discussions of the rationale for the use of combination therapy and the mechanism of action, efficacy, and side effects of various oral agents combined with insulin. The final article focuses on converting patients who have type 2 diabetes from insulin-requiring to noninsulin-requiring. Topics include the disadvantages of

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insulin utilization in people who have type 2 diabetes, once daily insulin and combination oral therapy, improved glycemic control on oral therapy, weight loss on combination oral therapy, oral monotherapy, and other potential drug combinations. •

Diabetes and How You Can Manage It Easily Source: San Diego, CA: H L Enterprises. 1993. (audiocassettes). Contact: Available from H L Enterprises. 12730 Carmel Country Road, Number 120, San Diego, CA 92130. (619) 792-8837. PRICE: $33.00. Summary: This set of four audiocassettes is designed to provide an overview of diabetes mellitus and its care. Topics include the importance of attitude; meal planning and food habits; medicines and exercise; and blood glucose, including monitoring and understanding hypoglycemia and hyperglycemia. The accompanying outline includes information on resources for further information.

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CHAPTER 8. PERIODICALS AND NEWS ON HYPERGLYCEMIA Overview In this chapter, we suggest a number of news sources and present various periodicals that cover hyperglycemia.

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

Hyperglycemia increases risk for vasospasm after subarachnoid hemorrhage Source: Reuters Medical News Date: March 01, 2004

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Hyperglycemia-activated uncoupling protein impairs glucose sensitivity Source: Reuters Industry Breifing Date: December 18, 2003

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Acute hyperglycemia tied to impaired ventricular function after MI Source: Reuters Medical News Date: November 14, 2003

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Hyperglycemia, not hypoinsulinemia, affects ICU outcomes Source: Reuters Medical News Date: October 14, 2003

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PARP inhibition blocks hyperglycemia-induced vascular damage Source: Reuters Medical News Date: October 02, 2003

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HIV/HCV coinfection and protease inhibitor treatment increase hyperglycemia risk Source: Reuters Medical News Date: August 28, 2003

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Admission hyperglycemia predicts a poor outcome in reperfused stroke patients Source: Reuters Medical News Date: May 23, 2003

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Insulin resistance, not hyperglycemia, predicts CAD in type 1 diabetes Source: Reuters Medical News Date: April 25, 2003

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Hyperglycemia appears to mediate vascular dysfunction in diabetes Source: Reuters Medical News Date: April 15, 2003

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Oxidative stress from hyperglycemia leads to neural tube defects in offspring Source: Reuters Industry Breifing Date: April 14, 2003

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Glipizide effectively controls postbreakfast hyperglycemia Source: Reuters Medical News Date: January 09, 2003

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Hyperglycemia in absence of diabetes diagnosis predicts poor outcome after AMI Source: Reuters Medical News Date: December 09, 2002

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Fasting hyperglycemia in gestational diabetes raises risk of infant malformation Source: Reuters Medical News Date: November 04, 2002

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High-intensity resistance training reduces hyperglycemia in older diabetics Source: Reuters Medical News Date: October 21, 2002

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Acute hyperglycemia adversely influences stroke outcomes Source: Reuters Medical News Date: July 11, 2002

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Helicobacter-induced gastritis increases hyperglycemia in diabetic mice Source: Reuters Medical News Date: June 12, 2002

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Clozapine use linked to onset of diabetes and hyperglycemia Source: Reuters Industry Breifing Date: January 28, 2002

Periodicals and News

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Postchallenge hyperglycemia common in type 2 diabetics Source: Reuters Medical News Date: October 24, 2001

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Hyperglycemia increases mortality risk in severely burned children Source: Reuters Medical News Date: October 10, 2001

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Acarbose may reduce hyperglycemia in patients with mild type 2 diabetes Source: Reuters Medical News Date: October 10, 2001

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Postchallenge hyperglycemia linked to increased mortality risk Source: Reuters Medical News Date: August 20, 2001

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Postprandial hyperglycemia common in diabetics Source: Reuters Medical News Date: June 26, 2001

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Hyperglycemia triggers expression of endothelin-1 through protein kinase C Source: Reuters Medical News Date: August 21, 2000

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Hyperglycemia linked to morbidity and mortality of myocardial infarction Source: Reuters Medical News Date: March 07, 2000

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Beta-blockers help prevent stress-induced hyperglycemia in diabetic dogs Source: Reuters Medical News Date: February 21, 2000

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Hyperglycemia common with severe head injury, associated with worse prognosis Source: Reuters Medical News Date: February 07, 2000

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Simvastatin beneficial in patients with coronary heart disease and mild hyperglycemia Source: Reuters Medical News Date: December 14, 1999

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The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name.

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Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “hyperglycemia” (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 “hyperglycemia” (or synonyms). If you know the name of a company that is relevant to hyperglycemia, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “hyperglycemia” (or synonyms).

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

Overcoming Obstacles to Exercise in the Child with Type 1 Diabetes Source: On the Cutting Edge. 22(6): 10-12. Winter 2001. Contact: Available from American Dietetic Association. 216 West Jackson Boulevard, Suite 800, Chicago, IL 60606-6995. (800) 877-4746. Summary: Children with type 1 diabetes need assistance in overcoming fears they may have in order to begin an exercise program. They need the knowledge to make appropriate adjustments in insulin and food so they can be successful and safe in an exercise regimen. Parents need to understand their responsibilities to educate others who may be involved in a child's care during a sport and to provide the needed diabetes

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supplies to ensure proper treatment of hypoglycemia (low levels of blood glucose) or hyperglycemia (high levels of blood glucose). This article reviews the benefits and risks of exercise and offers possible solutions to overcoming barriers that may hinder the implementation of a regular exercise regimen. The author focuses on those strategies that can help parents and children with diabetes begin a lifelong commitment to physical fitness. 1 table. 3 references. •

Childhood Obesity and the Emerging Epidemic of Type 2 Diabetes in Youth Source: On the Cutting Edge. 22(6):4-9. Winter 2001. Contact: Available from American Dietetic Association. 216 West Jackson Boulevard, Suite 800, Chicago, IL 60606-6995. (800) 877-4746. Summary: This article discusses the phenomenon of early onset of type 2 diabetes in children and adolescents, a condition that is increasing in prevalence. This observed increase is thought to be caused by societal factors that lead to sedentary lifestyles and increased prevalence of obesity. Metabolic and cardiovascular complications often associated with adult obesity have their onset in childhood. Hyperglycemia (high levels of blood glucose) can exist for years before diagnosis of type 2 diabetes is made and treatment is initiated. Children with type 2 diabetes are often asymptomatic at the time of diagnosis; therefore screening for this disorder in this high risk population is very important. The author addresses the metabolic effects of obesity in children, criteria for diagnosis of type 2 diabetes in youth, and treatment strategies. One sidebar describes the use of body mass index (BMI) and revised United States growth charts. 2 tables. 14 references.

Academic Periodicals covering Hyperglycemia Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to hyperglycemia. In addition to these sources, you can search for articles covering hyperglycemia 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 9. 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 hyperglycemia. 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 hyperglycemia. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The

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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to hyperglycemia: Antidiabetic Agents, Sulfonylurea •

Systemic - U.S. Brands: Amaryl; DiaBeta; Diabinese; Dymelor; Glucotrol; Glucotrol XL; Glynase PresTab; Micronase; Orinase; Tolinase http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202742.html

Metformin •

Systemic - U.S. Brands: Glucophage http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202756.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 adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee. If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

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APPENDICES

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

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute12: •

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

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

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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/

12

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

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

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

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

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

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

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

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

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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

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

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

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

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

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

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

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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.13 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:14 •

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/

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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/

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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

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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

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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

13

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). 14 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

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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 Gateway15 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.16 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “hyperglycemia” (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 22394 63 1008 68 495 24028

HSTAT17 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.18 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.19 Simply search by “hyperglycemia” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

15

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

16

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). 17 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 18 19

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 Biologists20 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.21 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.22 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/.

20 Adapted 21

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. 22 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 hyperglycemia 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 hyperglycemia. 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 hyperglycemia. 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 “hyperglycemia”:

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Other guides Diabetes http://www.nlm.nih.gov/medlineplus/diabetes.html Diabetes and Pregnancy http://www.nlm.nih.gov/medlineplus/diabetesandpregnancy.html Diabetic Diet http://www.nlm.nih.gov/medlineplus/diabeticdiet.html Diabetic Kidney Problems http://www.nlm.nih.gov/medlineplus/diabetickidneyproblems.html Juvenile Diabetes http://www.nlm.nih.gov/medlineplus/juvenilediabetes.html Tremor http://www.nlm.nih.gov/medlineplus/tremor.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 hyperglycemia. 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: •

Hyperglycemia (High Blood Glucose) Source: Cleveland, OH: Diabetes Association of Greater Cleveland. 2001. 2 p. Contact: Available from Diabetes Association of Greater Cleveland. 3601 South Green Road Suite 100, Cleveland, Ohio 44122. (216) 591-0800 Fax (216) 591-0320. E-mail: [email protected]. Website: www.dagc.org. PRICE: Single copy free. Summary: This fact sheet describes hyperglycemia, high blood glucose levels, a common problem associated with diabetes. The fact sheet defines hyperglycemia, then notes the symptoms of the problem. The fact sheet then discusses blood glucose testing, recordkeeping, determining how blood glucose levels may have gotten high, and management strategies. Readers are advised to adjust their food intake, increase the amount of physical activity they do, lose any extra weight, treat illness and infections quickly, reduce stress, and work in close tandem with a health care provider for adjusting diabetes medications. The fact sheet concludes with the contact information

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for the Diabetes Association of Greater Cleveland (www.dagc.org). 1 figure. 2 references. •

Hyperglycemia: High Blood Sugar Source: Lexington, KY: Lexington-Fayette County Health Department. 1995. 2 p. Contact: Available from Lexington-Fayette County Health Department. Division of Nutrition and Health Education, 650 Newtown Pike, Lexington, KY 40508. (606) 2882333. Fax (606) 288-2359. PRICE: $15.00 per 50 copies plus shipping. Summary: This general introduction to hyperglycemia (high blood glucose) is one in a series of 22 diabetes education materials that combine practical tips and humorous drawings with current diabetes information. The series is written at a sixth grade reading level and is designed to teach and motivate patients to take good care of themselves. The fact sheet provides a description of the causes of hyperglycemia, including too much food, missing one's usual exercise, not taking insulin or diabetes pills, not getting enough insulin or diabetes pills, and sickness or stress. The fact sheet illustrates how people may feel when their blood glucose levels are high, including being thirsty; having dry, itchy skin; feeling very hungry; needing to go to the bathroom a lot; having blurry vision; and being tired. The fact sheet provides practical recommendations for dealing with hyperglycemia, including steps to take to prevent it. The National Guideline Clearinghouse™

The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “hyperglycemia” (or synonyms). The following was recently posted: •

AACE medical guidelines for clinical practice for the diagnosis and treatment of dyslipidemia and prevention of atherogenesis Source: American Association of Clinical Endocrinologists - Medical Specialty Society; 2000 Mar-April; 52 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2199&nbr=1425&a mp;string=hyperglycemia

•

ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Source: American College of Cardiology Foundation - Medical Specialty Society; 2000 (revised online 2002 Mar); 95 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3190&nbr=2416&a mp;string=hyperglycemia

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Altered mental states Source: American Health Care Association - Professional Association; 1998 (reviewed 2003); 20 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1804&nbr=1030&a mp;string=hyperglycemia

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American Gastroenterological Association medical position statement: evaluation and management of occult and obscure gastrointestinal bleeding Source: American Gastroenterological Association - Medical Specialty Society; 1999 July 18 (reviewed 2001); 4 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3062&nbr=2288&a mp;string=hyperglycemia

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American Gastroenterological Association medical position statement: parenteral nutrition Source: American Gastroenterological Association - Medical Specialty Society; 2001 May 18; 4 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3056&nbr=2282&a mp;string=hyperglycemia

•

Apnea of prematurity Source: National Association of Neonatal Nurses - Professional Association; 1999; 22 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2147&nbr=1373&a mp;string=hyperglycemia

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ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery Source: American Society of Health-System Pharmacists - Professional Association; 1999; 36 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1875&nbr=1101&a mp;string=hyperglycemia

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Assessment and management of acute pain Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 2000 October (revised 2002 Oct); 74 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3500&nbr=2726&a mp;string=hyperglycemia

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Benefits and risks of controlling blood glucose levels in patients with type 2 diabetes mellitus Source: American Academy of Family Physicians - Medical Specialty Society; 1999 April; 39 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2377&nbr=1603&a mp;string=hyperglycemia

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Care of children with diabetes in the school and day care setting Source: American Diabetes Association - Professional Association; 1998 (revised 2000; republished 2003 Jan); 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3586&nbr=2812&a mp;string=hyperglycemia

•

Clinical practice guideline for the management of postoperative pain Source: Department of Defense - Federal Government Agency [U.S.]; 2001 July (revised 2002 May); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3284&nbr=2510&a mp;string=hyperglycemia

•

Diabetic foot disorders: a clinical practice guideline. Source: American College of Foot and Ankle Orthopedics and Medicine - Professional Association; 2000 September; 60 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2892&nbr=2118&a mp;string=hyperglycemia

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Diabetic nephropathy Source: American Diabetes Association - Professional Association; 1996 November (revised 2001 October; republished 2003 Jan); 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3578&nbr=2804&a mp;string=hyperglycemic

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Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease Source: American College of Chest Physicians - Medical Specialty Society; 2001 April 3; 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2762&nbr=1988&a mp;string=hyperglycemia

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Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications Source: American Diabetes Association - Professional Association; 2001 October (republished 2003 Jan); 11 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3568&nbr=2794&a mp;string=hyperglycemia

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Gestational diabetes mellitus Source: American Diabetes Association - Professional Association; 1986 (revised 2000; republished 2003 Jan); 3 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3580&nbr=2806&a mp;string=hyperglycemia

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Gestational diabetes practice guidelines Source: International Diabetes Center - Private Nonprofit Organization; 2000; 33 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2563&nbr=1789&a mp;string=hyperglycemia

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Guideline for prevention of surgical site infection, 1999 Source: Centers for Disease Control and Prevention - Federal Government Agency [U.S.]; 1999 April; 33 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1845&nbr=1071&a mp;string=hyperglycemia

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Herniated disc. In: North American Spine Society phase III clinical guidelines for multidisciplinary spine care specialists Source: North American Spine Society - Medical Specialty Society; 2000; 104 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2803&nbr=2029&a mp;string=hyperglycemia

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HIV disease management Source: University of Texas Medical Branch Correctional Managed Care - Academic Institution; 1996 September (revised 2002 Jul); 7 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3477&nbr=2703&a mp;string=hyperglycemia

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Hyperglycemic crises in patients with diabetes mellitus Source: American Diabetes Association - Professional Association; 2000 October (revised 2001; republished 2003 Jan); 9 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3582&nbr=2808&a mp;string=hyperglycemia

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Hyperlipidemia Source: University of Texas Medical Branch Correctional Managed Care - Academic Institution; 1998 February (revised 2002 Jul); 12 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3552&nbr=2778&a mp;string=hyperglycemia

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Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology Source: American Society of Hematology - Medical Specialty Society; 1996 January 25 (reviewed 2001) http://www.guideline.gov/summary/summary.aspx?doc_id=1922&nbr=1148&a mp;string=hyperglycemia

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Inpatient management guidelines for people with diabetes Source: American Healthways, Inc - Public For Profit Organization; 1999 (revised 2002 Mar); 18 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3217&nbr=2443&a mp;string=hyperglycemic

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Knee pain or swelling: acute or chronic Source: University of Michigan Health System - Academic Institution; 1997 November (revised 2002 Aug); 13 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3540&nbr=2766&a mp;string=hyperglycemia

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Management of chronic kidney disease and pre-ESRD in the primary care setting Source: Department of Defense - Federal Government Agency [U.S.]; 2000 November; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3099&nbr=2325&a mp;string=hyperglycemia

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Management of diabetes in correctional institutions Source: American Diabetes Association - Professional Association; 1989 (revised 2000; republished 2003 Jan); 2 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3585&nbr=2811&a mp;string=hyperglycemia

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Management of dyslipidemia in adults with diabetes Source: American Diabetes Association - Professional Association; 1997 November (reviewed 2000; republished 2003 Jan); 4 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3574&nbr=2800&a mp;string=hyperglycemia

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Management of type 2 diabetes mellitus Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1996 March (revised 2002 Sep); 77 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3499&nbr=2725&a mp;string=hyperglycemia

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Massachusetts guidelines for adult diabetes care Source: Massachusetts Department of Public Health, Bureau of Family and Community Health, Diabetes Control Program - State/Local Government Agency [U.S.]; 1999 June (revised 2001 Jun); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3429&nbr=2655&a mp;string=hyperglycemia

•

North American Spine Society Phase III: clinical guidelines for multidisciplinary spine care specialists. Spinal stenosis version 1.0. Source: North American Spine Society - Medical Specialty Society; 2002; 91 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3609&nbr=2835&a mp;string=hyperglycemia

•

Nutrition practice guidelines for gestational diabetes mellitus Source: American Dietetic Association - Professional Association; 2001 September; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3294&nbr=2520&a mp;string=hyperglycemia

•

Nutrition practice guidelines for type 1 and type 2 diabetes mellitus Source: American Dietetic Association - Professional Association; 2001 December; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3296&nbr=2522&a mp;string=hyperglycemia

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Pancreas transplantation for patients with type 1 diabetes Source: American Diabetes Association - Professional Association; 1999 November (republished 2003 Jan); 1 page http://www.guideline.gov/summary/summary.aspx?doc_id=3583&nbr=2809&a mp;string=hyperglycemia

•

Physical activity in the prevention, treatment and rehabilitation of diseases Source: Finnish Medical Society Duodecim - Professional Association; 2002 May 7; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3398&nbr=2624&a mp;string=hyperglycemia

•

Practice management guidelines for nutritional support of the trauma patient Source: Eastern Association for the Surgery of Trauma - Professional Association; 2001; 112 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2961&nbr=2187&a mp;string=hyperglycemia

•

Preconception care of women with diabetes Source: American Diabetes Association - Professional Association; 1995 (revised 2000; republished 2003 Jan); 3 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3577&nbr=2803&a mp;string=hyperglycemic

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Primary care guidelines for the management of core aspects of diabetes care Source: New Zealand Guidelines Group - Private Nonprofit Organization; 2000 June; 19 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3110&nbr=2336&a mp;string=hyperglycemia

•

Public Health Service Task Force recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States Source: Centers for Disease Control and Prevention - Federal Government Agency [U.S.]; 1998 January 30 (revised 2003 November 26); 46 pages http://www.guideline.gov/summary/summary.aspx?doc_id=4378&nbr=3300&a mp;string=hyperglycemia

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Screening for type 2 diabetes mellitus in adults: recommendations and rationale Source: United States Preventive Services Task Force - Independent Expert Panel; 1996 (revised 2003 Feb); 15 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3523&nbr=2749&a mp;string=hyperglycemia

•

Spondylolysis, lytic spondylolisthesis and degenerative spondylolisthesis (SLD). In: North American Spine Society phase III clinical guidelines for multidisciplinary spine care specialists Source: North American Spine Society - Medical Specialty Society; 2000; 106 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2804&nbr=2030&a mp;string=hyperglycemia

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Standards of medical care for patients with diabetes mellitus Source: American Diabetes Association - Professional Association; 1988 (revised 2002 October; republished 2003 Jan); 18 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3567&nbr=2793&a mp;string=hyperglycemic

•

The management of diabetes mellitus in the primary care setting Source: Department of Defense - Federal Government Agency [U.S.]; 1999 December; 147 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2583&nbr=1809&a mp;string=hyperglycemia

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The prevention or delay of type 2 diabetes Source: American Diabetes Association - Professional Association; 2003 January; 8 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3569&nbr=2795&a mp;string=hyperglycemia

•

Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Source: National Cholesterol Education Program - Federal Government Agency [U.S.]; 1993 September (updated 2001); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=2969&nbr=2195&a mp;string=hyperglycemia

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Translation of the diabetes nutrition recommendations for health care institutions Source: American Diabetes Association - Professional Association; 1996 August (reviewed 1997; republished 2003 Jan); 3 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3570&nbr=2796&a mp;string=hyperglycemia

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Type I diabetes practice guidelines Source: International Diabetes Center - Private Nonprofit Organization; 2000; 39 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2561&nbr=1787&a mp;string=hyperglycemia

•

Universe of Florida patients with acute ischemic brain attack Source: Florida Agency for Health Care Administration - State/Local Government Agency [U.S.]; 1999 March 5; 16 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1801&nbr=1027&a mp;string=hyperglycemia

•

VHA/DOD clinical practice guideline for the management of chronic obstructive pulmonary disease. Source: Department of Defense - Federal Government Agency [U.S.]; 1999 August; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=2584&nbr=1810&a mp;string=hyperglycemia 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 hyperglycemia. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

•

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

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•

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

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

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

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

•

WebMD®Health: 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 hyperglycemia. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with hyperglycemia. 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 hyperglycemia. 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 “hyperglycemia” (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 “hyperglycemia”. Type the following hyperlink into

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your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “hyperglycemia” (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 “hyperglycemia” (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.23

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

23

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)24: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

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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

•

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)

•

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/

•

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/

24

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

Finding Medical Libraries 211 •

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

•

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

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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

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

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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

•

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/

•

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/

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

Finding Medical Libraries 213 •

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

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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•

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

•

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

•

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

•

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

215

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

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

•

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

•

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

•

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

•

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

•

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

•

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

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

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

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

•

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

•

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

•

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

217

HYPERGLYCEMIA 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 fat: Fat (adipose tissue) that is centrally distributed between the thorax and pelvis and that induces greater health risk. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak antiinflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [NIH] Acetic Acids: Acetic acid and its derivatives which may be formed by substitution reactions. Mono- and di-substituted, as well as halogenated compounds have been synthesized. [NIH] Acetohexamide: A sulfonylurea hypoglycemic agent that is metabolized in the liver to 1hydrohexamide. [NIH] Acetone: A colorless liquid used as a solvent and an antiseptic. It is one of the ketone bodies produced during ketoacidosis. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Activities of Daily Living: The performance of the basic activities of self care, such as dressing, ambulation, eating, etc., in rehabilitation. [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

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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] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [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] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH] Adenylate Kinase: An enzyme that catalyzes the phosphorylation of AMP to ADP in the presence of ATP or inorganic triphosphate. EC 2.7.4.3. [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] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal insufficiency: The reduced secretion of adrenal glands. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] 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

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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] Age-Adjusted: Summary measures of rates of morbidity or mortality in a population using statistical procedures to remove the effect of age differences in populations that are being compared. Age is probably the most important and the most common variable in determining the risk of morbidity and mortality. [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] Agoraphobia: Obsessive, persistent, intense fear of open places. [NIH] Akathisia: 1. A condition of motor restlessness in which there is a feeling of muscular quivering, an urge to move about constantly, and an inability to sit still, a common extrapyramidal side effect of neuroleptic drugs. 2. An inability to sit down because of intense anxiety at the thought of doing so. [EU] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehyde Dehydrogenase: An enzyme that oxidizes an aldehyde in the presence of NAD+ and water to an acid and NADH. EC 1.2.1.3. Before 1978, it was classified as EC 1.1.1.70. [NIH]

Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Aldose Reductase Inhibitor: A class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes. Aldose reductase is an enzyme that is normally present in the eye and in many other parts of the body. It helps change glucose (sugar) into a sugar alcohol called sorbitol. Too much sorbitol trapped in eye and nerve cells can damage these cells, leading to retinopathy and neuropathy. Drugs that prevent or slow (inhibit) the action of aldose reductase are being studied as a way to prevent or delay these complications of diabetes. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH]

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Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Amylase: An enzyme that helps the body digest starches. [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] 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] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses.

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[NIH]

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] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] 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] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] 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] Angiotensin converting enzyme inhibitor: A drug used to decrease pressure inside blood vessels. [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] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory

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and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anorexia Nervosa: The chief symptoms are inability to eat, weight loss, and amenorrhea. [NIH]

Anovulation: Suspension or cessation of ovulation in animals and humans. [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] 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] Antidiabetic Agent: A substance that helps a person with diabetes control the level of glucose (sugar) in the blood so that the body works as it should. [NIH] Antidiuretic: Suppressing the rate of urine formation. [EU] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]

Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [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] Antipsychotic: Effective in the treatment of psychosis. Antipsychotic drugs (called also neuroleptic drugs and major tranquilizers) are a chemically diverse (including

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phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines, and diphenylbutylpiperidines) but pharmacologically similar class of drugs used to treat schizophrenic, paranoid, schizoaffective, and other psychotic disorders; acute delirium and dementia, and manic episodes (during induction of lithium therapy); to control the movement disorders associated with Huntington's chorea, Gilles de la Tourette's syndrome, and ballismus; and to treat intractable hiccups and severe nausea and vomiting. Antipsychotic agents bind to dopamine, histamine, muscarinic cholinergic, a-adrenergic, and serotonin receptors. Blockade of dopaminergic transmission in various areas is thought to be responsible for their major effects : antipsychotic action by blockade in the mesolimbic and mesocortical areas; extrapyramidal side effects (dystonia, akathisia, parkinsonism, and tardive dyskinesia) by blockade in the basal ganglia; and antiemetic effects by blockade in the chemoreceptor trigger zone of the medulla. Sedation and autonomic side effects (orthostatic hypotension, blurred vision, dry mouth, nasal congestion and constipation) are caused by blockade of histamine, cholinergic, and adrenergic receptors. [EU] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Apathy: Lack of feeling or emotion; indifference. [EU] 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] Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [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] Appendicitis: Acute inflammation of the vermiform appendix. [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] Arachidonate 12-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 12-hydroperoxyarachidonate (12-HPETE) which is itself rapidly converted by a peroxidase to 12-hydroxy-5,8,10,14-eicosatetraenoate (12-HETE). The 12-hydroperoxides are preferentially formed in platelets. EC 1.13.11.31. [NIH] Arachidonate 15-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 15-hydroperoxyarachidonate (15-HPETE) which is rapidly converted to 15-hydroxy5,8,11,13-eicosatetraenoate (15-HETE). The 15-hydroperoxides are preferentially formed in neutrophils and lymphocytes. EC 1.13.11.33. [NIH] Arachidonate Lipoxygenases: Enzymes catalyzing the oxidation of arachidonic acid to

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hydroperoxyarachidonates (HPETES). These products are then rapidly converted by a peroxidase to hydroxyeicosatetraenoic acids (HETES). The positional specificity of the enzyme reaction varies from tissue to tissue. The final lipoxygenase pathway leads to the leukotrienes. EC 1.13.11.- . [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] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] 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 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] Asparaginase: A hydrolase enzyme that converts L-asparagine and water to L-aspartate and NH3. EC 3.5.1.1. [NIH] 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] Atrial: Pertaining to an atrium. [EU] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] 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] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that

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produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] 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] Autosuggestion: Suggestion coming from the subject himself. [NIH] Back Pain: Acute or chronic pain located in the posterior regions of the trunk, including the thoracic, lumbar, sacral, or adjacent regions. [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] Bacterial Physiology: Physiological processes and activities of 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] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of

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donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [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] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benign prostatic hyperplasia: A benign (noncancerous) condition in which an overgrowth of prostate tissue pushes against the urethra and the bladder, blocking the flow of urine. Also called benign prostatic hypertrophy or BPH. [NIH] Benzoic Acid: A fungistatic compound that is widely used as a food preservative. It is conjugated to glycine in the liver and excreted as hippuric acid. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] 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 Ducts: Tubes that carry bile from the liver to the gallbladder for storage and to the small intestine for use in digestion. [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] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] 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] 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

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constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bladder: The organ that stores urine. [NIH] 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 Coagulation Factors: Endogenous substances, usually proteins, that are involved in the blood coagulation process. [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] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blotting and transferred to strips of nitrocellulose paper. The blots are then detected by radiolabeled antibody probes. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bolus injection: The injection of a drug (or drugs) in a high quantity (called a bolus) at once, the opposite of gradual administration (as in intravenous infusion). [EU] 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 Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion.

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There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [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] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchiseptica: A small, gram-negative, motile bacillus. A normal inhabitant of the respiratory tract in man, dogs, and pigs, but is also associated with canine infectious tracheobronchitis and atrophic rhinitis in pigs. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchodilator: A drug that relaxes the smooth muscles in the constricted airway. [NIH] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge of electricity. [NIH] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Caesarean section: A surgical incision through the abdominal and uterine walls in order to deliver a baby. [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] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [NIH] Caloric intake: Refers to the number of calories (energy content) consumed. [NIH] Canonical: A particular nucleotide sequence in which each position represents the base more often found when many actual sequences of a given class of genetic elements are

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compared. [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] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Captopril: A potent and specific inhibitor of peptidyl-dipeptidase A. It blocks the conversion of angiotensin I to angiotensin II, a vasoconstrictor and important regulator of arterial blood pressure. Captopril acts to suppress the renin-angiotensin system and inhibits pressure responses to exogenous angiotensin. [NIH] Carbenoxolone: An agent derived from licorice root. It is used for the treatment of digestive tract ulcers, especially in the stomach. Antidiuretic side effects are frequent, but otherwise the drug is low in toxicity. [NIH] Carbogen: An inhalant of oxygen and carbon dioxide that increases the sensitivity of tumor cells to the effects of radiation therapy. [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] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoid: A type of tumor usually found in the gastrointestinal system (most often in the appendix), and sometimes in the lungs or other sites. Carcinoid tumors are usually benign. [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] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiotoxic: Having a poisonous or deleterious effect upon the heart. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH]

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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] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [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] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be 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 Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH]

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Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell Extracts: Preparations of cell constituents or subcellular materials, isolates, or substances. [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 proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] 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] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Centromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellar Diseases: Diseases that affect the structure or function of the cerebellum. Cardinal manifestations of cerebellar dysfunction include dysmetria, gait ataxia, and muscle hypotonia. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Arteries: The arteries supplying the cerebral cortex. [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]

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Chemoreceptor: A receptor adapted for excitation by chemical substances, e.g., olfactory and gustatory receptors, or a sense organ, as the carotid body or the aortic (supracardial) bodies, which is sensitive to chemical changes in the blood stream, especially reduced oxygen content, and reflexly increases both respiration and blood pressure. [EU] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chest Pain: Pressure, burning, or numbness in the chest. [NIH] 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] Cholera Toxin: The enterotoxin from Vibrio cholerae. It is a protein that consists of two major components, the heavy (H) or A peptide and the light (L) or B peptide or choleragenoid. The B peptide anchors the protein to intestinal epithelial cells, while the A peptide, enters the cytoplasm, and activates adenylate cyclase, and production of cAMP. Increased levels of cAMP are thought to modulate release of fluid and electrolytes from intestinal crypt cells. [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] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chorea: Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. [NIH] Choreatic Disorders: Acquired and hereditary conditions which feature chorea as a primary manifestation of the disease process. [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] Chromium: A trace element that plays a role in glucose metabolism. It has the atomic symbol Cr, atomic number 24, and atomic weight 52. According to the Fourth Annual Report on Carcinogens (NTP85-002,1985), chromium and some of its compounds have been listed as known carcinogens. [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]

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Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [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] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Ciliary Neurotrophic Factor: A neurotrophic factor that promotes the survival of various neuronal cell types and may play an important role in the injury response in the nervous system. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] Circadian Rhythm: The regular recurrence, in cycles of about 24 hours, of biological processes or activities, such as sensitivity to drugs and stimuli, hormone secretion, sleeping, feeding, etc. This rhythm seems to be set by a 'biological clock' which seems to be set by recurring daylight and darkness. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] 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] Clozapine: A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a

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sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] 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] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [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] 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] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Common Bile Duct: The largest biliary duct. It is formed by the junction of the cystic duct and the hepatic duct. [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

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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] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Concretion: Minute, hard, yellow masses found in the palpebral conjunctivae of elderly people or following chronic conjunctivitis, composed of the products of cellular degeneration retained in the depressions and tubular recesses in the conjunctiva. [NIH] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] 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] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU]

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Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contralateral: Having to do with the opposite side of the body. [NIH] 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] Contusion: A bruise; an injury of a part without a break in the skin. [EU] Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneal Neovascularization: New blood vessels originating from the corneal veins and extending from the limbus into the adjacent corneal stroma. These vessels may lie in the superficial and/or deep corneal stroma. Neovascularization is a sequel to numerous inflammatory diseases of the ocular anterior segment, including trachoma, viral interstitial keratitis, microbial keratoconjunctivitis, and the immune response elicited by corneal transplantation. [NIH] Corneal Stroma: The lamellated connective tissue constituting the thickest layer of the cornea between the Bowman and Descemet membranes. [NIH] Corneal Transplantation: Partial or total replacement of the cornea from one human or animal to another. [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

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pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary Circulation: The circulation of blood through the coronary vessels of the heart. [NIH]

Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Coronary Vasospasm: Spasm of the large- or medium-sized coronary arteries. [NIH] Coronary Vessels: The veins and arteries of the heart. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cowpox: A mild, eruptive skin disease of milk cows caused by cowpox virus, with lesions occurring principally on the udder and teats. Human infection may occur while milking an infected animal. [NIH] Cowpox Virus: A species of orthopoxvirus that is the etiologic agent of cowpox. It is closely related to but antigenically different from vaccina virus. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] 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

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homologous chromosomes during meiosia, forming a chiasma. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] 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] Cytotoxic: Cell-killing. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] Day Care: Institutional health care of patients during the day. The patients return home at night. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [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] Decompensation: Failure of compensation; cardiac decompensation is marked by dyspnea, venous engorgement, and edema. [EU] Decubitus: An act of lying down; also the position assumed in lying down. [EU] Decubitus Ulcer: An ulceration caused by prolonged pressure in patients permitted to lie too still for a long period of time. The bony prominences of the body are the most frequently affected sites. The ulcer is caused by ischemia of the underlying structures of the skin, fat, and muscles as a result of the sustained and constant pressure. [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] Delirium: (DSM III-R) an acute, reversible organic mental disorder characterized by reduced ability to maintain attention to external stimuli and disorganized thinking as manifested by rambling, irrelevant, or incoherent speech; there are also a reduced level of consciousness, sensory misperceptions, disturbance of the sleep-wakefulness cycle and level of psychomotor activity, disorientation to time, place, or person, and memory impairment.

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Delirium may be caused by a large number of conditions resulting in derangement of cerebral metabolism, including systemic infection, poisoning, drug intoxication or withdrawal, seizures or head trauma, and metabolic disturbances such as hypoxia, hypoglycaemia, fluid, electrolyte, or acid-base imbalances, or hepatic or renal failure. Called also acute confusional state and acute brain syndrome. [EU] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [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] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]

Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Care: The total of dental diagnostic, preventive, and restorative services provided to meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Dermal: Pertaining to or coming from the skin. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which

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results in a change in the social, political, and economic structures. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetes, Gestational: Either symptomatic diabetes or impaired glucose tolerance induced by pregnancy but resolved at the end of pregnancy. It does not include previously diagnosed diabetics who become pregnant (pregnancy in diabetics). [NIH] Diabetic Foot: Ulcers of the foot as a complication of diabetes. Diabetic foot, often with infection, is a common serious complication of diabetes and may require hospitalization and disfiguring surgery. The foot ulcers are probably secondary to neuropathies and vascular problems. [NIH] Diabetic Ketoacidosis: Complication of diabetes resulting from severe insulin deficiency coupled with an absolute or relative increase in glucagon concentration. The metabolic acidosis is caused by the breakdown of adipose stores and resulting increased levels of free fatty acids. Glucagon accelerates the oxidation of the free fatty acids producing excess ketone bodies (ketosis). [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [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] Diaphoresis: Perspiration, especially profuse perspiration. Called also sudoresis. [EU] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastolic: Of or pertaining to the diastole. [EU] 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]

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 system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [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] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH]

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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] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [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] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Dislocation: The displacement of any part, more especially of a bone. Called also luxation. [EU]

Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Disparity: Failure of the two retinal images of an object to fall on corresponding retinal points. [NIH] Disposition: A tendency either physical or mental toward certain diseases. [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] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [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] 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]

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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] 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] Dysmenorrhea: Painful menstruation. [NIH] Dysphoric: A feeling of unpleasantness and discomfort. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystonia: Disordered tonicity of muscle. [EU] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eating Disorders: A group of disorders characterized by physiological and psychological disturbances in appetite or food intake. [NIH] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]

Ectopic: Pertaining to or characterized by ectopia. [EU] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [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]

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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]

Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryo Transfer: Removal of a mammalian embryo from one environment and replacement in the same or a new environment. The embryo is usually in the pre-nidation phase, i.e., a blastocyst. The process includes embryo or blastocyst transplantation or transfer after in vitro fertilization and transfer of the inner cell mass of the blastocyst. It is not used for transfer of differentiated embryonic tissue, e.g., germ layer cells. [NIH] Emollient: Softening or soothing; called also malactic. [EU] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]

Encephalocele: Cerebral tissue herniation through a congenital or acquired defect in the skull. The majority of congenital encephaloceles occur in the occipital or frontal regions. Clinical features include a protuberant mass that may be pulsatile. The quantity and location of protruding neural tissue determines the type and degree of neurologic deficit. Visual defects, psychomotor developmental delay, and persistent motor deficits frequently occur. [NIH]

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 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] 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] Endonucleases: Enzymes that catalyze the hydrolysis of the internal bonds and thereby the formation of polynucleotides or oligonucleotides from ribo- or deoxyribonucleotide chains. EC 3.1.-. [NIH]

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Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [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] Energetic: Exhibiting energy : strenuous; operating with force, vigour, or effect. [EU] 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] Energy Intake: Total number of calories taken in daily whether ingested or by parenteral routes. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enteric-coated: A term designating a special coating applied to tablets or capsules which prevents release and absorption of their contents until they reach the intestines. [EU] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] 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 health-

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related event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] 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] 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] Equipment and Supplies: Expendable and nonexpendable equipment, supplies, apparatus, and instruments that are used in diagnostic, surgical, therapeutic, scientific, and experimental procedures. [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] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Escalation: Progressive use of more harmful drugs. [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] Estrogens: A class of sex hormones associated with the development and maintenance of secondary female sex characteristics and control of the cyclical changes in the reproductive cycle. They are also required for pregnancy maintenance and have an anabolic effect on protein metabolism and water retention. [NIH] Estrone: 3-Hydroxyestra-1,3,5(10)-trien-17-one. A metabolite of estradiol but possessing less biological activity. It is found in the urine of pregnant women and mares, in the human

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placenta, and in the urine of bulls and stallions. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), estrone may reasonably be anticipated to be a carcinogen (Merck, 11th ed). [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] 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] Excrete: To get rid of waste from the body. [NIH] Exercise Therapy: Motion of the body or its parts to relieve symptoms or to improve function, leading to physical fitness, but not physical education and training. [NIH] 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] Expiration: The act of breathing out, or expelling air from the lungs. [EU] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [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] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [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]

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Faecal: Pertaining to or of the nature of feces. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] 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] Fertilization in Vitro: Fertilization of an egg outside the body when the egg is normally fertilized in the body. [NIH] Fetal Blood: Blood of the fetus. Exchange of nutrients and waste between the fetal and maternal blood occurs via the placenta. The cord blood is blood contained in the umbilical vessels at the time of delivery. [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] Fibrillation: A small, local, involuntary contraction of muscle, invisible under the skin, resulting from spontaneous activation of single muscle cells or muscle fibres. [EU] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [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 other enzymes yields different fibrinogen degradation products. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibronectins: Glycoproteins found on the surfaces of cells, particularly in fibrillar structures. The proteins are lost or reduced when these cells undergo viral or chemical transformation. They are highly susceptible to proteolysis and are substrates for activated blood coagulation factor VIII. The forms present in plasma are called cold-insoluble globulins. [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] Fluid Therapy: Therapy whose basic objective is to restore the volume and composition of the body fluids to normal with respect to water-electrolyte balance. Fluids may be administered intravenously, orally, by intermittent gavage, or by hypodermoclysis. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Food Habits: Acquired or learned food preferences. [NIH]

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Food Preferences: The selection of one food over another. [NIH] Foot Care: Taking special steps to avoid foot problems such as sores, cuts, bunions, and calluses. Good care includes daily examination of the feet, toes, and toenails and choosing shoes and socks or stockings that fit well. People with diabetes have to take special care of their feet because nerve damage and reduced blood flow sometimes mean they will have less feeling in their feet than normal. They may not notice cuts and other problems as soon as they should. [NIH] Foot Ulcer: Lesion on the surface of the skin of the foot, usually accompanied by inflammation. The lesion may become infected or necrotic and is frequently associated with diabetes or leprosy. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Forskolin: Potent activator of the adenylate cyclase system and the biosynthesis of cyclic AMP. From the plant Coleus forskohlii. Has antihypertensive, positive ionotropic, platelet aggregation inhibitory, and smooth muscle relaxant activities; also lowers intraocular pressure and promotes release of hormones from the pituitary gland. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Fructosamine: An amino sugar formed when glucose non-enzymatically reacts with the Nterminal amino group of proteins. The fructose moiety is dervied from glucose by the "classical" Amadori rearrangement. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Functional magnetic resonance imaging: A noninvasive tool used to observe functioning in the brain or other organs by detecting changes in chemical composition, blood flow, or both. [NIH]

Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungistatic: Inhibiting the growth of fungi. [EU] GABA: The most common inhibitory neurotransmitter in the central nervous system. [NIH] Galanin: A neurotransmitter. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous

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capsule enclosing a clear mucinous fluid. [EU] Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Emptying: The evacuation of food from the stomach into the duodenum. [NIH] Gastric Mucosa: Surface epithelium in the stomach that invaginates into the lamina propria, forming gastric pits. Tubular glands, characteristic of each region of the stomach (cardiac, gastric, and pyloric), empty into the gastric pits. The gastric mucosa is made up of several different kinds of cells. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastritis: Inflammation of the stomach. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastroparesis: Nerve or muscle damage in the stomach. Causes slow digestion and emptying, vomiting, nausea, or bloating. Also called delayed gastric emptying. [NIH] Gavage: Feeding by a tube passed into the stomach; called also tube feeding. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [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 Counseling: Advising families of the risks involved pertaining to birth defects, in order that they may make an informed decision on current or future pregnancies. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] 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

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fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gestational Age: Age of the conceptus. In humans, this may be assessed by medical history, physical examination, early immunologic pregnancy tests, radiography, ultrasonography, and amniotic fluid analysis. [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] Gliclazide: An oral sulfonylurea hypoglycemic agent which stimulates insulin secretion. [NIH]

Glipizide: An oral hypoglycemic agent which is rapidly absorbed and completely metabolized. [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] Glomeruli: Plural of glomerulus. [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] Glottis: The vocal apparatus of the larynx, consisting of the true vocal cords (plica vocalis) and the opening between them (rima glottidis). [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucokinase: A group of enzymes that catalyzes the conversion of ATP and D-glucose to ADP and D-glucose 6-phosphate. They are found in invertebrates and microorganisms and are highly specific for glucose. (Enzyme Nomenclature, 1992) EC 2.7.1.2. [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 Clamp Technique: Maintenance of a constant blood glucose level by perfusion or infusion with glucose or insulin. It is used for the study of metabolic rates (e.g., in glucose, lipid, amino acid metabolism) at constant glucose concentration. [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

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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] Glucose-6-Phosphatase: An enzyme that catalyzes the conversion of D-glucose 6-phosphate and water to D-glucose and orthophosphate. EC 3.1.3.9. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamate Decarboxylase: A pyridoxal-phosphate protein that catalyzes the alphadecarboxylation of L-glutamic acid to form gamma-aminobutyric acid and carbon dioxide. The enzyme is found in bacteria and in invertebrate and vertebrate nervous systems. It is the rate-limiting enzyme in determining gaba levels in normal nervous tissues. The brain enzyme also acts on L-cysteate, L-cysteine sulfinate, and L-aspartate. EC 4.1.1.15. [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]

Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Glyburide: An antidiabetic sulfonylurea derivative with actions similar to those of chlorpropamide. [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 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] Glycogen Synthase: An enzyme that catalyzes the transfer of D-glucose from UDPglucose into 1,4-alpha-D-glucosyl chains. EC 2.4.1.11. [NIH] Glycolysis: The pathway by which glucose is catabolized into two molecules of pyruvic acid with the generation of ATP. [NIH]

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Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [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] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Glycosuria: The presence of glucose in the urine; especially the excretion of an abnormally large amount of sugar (glucose) in the urine, i.e., more than 1 gm. in 24 hours. [EU] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadorelin: A decapeptide hormone released by the hypothalamus. It stimulates the synthesis and secretion of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. [NIH] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [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]

Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [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] 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]

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Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] 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] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Care Costs: The actual costs of providing services related to the delivery of health care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Health Expenditures: The amounts spent by individuals, groups, nations, or private or public organizations for total health care and/or its various components. These amounts may or may not be equivalent to the actual costs (health care costs) and may or may not be shared among the patient, insurers, and/or employers. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartburn: Substernal pain or burning sensation, usually associated with regurgitation of gastric juice into the esophagus. [NIH] Helix-loop-helix: Regulatory protein of cell cycle. [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 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] Hemorrhage: Bleeding or escape of blood from a vessel. [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]

Hepatic: Refers to the liver. [NIH]

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Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocyte: A liver cell. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] High-density lipoproteins: Lipoproteins that contain a small amount of cholesterol and carry cholesterol away from body cells and tissues to the liver for excretion from the body. Low-level HDL increases the risk of heart disease, so the higher the HDL level, the better. The HDL component normally contains 20 to 30 percent of total cholesterol, and HDL levels are inversely correlated with coronary heart disease risk. [NIH] Hirsutism: Excess hair in females and children with an adult male pattern of distribution. The concept does not include hypertrichosis, which is localized or generalized excess hair. [NIH]

Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Histocompatibility Antigens: A group of antigens that includes both the major and minor histocompatibility antigens. The former are genetically determined by the major histocompatibility complex. They determine tissue type for transplantation and cause allograft rejections. The latter are systems of allelic alloantigens that can cause weak transplant rejection. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Holidays: Days commemorating events. Holidays also include vacation periods. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] 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] Hospital Mortality: A vital statistic measuring or recording the rate of death from any cause in hospitalized populations. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Humulin: A diabetes drug. [NIH] 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

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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] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] 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] Hygienic: Pertaining to hygiene, or conducive to health. [EU] Hyperalgesia: Excessive sensitiveness or sensibility to pain. [EU] Hyperandrogenism: A state characterized or caused by an excessive secretion of androgens by the adrenal cortex, ovaries, or testes. The clinical significance in males is negligible, so the term is used most commonly with reference to the female. The common manifestations in women are hirsutism and virilism. It is often caused by ovarian disease (particularly the polycystic ovary syndrome) and by adrenal diseases (particularly adrenal gland hyperfunction). [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperlipidaemia: A general term for elevated concentrations of any or all of the lipids in the plasma, including hyperlipoproteinaemia, hypercholesterolaemia, etc. [EU] 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] 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

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an increase in the number of cells. [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] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamic: Of or involving the hypothalamus. [EU] 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] 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] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Ice Cream: A frozen dairy food made from cream or butterfat, milk, sugar, and flavorings. Frozen custard and French-type ice creams also contain eggs. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Ileum: The lower end of the small intestine. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization

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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] Immunoblotting: Immunologic methods for isolating and quantitatively measuring immunoreactive substances. When used with immune reagents such as monoclonal antibodies, the process is known generically as western blot analysis (blotting, western). [NIH]

Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [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] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] 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] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] 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

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or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] 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]

Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inorganic: Pertaining to substances not of organic origin. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] 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] Insulin-like: Muscular growth factor. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]

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]

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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] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [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] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intraindividual: Being or occurring within the individual. [EU] Intramuscular: IM. Within or into muscle. [NIH] Intraocular: Within the eye. [EU] Intraocular pressure: Pressure of the fluid inside the eye; normal IOP varies among individuals. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Intubation: Introduction of a tube into a hollow organ to restore or maintain patency if obstructed. It is differentiated from catheterization in that the insertion of a catheter is usually performed for the introducing or withdrawing of fluids from the body. [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]

Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a

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gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Ischemic stroke: A condition in which the blood supply to part of the brain is cut off. Also called "plug-type" strokes. Blocked arteries starve areas of the brain controlling sight, speech, sensation, and movement so that these functions are partially or completely lost. Ischemic stroke is the most common type of stroke, accounting for 80 percent of all strokes. Most ischemic strokes are caused by a blood clot called a thrombus, which blocks blood flow in the arteries feeding the brain, usually the carotid artery in the neck, the major vessel bringing blood to the brain. When it becomes blocked, the risk of stroke is very high. [NIH] Islet: Cell producing insulin in pancreas. [NIH] 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] Isoproterenol: Isopropyl analog of epinephrine; beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract, etc. It is used mainly as bronchodilator and heart stimulant. [NIH] Jejunum: That portion of the small intestine which extends from the duodenum to the ileum; called also intestinum jejunum. [EU] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Joint Capsule: The sac enclosing a joint. It is composed of an outer fibrous articular capsule and an inner synovial membrane. [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] Keratitis: Inflammation of the cornea. [NIH] Keratoconjunctivitis: Simultaneous inflammation of the cornea and conjunctiva. [NIH] Ketone Bodies: Chemicals that the body makes when there is not enough insulin in the blood and it must break down fat for its energy. Ketone bodies can poison and even kill body cells. When the body does not have the help of insulin, the ketones build up in the blood and then "spill" over into the urine so that the body can get rid of them. The body can also rid itself of one type of ketone, called acetone, through the lungs. This gives the breath a fruity odor. Ketones that build up in the body for a long time lead to serious illness and coma. [NIH] Ketosis: A condition of having ketone bodies build up in body tissues and fluids. The signs of ketosis are nausea, vomiting, and stomach pain. Ketosis can lead to ketoacidosis. [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]

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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 Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [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] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [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] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Leprosy: A chronic granulomatous infection caused by Mycobacterium leprae. The granulomatous lesions are manifested in the skin, the mucous membranes, and the peripheral nerves. Two polar or principal types are lepromatous and tuberculoid. [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] Lethal: Deadly, fatal. [EU] Lethargy: Abnormal drowsiness or stupor; a condition of indifference. [EU] 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] Leuprolide: A potent and long acting analog of naturally occurring gonadotropin-releasing hormone (gonadorelin). Its action is similar to gonadorelin, which regulates the synthesis and release of pituitary gonadotropins. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [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] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] 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] Lipolysis: The hydrolysis of lipids. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] 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 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]

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Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution to the tumor site is improved. [NIH]

Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [NIH] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]

Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. [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] 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] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] 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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Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lumen: The cavity or channel within a tube or tubular organ. [EU] Luteal Phase: The period of the menstrual cycle that begins with ovulation and ends with menstruation. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] 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] 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] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] 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] Macrophage Colony-Stimulating Factor: A mononuclear phagocyte colony-stimulating factor synthesized by mesenchymal cells. The compound stimulates the survival, proliferation, and differentiation of hematopoietic cells of the monocyte-macrophage series. M-CSF is a disulfide-bonded glycoprotein dimer with a MW of 70 kDa. It binds to a specific high affinity receptor (receptor, macrophage colony-stimulating factor). [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [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] Malformation: A morphologic developmental process. [EU]

defect

resulting

from

an

intrinsically

abnormal

Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and

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spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Manic: Affected with mania. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] 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]

Meat Products: Articles of food which are derived by a process of manufacture from any portion of carcasses of any animal used for food (e.g., head cheese, sausage, scrapple). [NIH] Meatus: A canal running from the internal auditory foramen through the petrous portion of the temporal bone. It gives passage to the facial and auditory nerves together with the auditory branch of the basilar artery and the internal auditory veins. [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] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [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 Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH]

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Menopause: Permanent cessation of menstruation. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] 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] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Mesoderm: The middle germ layer of the embryo. [NIH] Mesolimbic: Inner brain region governing emotion and drives. [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] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Metastatic cancer: Cancer that has spread from the place in which it started to other parts of the body. [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] Mice, Transgenic: Laboratory mice that have been produced from a genetically manipulated egg or embryo. The technique involves microinjection of DNA fragments from another species into the nucleus of the fertilized egg. [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]

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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] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milligram: A measure of weight. A milligram is approximately 450,000-times smaller than a pound and 28,000-times smaller than an ounce. [NIH] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] Minor Histocompatibility Antigens: Allelic alloantigens often responsible for weak graft rejection in cases when (major) histocompatibility has been established by standard tests. In the mouse they are coded by more than 500 genes at up to 30 minor histocompatibility loci. The most well-known minor histocompatibility antigen in mammals is the H-Y antigen. [NIH]

Minority Groups: A subgroup having special characteristics within a larger group, often bound together by special ties which distinguish it from the larger group. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] 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] Mitotic: Cell resulting from mitosis. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [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] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other

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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] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Monogenic: A human disease caused by a mutation in a single gene. [NIH] Mononuclear: A cell with one nucleus. [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] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Motor Activity: The physical activity of an organism as a behavioral phenomenon. [NIH] Movement Disorders: Syndromes which feature dyskinesias as a cardinal manifestation of the disease process. Included in this category are degenerative, hereditary, post-infectious, medication-induced, post-inflammatory, and post-traumatic conditions. [NIH] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Musculature: The muscular apparatus of the body, or of any part of it. [EU] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myeloid Cells: Cells which include the monocytes and the granulocytes. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source

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including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Natriuresis: The excretion of abnormal amounts of sodium in the urine. [EU] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [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] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatal period: The first 4 weeks after birth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephron: A tiny part of the kidneys. Each kidney is made up of about 1 million nephrons, which are the working units of the kidneys, removing wastes and extra fluids from the blood. [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]

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Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural tube defects: These defects include problems stemming from fetal development of the spinal cord, spine, brain, and skull, and include birth defects such as spina bifida, anencephaly, and encephalocele. Neural tube defects occur early in pregnancy at about 4 to 6 weeks, usually before a woman knows she is pregnant. Many babies with neural tube defects have difficulty walking and with bladder and bowel control. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neuroendocrinology: The study of the anatomical and functional relationships between the nervous system and the endocrine system. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neuropsychological Tests: Tests designed to assess neurological function associated with certain behaviors. They are used in diagnosing brain dysfunction or damage and central nervous system disorders or injury. [NIH] Neurosis: Functional derangement due to disorders of the nervous system which does not affect the psychic personality of the patient. [NIH] Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH] Neutralization: An act or process of neutralizing. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant

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tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] 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] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Nutritional Support: The administration of nutrients for assimilation and utilization by a patient by means other than normal eating. It does not include fluid therapy which normalizes body fluids to restore water-electrolyte balance. [NIH] Occult: Obscure; concealed from observation, difficult to understand. [EU] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] 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] Oligomenorrhea: Abnormally infrequent menstruation. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH]

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Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]

Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [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] 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] Organizational Culture: Beliefs and values shared by all members of the organization. These shared values are reflected in the day to day operations of the organization. [NIH] Orthostatic: Pertaining to or caused by standing erect. [EU] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [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] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [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] 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] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Ovum Implantation: Endometrial implantation of the blastocyst. [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)

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from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidative 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] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] 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] Pancreas Transplant: A surgical procedure that involves replacing the pancreas of a person who has diabetes with a healthy pancreas that can make insulin. The healthy pancreas comes from a donor who has just died or from a living relative. A person can donate half a pancreas and still live normally. [NIH] Pancreas Transplantation: The transference of a pancreas from one human or animal to another. [NIH] Pancreatectomy: Surgery to remove the pancreas. In a total pancreatectomy, a portion of the stomach, the duodenum, common bile duct, gallbladder, spleen, and nearby lymph nodes also are removed. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [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] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [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] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and

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muscular rigidity. [EU] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] 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] Partnership Practice: A voluntary contract between two or more doctors who may or may not share responsibility for the care of patients, with proportional sharing of profits and losses. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Care Team: Care of patients by a multidisciplinary team usually organized under the leadership of a physician; each member of the team has specific responsibilities and the whole team contributes to the care of the patient. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Patient Selection: Criteria and standards used for the determination of the appropriateness of the inclusion of patients with specific conditions in proposed treatment plans and the criteria used for the inclusion of subjects in various clinical trials and other research protocols. [NIH] Pelvic: Pertaining to the pelvis. [EU] Penicillin: An antibiotic drug used to treat infection. [NIH] Pentosephosphate Pathway: A pathway of hexose oxidation in which glucose-6-phosphate undergoes two successive oxidations by NADP, the final one being an oxidative decarboxylation to form a pentose phosphate. [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] 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] Pericytes: Smooth muscle cell that wraps around normal blood vessels. [NIH] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously

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defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Perioperative: Around the time of surgery; usually lasts from the time of going into the hospital or doctor's office for surgery until the time the patient goes home. [NIH] 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] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH] 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] Peroneal Nerve: The lateral of the two terminal branches of the sciatic nerve. The peroneal (or fibular) nerve provides motor and sensory innervation to parts of the leg and foot. [NIH] Perspiration: Sweating; the functional secretion of sweat. [EU] Pertussis: An acute, highly contagious infection of the respiratory tract, most frequently affecting young children, usually caused by Bordetella pertussis; a similar illness has been associated with infection by B. parapertussis and B. bronchiseptica. It is characterized by a catarrhal stage, beginning after an incubation period of about two weeks, with slight fever, sneezing, running at the nose, and a dry cough. In a week or two the paroxysmal stage begins, with the characteristic paroxysmal cough, consisting of a deep inspiration, followed by a series of quick, short coughs, continuing until the air is expelled from the lungs; the close of the paroxysm is marked by a long-drawn, shrill, whooping inspiration, due to spasmodic closure of the glottis. This stage lasts three to four weeks, after which the convalescent stage begins, in which paroxysms grow less frequent and less violent, and finally cease. Called also whooping cough. [EU] 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 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] Pharmacist: A person trained to prepare and distribute medicines and to give information about them. [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

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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] 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] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phobia: A persistent, irrational, intense fear of a specific object, activity, or situation (the phobic stimulus), fear that is recognized as being excessive or unreasonable by the individual himself. When a phobia is a significant source of distress or interferes with social functioning, it is considered a mental disorder; phobic disorder (or neurosis). In DSM III phobic disorders are subclassified as agoraphobia, social phobias, and simple phobias. Used as a word termination denoting irrational fear of or aversion to the subject indicated by the stem to which it is affixed. [EU] Phobic Disorders: Anxiety disorders in which the essential feature is persistent and irrational fear of a specific object, activity, or situation that the individual feels compelled to avoid. The individual recognizes the fear as excessive or unreasonable. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylate: Attached to a phosphate group. [NIH] Phosphorylating: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] 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]

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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] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [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] Placental Circulation: The circulation of blood, of both the mother and the fetus, through the placenta. [NIH] Placental tissue: The tissue intervening between fetal blood and maternal blood in the placenta; it acts as a selective membrane regulating the passage of substances from the maternal to the fetal blood. [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] 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] Plasma Volume: Volume of plasma in the circulation. It is usually measured by indicator dilution techniques. [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]

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Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]

Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polycystic Ovary Syndrome: Clinical symptom complex characterized by oligomenorrhea or amenorrhea, anovulation, and regularly associated with bilateral polycystic ovaries. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [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] 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] Postoperative: After surgery. [NIH]

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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] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Postural: Pertaining to posture or position. [EU] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precipitating Factors: Factors associated with the definitive onset of a disease, illness, accident, behavioral response, or course of action. Usually one factor is more important or more obviously recognizable than others, if several are involved, and one may often be regarded as "necessary". Examples include exposure to specific disease; amount or level of an infectious organism, drug, or noxious agent, etc. [NIH] Preclinical: Before a disease becomes clinically recognizable. [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] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Preeclampsia: A toxaemia of late pregnancy characterized by hypertension, edema, and proteinuria, when convulsions and coma are associated, it is called eclampsia. [EU] Pregnancy in Diabetics: Previously diagnosed diabetics that become pregnant. This does not include either symptomatic diabetes or impaired glucose tolerance induced by pregnancy but resolved at the end of pregnancy (diabetes, gestational). [NIH] Pregnancy Outcome: Results of conception and ensuing pregnancy, including live birth, stillbirth, spontaneous abortion, induced abortion. The outcome may follow natural or artificial insemination or any of the various reproduction techniques, such as embryo transfer or fertilization in vitro. [NIH] Pregnancy Tests: Tests to determine whether or not an individual is pregnant. [NIH] 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] 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

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in the population at a given time. [NIH] Private Practice: Practice of a health profession by an individual, offering services on a person-to-person basis, as opposed to group or partnership practice. [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] Problem Solving: A learning situation involving more than one alternative from which a selection is made in order to attain a specific goal. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progeny: The offspring produced in any generation. [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] Proinsulin: The substance made first in the pancreas that is then made into insulin. When insulin is purified from the pancreas of pork or beef, all the proinsulin is not fully removed. When some people use these insulins, the proinsulin can cause the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin is injected. The purified insulins have less proinsulin and other impurities than the other types of insulins. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential 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] Prone: Having the front portion of the body downwards. [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] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostaglandins D: Physiologically active prostaglandins found in many tissues and organs. They show pressor activity, are mediators of inflammation, and have potential

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antithrombotic effects. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prostatic Hyperplasia: Enlargement or overgrowth of the prostate gland as a result of an increase in the number of its constituent cells. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to 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] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycans: Glycoproteins which have a very high polysaccharide content. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] 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] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [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] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU]

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Proxy: A person authorized to decide or act for another person, for example, a person having durable power of attorney. [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] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychosis: A mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour without apparent awareness on the part of the patient of the incomprehensibility of his behaviour; the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g. manic-depressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] 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] Purified Insulins: Insulins with much less of the impure proinsulin. It is thought that the use of purified insulins may help avoid or reduce some of the problems of people with diabetes such as allergic reactions. [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] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Purulent: Consisting of or containing pus; associated with the formation of or caused by

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pus. [EU] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [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] 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] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioactivity: The quality of emitting or the emission of corpuscular or electromagnetic radiations consequent to nuclear disintegration, a natural property of all chemical elements of atomic number above 83, and possible of induction in all other known elements. [EU] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [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] 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

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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 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] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU] Relaxant: 1. Lessening or reducing tension. 2. An agent that lessens tension. [EU] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal Plasma Flow: The amount of plasma that perfuses the kidneys per unit time, approximately 10% greater than effective renal plasma flow (renal plasma flow, effective). It should be differentiated from the renal blood flow (RBF) which refers to the total volume of blood flowing through the renal vasculature, while the renal plasma flow refers to the rate of plasma flow (RPF). [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] 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

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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] Reproduction Techniques: Methods pertaining to the generation of new individuals. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Research Design: A plan for collecting and utilizing data so that desired information can be obtained with sufficient precision or so that an hypothesis can be tested properly. [NIH] Research Support: Financial support of research activities. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Vessels: The vessels which supply and drain the retina. [NIH] Retinoids: Derivatives of vitamin A. Used clinically in the treatment of severe cystic acne, psoriasis, and other disorders of keratinization. Their possible use in the prophylaxis and treatment of cancer is being actively explored. [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] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] 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]

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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] 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] Rickettsiae: One of a group of obligate intracellular parasitic microorganisms, once regarded as intermediate in their properties between bacteria and viruses but now classified as bacteria in the order Rickettsiales, which includes 17 genera and 3 families: Rickettsiace. [NIH]

Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risperidone: A selective blocker of dopamine D2 and serotonin-5-HT-2 receptors that acts as an atypical antipsychotic agent. It has been shown to improve both positive and negative symptoms in the treatment of schizophrenia. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rosiglitazone: A drug taken to help reduce the amount of sugar in the blood. Rosiglitazone helps make insulin more effective and improves regulation of blood sugar. It belongs to the family of drugs called thiazolidinediones. [NIH] Saline: A solution of salt and water. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Salivation: 1. The secretion of saliva. 2. Ptyalism (= excessive flow of saliva). [EU] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Sciatic Nerve: A nerve which originates in the lumbar and sacral spinal cord (L4 to S3) and supplies motor and sensory innervation to the lower extremity. The sciatic nerve, which is the main continuation of the sacral plexus, is the largest nerve in the body. It has two major branches, the tibial nerve and the peroneal nerve. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH]

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Sebaceous gland: Gland that secretes sebum. [NIH] Sebum: The oily substance secreted by sebaceous glands. It is composed of keratin, fat, and cellular debris. [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] Sedentary: 1. Sitting habitually; of inactive habits. 2. Pertaining to a sitting posture. [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] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Self Care: Performance of activities or tasks traditionally performed by professional health care providers. The concept includes care of oneself or one's family and friends. [NIH] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensibility: The ability to receive, feel and appreciate sensations and impressions; the quality of being sensitive; the extend to which a method gives results that are free from false negatives. [NIH] Sepsis: The presence of bacteria in the bloodstream. [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] 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] Sexually Transmitted Diseases: Diseases due to or propagated by sexual contact. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the

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circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] 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] Skin Care: Maintenance of the hygienic state of the skin under optimal conditions of cleanliness and comfort. Effective in skin care are proper washing, bathing, cleansing, and the use of soaps, detergents, oils, etc. In various disease states, therapeutic and protective solutions and ointments are useful. The care of the skin is particularly important in various occupations, in exposure to sunlight, in neonates, and in decubitus ulcer. [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] Smallpox: A generalized virus infection with a vesicular rash. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Soaps: Sodium or potassium salts of long chain fatty acids. These detergent substances are obtained by boiling natural oils or fats with caustic alkali. Sodium soaps are harder and are used as topical anti-infectives and vehicles in pills and liniments; potassium soaps are soft, used as vehicles for ointments and also as topical antimicrobials. [NIH] Social Behavior: Any behavior caused by or affecting another individual, usually of the

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same species. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Socioeconomic Factors: Social and economic factors that characterize the individual or group within the social structure. [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] Solitary Nucleus: Gray matter located in the dorsomedial part of the medulla oblongata associated with the solitary tract. The solitary nucleus receives inputs from most organ systems including the terminations of the facial, glossopharyngeal, and vagus nerves. It is a major coordinator of autonomic nervous system regulation of cardiovascular, respiratory, gustatory, gastrointestinal, and chemoreceptive aspects of homeostasis. The solitary nucleus is also notable for the large number of neurotransmitters which are found therein. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [NIH] Sorbitol: A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. [NIH] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [NIH] Spasmodic: Of the nature of a spasm. [EU] Spatial disorientation: Loss of orientation in space where person does not know which way is up. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH]

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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] Sperm: The fecundating fluid of the male. [NIH] Spina bifida: A defect in development of the vertebral column in which there is a central deficiency of the vertebral lamina. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinal Nerves: The 31 paired peripheral nerves formed by the union of the dorsal and ventral spinal roots from each spinal cord segment. The spinal nerve plexuses and the spinal roots are also included. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Spondylolisthesis: Forward displacement of one vertebra over another. [NIH] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sprains and Strains: A collective term for muscle and ligament injuries without dislocation or fracture. A sprain is a joint injury in which some of the fibers of a supporting ligament are ruptured but the continuity of the ligament remains intact. A strain is an overstretching or overexertion of some part of the musculature. [NIH] Stabilization: The creation of a stable state. [EU] Stasis: A word termination indicating the maintenance of (or maintaining) a constant level; preventing increase or multiplication. [EU] Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Status Epilepticus: Repeated and prolonged epileptic seizures without recovery of consciousness between attacks. [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] 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] Sterile: Unable to produce children. [NIH] 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,

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bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] 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] 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] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] 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]

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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] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] 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] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synovial: Of pertaining to, or secreting synovia. [EU] Synovial Fluid: The clear, viscous fluid secreted by the synovial membrane. It contains mucin, albumin, fat, and mineral salts and serves to lubricate joints. [NIH] Synovial Membrane: The inner membrane of a joint capsule surrounding a freely movable joint. It is loosely attached to the external fibrous capsule and secretes synovial fluid. [NIH] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Systolic blood pressure: The maximum pressure in the artery produced as the heart contracts and blood begins to flow. [NIH] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU]

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Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [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] Teratoma: A type of germ cell tumor that may contain several different types of tissue, such as hair, muscle, and bone. Teratomas occur most often in the ovaries in women, the testicles in men, and the tailbone in children. Not all teratomas are malignant. [NIH] Testicles: The two egg-shaped glands found inside the scrotum. They produce sperm and male hormones. Also called testes. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Thoracic: Having to do with the chest. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [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.

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[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] Thyroid Hormones: Hormones secreted by the thyroid gland. [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] Tibial Nerve: The medial terminal branch of the sciatic nerve. The tibial nerve fibers originate in lumbar and sacral spinal segments (L4 to S2). They supply motor and sensory innervation to parts of the calf and foot. [NIH] Tin: A trace element that is required in bone formation. It has the atomic symbol Sn, atomic number 50, and atomic weight 118.71. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Plasminogen Activator: A proteolytic enzyme in the serine protease family found in many tissues which converts plasminogen to plasmin. It has fibrin-binding activity and is immunologically different from urinary plasminogen activator. The primary sequence, composed of 527 amino acids, is identical in both the naturally occurring and synthetic proteases. EC 3.4.21.68. [NIH] Tocolysis: Any drug treatment modality designed to inhibit uterine contractions in pregnant women at risk for preterm labor. [NIH] Tolazamide: A sulphonylurea hypoglycemic agent with actions and uses similar to those of chlorpropamide. [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] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Total pancreatectomy: Surgery to remove the entire pancreas. [NIH] Toxaemia: 1. The condition resulting from the spread of bacterial products (toxins) by the bloodstream. 2. A condition resulting from metabolic disturbances, e.g. toxaemia of

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pregnancy. [EU] 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] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Trachoma: A chronic infection of the conjunctiva and cornea caused by Chlamydia trachomatis. [NIH] Traction: The act of pulling. [NIH] Transaldolase: An enzyme of the transferase class that catalyzes the reaction sedoheptulose 7-phosphate and D-glyceraldehyde 3-phosphate to yield D-erythrose 4-phosphate and Dfructose phosphate in the pentosephosphate pathway. (Dorland, 27th ed) EC 2.2.1.2. [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] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] 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]

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Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [NIH] Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [NIH] Trigger zone: Dolorogenic zone (= producing or causing pain). [EU] 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]

Troglitazone: A drug used in diabetes treatment that is being studied for its effect on reducing the risk of cancer cell growth in fat tissue. [NIH] Trophic: Of or pertaining to nutrition. [EU] Trophoblast: The outer layer of cells of the blastocyst which works its way into the endometrium during ovum implantation and grows rapidly, later combining with mesoderm. [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] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [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] Tympanic membrane: A thin, tense membrane forming the greater part of the outer wall of the tympanic cavity and separating it from the external auditory meatus; it constitutes the boundary between the external and middle ear. [NIH] 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 also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ultralente Insulin: A type of insulin that is long acting. [NIH] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10

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megahertz. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Unresectable: Unable to be surgically removed. [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [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]

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] Uridine Diphosphate: A uracil nucleotide containing a pyrophosphate group esterified to C5 of the sugar moiety. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary Plasminogen Activator: A proteolytic enzyme that converts plasminogen to plasmin where the preferential cleavage is between arginine and valine. It was isolated originally from human urine, but is found in most tissues of most vertebrates. EC 3.4.21.73. [NIH]

Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [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] Urine Testing: Checking urine to see if it contains glucose (sugar) and ketones. Special strips of paper or tablets (called reagents) are put into a small amount of urine or urine plus water. Changes in the color of the strip show the amount of glucose or ketones in the urine. Urine testing is the only way to check for the presence of ketones, a sign of serious illness. However, urine testing is less desirable then blood testing for monitoring the level of glucose in the body. [NIH] Uterine Contraction: Contraction of the uterine muscle. [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] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond

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to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vaccinia: The cutaneous and occasional systemic reactions associated with vaccination using smallpox (variola) vaccine. [NIH] Vaccinia Virus: The type species of Orthopoxvirus, related to cowpox virus, but whose true origin is unknown. It has been used as a live vaccine against smallpox. It is also used as a vector for inserting foreign DNA into animals. Rabbitpox virus is a subspecies of vaccinia virus. [NIH] Vacuole: A fluid-filled cavity within the cytoplasm of a cell. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [NIH] Variola: A generalized virus infection with a vesicular rash. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] 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] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Function: The hemodynamic and electrophysiological action of the ventricles. [NIH]

Ventricular Remodeling: The geometric and structural changes that the ventricle undergoes, usually following myocardial infarction. It comprises expansion of the infarct and dilatation of the healthy ventricle segments. While most prevalent in the left ventricle, it can also occur in the right ventricle. [NIH] 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]

Dictionary 299

Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vibrio: A genus of Vibrionaceae, made up of short, slightly curved, motile, gram-negative rods. Various species produce cholera and other gastrointestinal disorders as well as abortion in sheep and cattle. [NIH] Vibrio cholerae: The etiologic agent of cholera. [NIH] Villi: The tiny, fingerlike projections on the surface of the small intestine. Villi help absorb nutrients. [NIH] Villous: Of a surface, covered with villi. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virilism: Development of masculine traits in the female. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] 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] Virus Diseases: A general term for diseases produced by viruses. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Afferents: The sensory fibers innervating the viscera. [NIH] Visceral fat: One of the three compartments of abdominal fat. Retroperitoneal and subcutaneous are the other two compartments. [NIH] Visually Impaired Persons: Persons with loss of vision such that there is an impact on activities of daily living. [NIH] 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] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [NIH] Vitreous Humor: The transparent, colorless mass of gel that lies behind the lens and in front of the retina and fills the center of the eyeball. [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] Weight Gain: Increase in body weight over existing weight. [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]

Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH]

300

Hyperglycemia

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [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] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

301

INDEX A Abdomen, 217, 227, 245, 259, 263, 273, 290, 291, 293, 299 Abdominal, 84, 217, 218, 228, 266, 273, 299 Abdominal fat, 217, 299 Aberrant, 43, 145, 217 Acatalasia, 217, 230 Acceptor, 217, 262, 273, 295 Acetaminophen, 9, 217 Acetic Acids, 123, 217 Acetohexamide, 121, 144, 217 Acetone, 217, 260 Acetylcholine, 217, 232, 271 Acidosis, 5, 11, 127, 162, 167, 217, 240 Activities of Daily Living, 217, 299 Acyl, 50, 55, 127, 217, 245, 265 Adaptability, 217, 231 Adaptation, 55, 57, 168, 217 Adenocarcinoma, 218, 254 Adenovirus, 50, 218 Adenylate Cyclase, 141, 218, 232, 248 Adenylate Kinase, 135, 218 Adipocytes, 28, 60, 67, 118, 218, 235, 261 Adipose Tissue, 46, 51, 68, 112, 114, 115, 117, 118, 132, 138, 140, 147, 217, 218, 262 Adjustment, 155, 162, 163, 217, 218 Adoptive Transfer, 29, 218 Adrenal Cortex, 218, 237, 245, 255, 280, 284 Adrenal Glands, 218 Adrenal insufficiency, 137, 218 Adrenal Medulla, 218, 230, 245, 271 Adrenergic, 74, 137, 218, 223, 241, 245, 292 Adverse Effect, 4, 30, 88, 127, 176, 218, 233, 288 Aerobic, 68, 218, 267 Aerobic Exercise, 68, 218 Afferent, 36, 218, 261 Affinity, 218, 219, 233, 262, 264, 289 Agar, 219, 277 Age of Onset, 219, 296 Age-Adjusted, 45, 70, 219 Agonist, 22, 25, 27, 99, 126, 135, 136, 219, 241, 271 Agoraphobia, 219, 276 Akathisia, 219, 223 Albumin, 12, 49, 219, 277, 292 Aldehyde Dehydrogenase, 16, 219

Aldehydes, 16, 90, 219 Aldose Reductase Inhibitor, 123, 219 Algorithms, 219, 227 Alimentary, 119, 130, 219, 260, 273 Alkaline, 217, 219, 220, 228, 293 Alkaloid, 219, 271 Alleles, 20, 220, 254 Allergen, 220, 239 Allogeneic, 40, 220 Allograft, 220, 254 Alpha Particles, 220, 283 Alpha-1, 220, 276 Alternative medicine, 182, 220 Ameliorating, 17, 220 Amenorrhea, 220, 222, 278 Amino Acid Sequence, 147, 220, 222, 249 Ammonia, 220, 251 Amniotic Fluid, 220, 250 Amputation, 44, 137, 156, 173, 220 Amylase, 130, 220 Anaesthesia, 220, 258 Anal, 220, 263 Analgesic, 217, 220 Analog, 128, 176, 220, 260, 262 Analogous, 29, 67, 128, 220, 295 Analytes, 27, 220 Anaphylatoxins, 221, 235 Anatomical, 221, 224, 235, 240, 257, 270, 286 Androgens, 218, 221, 255 Anemia, 142, 221 Anesthesia, 89, 162, 221 Anesthetics, 221, 245 Aneuploidy, 145, 221 Aneurysm, 221, 298 Angina, 79, 121, 162, 197, 221 Angina Pectoris, 79, 121, 221 Angiogenesis, 24, 33, 95, 123, 221 Angiotensin converting enzyme inhibitor, 123, 221 Angiotensinogen, 38, 61, 63, 221, 284 Animal model, 29, 31, 36, 42, 47, 66, 68, 73, 126, 139, 145, 153, 221 Anions, 219, 221, 260, 292 Anorexia, 141, 167, 221, 222, 297 Anorexia Nervosa, 167, 222 Anovulation, 222, 278 Antagonism, 85, 222, 233

302

Hyperglycemia

Antibiotic, 222, 245, 274 Antibodies, 37, 39, 126, 148, 222, 224, 245, 254, 256, 264, 268, 277 Antibody, 219, 222, 227, 234, 254, 257, 258, 265, 268, 283, 290 Anticoagulant, 222, 281 Antidiabetic, 7, 113, 115, 120, 122, 127, 140, 186, 222, 251 Antidiabetic Agent, 7, 120, 127, 186, 222 Antidiuretic, 141, 222, 229 Antiemetic, 222, 223 Antigen, 34, 218, 222, 234, 239, 245, 254, 255, 256, 257, 258, 265, 267 Antigen-Antibody Complex, 222, 234 Antigen-presenting cell, 222, 239 Antihypertensive, 162, 222, 248 Anti-infective, 222, 255, 288 Anti-inflammatory, 17, 142, 217, 222, 250 Antioxidant, 14, 30, 44, 53, 63, 88, 94, 143, 222, 273 Antipsychotic, 83, 222, 233, 270, 286 Antipyretic, 217, 223 Antiviral, 223, 274 Anuria, 223, 261 Anxiety, 137, 141, 219, 223, 276 Aorta, 144, 223, 237, 298 Apathy, 223, 270 Apolipoproteins, 223, 262 Aponeurosis, 223, 248 Apoptosis, 16, 25, 33, 38, 52, 57, 70, 72, 223, 230 Appendicitis, 164, 223 Applicability, 40, 223 Aqueous, 223, 225, 238, 255, 261, 263 Arachidonate 12-Lipoxygenase, 223, 263 Arachidonate 15-Lipoxygenase, 223, 263 Arachidonate Lipoxygenases, 223, 263 Arachidonic Acid, 223, 224, 280 Arginine, 26, 99, 221, 224, 271, 297 Arterial, 70, 145, 224, 229, 232, 236, 255, 281, 292 Arteries, 19, 48, 144, 223, 224, 226, 227, 231, 236, 237, 260, 263, 266, 268, 282 Arteriolar, 32, 224, 228, 284 Arterioles, 33, 224, 227, 229, 267, 268, 298 Arteriolosclerosis, 224 Arteriosclerosis, 88, 131, 224, 255 Arteriovenous, 224, 267 Asparaginase, 79, 224 Aspartate, 224, 251 Assay, 58, 119, 224 Asymptomatic, 23, 137, 183, 217, 224, 273

Atrial, 76, 224, 236, 296 Atrioventricular, 224, 236 Atrium, 224, 236, 296, 298 Atrophy, 82, 138, 224 Attenuated, 71, 224, 241 Atypical, 224, 233, 286 Auditory, 9, 224, 265, 296 Autoantibodies, 37, 139, 224, 225 Autoantigens, 37, 69, 224, 225 Autodigestion, 225, 273 Autoimmune disease, 37, 69, 139, 225 Autoimmunity, 21, 225 Autologous, 40, 225 Autonomic, 15, 131, 153, 159, 217, 223, 225, 271, 275, 289, 292 Autonomic Nervous System, 15, 159, 225, 275, 289, 292 Autonomic Neuropathy, 153, 225 Autosuggestion, 225, 256 B Back Pain, 154, 164, 225 Backcross, 29, 225 Bacteria, 217, 222, 225, 226, 243, 244, 246, 247, 251, 263, 266, 267, 283, 286, 287, 295, 297, 298 Bacterial Physiology, 218, 225 Bacteriophage, 225, 277, 295 Bacteriostatic, 225, 245 Basal Ganglia, 76, 223, 225, 232, 248 Basal Ganglia Diseases, 225, 232 Base, 199, 225, 228, 239, 249, 260, 261, 293, 297 Basement Membrane, 24, 58, 226, 246, 261 Basilar Artery, 19, 226, 265 Basophils, 226, 252, 262 Benign, 92, 224, 226, 229, 248, 253, 269, 283 Benign prostatic hyperplasia, 92, 226 Benzoic Acid, 122, 226 Bewilderment, 226, 235 Bilateral, 226, 278 Bile, 135, 143, 226, 248, 263, 291 Bile Acids, 135, 226, 291 Bile Acids and Salts, 226 Bile Ducts, 226, 248 Biliary, 118, 226, 228, 234, 273 Biliary Tract, 118, 226, 228, 273 Bilirubin, 219, 226, 248 Bioavailability, 26, 44, 113, 122, 226 Biochemical, 18, 34, 36, 41, 47, 49, 54, 61, 65, 123, 220, 226, 252, 261, 287 Biological therapy, 226, 252

Index 303

Biosynthesis, 50, 124, 143, 224, 226, 248, 263, 281, 287, 288 Biotechnology, 71, 73, 169, 182, 191, 226 Bladder, 141, 162, 225, 226, 227, 257, 270, 281, 297 Blastocyst, 227, 235, 243, 272, 277, 296 Bloating, 227, 249 Blood Coagulation, 13, 227, 228, 247, 293 Blood Coagulation Factors, 227 Blood Platelets, 227, 265, 287, 293 Blot, 25, 33, 227, 257 Blotting, Western, 227, 257 Body Fluids, 227, 242, 247, 271, 289 Body Mass Index, 39, 147, 183, 227, 272 Bolus, 51, 128, 165, 227 Bolus infusion, 227 Bolus injection, 51, 128, 227 Bone Marrow, 29, 52, 227, 257, 264, 265, 289, 291 Bone Marrow Cells, 52, 227, 265 Bowel, 220, 227, 228, 240, 259, 261, 270, 291 Bowel Movement, 228, 240, 291 Brachytherapy, 228, 259, 283 Bradykinin, 228, 271, 277 Branch, 200, 201, 213, 228, 243, 264, 265, 274, 282, 289, 293, 294 Breakdown, 18, 42, 67, 141, 228, 240, 249, 272, 288 Bronchi, 228, 245, 260, 295 Bronchial, 85, 228, 254 Bronchiseptica, 228, 275 Bronchitis, 153, 154, 164, 228, 233 Bronchodilator, 228, 260 Burns, 164, 228 Burns, Electric, 228 C Cachexia, 138, 228 Caesarean section, 32, 228 Calcification, 224, 228 Calcium, 16, 79, 105, 122, 228, 234, 269, 273, 281, 288, 293 Calculi, 118, 228 Caloric intake, 68, 147, 228 Canonical, 20, 228 Capillary, 8, 24, 33, 228, 229, 250, 262, 298 Capsules, 229, 241, 244, 250 Captopril, 45, 63, 229 Carbenoxolone, 127, 229 Carbogen, 64, 229 Carbon Dioxide, 229, 238, 251, 277, 285 Carcinogen, 229, 246

Carcinogenic, 229, 258, 280, 291 Carcinoid, 102, 229 Carcinoma, 229 Cardiac, 22, 38, 48, 53, 89, 117, 118, 141, 162, 229, 236, 238, 245, 249, 251, 268, 269, 290 Cardiology, 15, 74, 75, 79, 83, 87, 92, 197, 229 Cardiomyopathy, 22, 37, 116, 144, 229 Cardiopulmonary, 89, 229 Cardiorespiratory, 218, 229 Cardiotoxic, 25, 229 Cardiovascular, 4, 7, 10, 15, 26, 31, 38, 48, 59, 70, 75, 78, 84, 85, 93, 94, 98, 114, 135, 136, 167, 174, 183, 225, 229, 262, 287, 289 Cardiovascular disease, 7, 10, 15, 26, 31, 59, 70, 94, 114, 135, 136, 167, 174, 229, 262 Cardiovascular System, 225, 229 Carnitine, 135, 229 Carotene, 230, 285 Carotenoids, 91, 230 Carrier Proteins, 230, 277 Case report, 76, 89, 91, 92, 93, 155, 230, 233 Caspase, 25, 230 Catabolism, 143, 230 Catalase, 39, 217, 230 Cataract, 16, 131, 230 Catecholamine, 230, 241, 276 Catheterization, 41, 230, 259, 269 Catheters, 163, 230, 257, 259 Caudal, 230, 240, 256, 278 Causal, 34, 230 Cause of Death, 17, 44, 47, 114, 137, 144, 230 Caveolae, 27, 230 Caveolins, 230 Cell Cycle, 46, 51, 145, 230, 253 Cell Death, 38, 44, 223, 231, 269 Cell Differentiation, 119, 231, 288 Cell Division, 225, 230, 231, 252, 267, 277, 287 Cell Extracts, 39, 231 Cell membrane, 121, 123, 132, 230, 231, 239, 259, 276 Cell Membrane Structures, 230, 231 Cell proliferation, 44, 66, 138, 224, 231, 288 Cell Respiration, 231, 267, 285 Cell Survival, 231, 252 Central Nervous System, 141, 217, 225, 231, 233, 248, 251, 253, 270, 272, 278, 287

304

Hyperglycemia

Central Nervous System Infections, 231, 253 Centromere, 145, 231 Cerebellar, 231, 296 Cerebellar Diseases, 231, 296 Cerebral, 11, 19, 34, 61, 76, 80, 83, 90, 91, 144, 225, 226, 231, 236, 239, 243, 245, 246, 282, 293 Cerebral Arteries, 19, 61, 144, 226, 231 Cerebrovascular, 34, 225, 229, 231 Cerebrum, 231, 293 Character, 126, 152, 221, 231, 238 Chemokines, 31, 231 Chemoreceptor, 223, 232 Chemotactic Factors, 72, 232, 235 Chemotherapy, 92, 198, 232 Chest Pain, 154, 164, 232 Cholera, 70, 232, 299 Cholera Toxin, 70, 232 Cholesterol Esters, 232, 262 Cholinergic, 137, 223, 232, 271 Chorea, 76, 78, 223, 232 Choreatic Disorders, 232 Choroid, 232, 285 Chromatin, 223, 232, 244 Chromium, 102, 103, 136, 232 Chromosomal, 145, 221, 232 Chromosome, 148, 221, 231, 232, 254, 262, 268, 287, 296 Chronic Disease, 25, 27, 154, 228, 232 Chronic Obstructive Pulmonary Disease, 199, 205, 233 Chronic renal, 114, 233, 278, 297 Chylomicrons, 131, 233, 262 Ciliary, 147, 233 Ciliary Neurotrophic Factor, 147, 233 Circadian, 141, 233 Circadian Rhythm, 141, 233 CIS, 122, 142, 233, 285 Clamp, 9, 51, 68, 233 Clear cell carcinoma, 233, 239 Clinical Medicine, 233, 279 Clinical study, 233, 236 Clinical trial, 12, 14, 34, 38, 48, 49, 107, 108, 191, 233, 236, 274, 281, 283 Clone, 35, 68, 233 Cloning, 29, 227, 233 Clozapine, 95, 180, 233 Coagulation, 13, 227, 233, 253, 277, 294 Coenzyme, 234, 263, 288 Cofactor, 234, 281, 293 Cognition, 21, 142, 234, 270

Cohort Studies, 48, 234 Collagen, 58, 66, 144, 226, 234, 246, 247, 278, 280 Collapse, 228, 234 Colloidal, 219, 234, 243 Combination Therapy, 162, 176, 234 Common Bile Duct, 234, 273 Complement, 14, 47, 66, 221, 234, 249, 264, 277 Complete remission, 235, 284 Computational Biology, 191, 235 Conception, 235, 247, 279 Concomitant, 6, 11, 53, 119, 235 Concretion, 228, 235 Conduction, 39, 235 Cones, 235, 285 Confounding, 26, 92, 235 Confusion, 137, 154, 235, 241, 270, 297 Congestion, 223, 235 Congestive heart failure, 53, 121, 141, 162, 235 Conjugated, 136, 226, 235 Connective Tissue, 42, 132, 227, 234, 235, 236, 247, 248, 264, 266, 285, 291 Connective Tissue Cells, 235 Consciousness, 137, 154, 170, 220, 235, 238, 239, 290 Constipation, 164, 223, 235 Constriction, 235, 260, 298 Constriction, Pathologic, 235, 298 Consumption, 79, 161, 163, 175, 235, 239, 271, 273 Continuous infusion, 125, 235 Contractility, 118, 235 Contraindications, ii, 236 Contralateral, 36, 236, 272 Control group, 21, 236 Controlled clinical trial, 54, 59, 236 Contusion, 100, 236 Conventional therapy, 236 Conventional treatment, 126, 152, 236 Convulsions, 154, 236, 242, 279 Coordination, 101, 236 Cor, 141, 236 Cornea, 236, 260, 291, 295 Corneal Neovascularization, 101, 236 Corneal Stroma, 236 Corneal Transplantation, 236 Coronary Arteriosclerosis, 237, 268 Coronary Artery Bypass, 11, 89, 90, 237 Coronary Circulation, 27, 221, 237

Index 305

Coronary heart disease, 51, 112, 121, 124, 125, 181, 229, 237, 254 Coronary Thrombosis, 237, 266, 268 Coronary Vasospasm, 141, 237 Coronary Vessels, 237 Cortex, 231, 237, 246 Cortical, 237, 287 Corticosteroids, 237, 250, 267 Cortisol, 7, 30, 219, 237 Cowpox, 237, 298 Cowpox Virus, 237, 298 Cranial, 237, 253, 272, 275 Craniocerebral Trauma, 225, 237, 253 Creatine, 138, 237 Creatine Kinase, 138, 237 Creatinine, 237, 261, 297 Crossing-over, 237, 284 Curative, 238, 271, 293 Cutaneous, 78, 162, 238, 298 Cyclic, 52, 56, 218, 238, 248, 252, 271, 276 Cysteine, 231, 238, 244, 251, 291 Cytokine, 12, 17, 18, 86, 140, 238 Cytoplasm, 41, 223, 226, 231, 232, 238, 244, 252, 286, 298 Cytotoxic, 75, 238, 283, 288 D Data Collection, 32, 36, 238 Databases, Bibliographic, 191, 238 Day Care, 164, 199, 238 De novo, 117, 238 Decarboxylation, 238, 251, 254, 274 Decidua, 238, 277 Decompensation, 32, 35, 238 Decubitus, 238, 288 Decubitus Ulcer, 238, 288 Degenerative, 138, 204, 238, 268, 285 Dehydration, 8, 11, 170, 232, 238 Deletion, 34, 223, 238 Delirium, 223, 238 Delivery of Health Care, 239, 253 Dementia, 127, 223, 239 Dendrites, 239, 270 Dendritic, 35, 239, 265 Dendritic cell, 35, 239 Density, 51, 60, 124, 135, 158, 227, 239, 242, 262, 271, 289 Dental Care, 155, 157, 161, 239 Depolarization, 239, 288 Depressive Disorder, 21, 239, 263 Dermal, 142, 239 DES, 55, 221, 239 Desensitization, 28, 239

Detergents, 239, 288 Detoxification, 44, 239 Deuterium, 239, 255 Developed Countries, 38, 239 Developing Countries, 153, 239 Diabetes Mellitus, 4, 9, 12, 17, 18, 19, 20, 24, 26, 29, 30, 32, 35, 40, 41, 44, 45, 47, 50, 51, 53, 54, 58, 62, 68, 70, 72, 74, 75, 77, 79, 80, 82, 87, 89, 95, 112, 113, 114, 115, 116, 117, 121, 122, 123, 129, 130, 131, 132, 133, 138, 144, 146, 148, 153, 161, 162, 166, 167, 169, 171, 176, 177, 199, 200, 202, 204, 240, 250, 253, 258 Diabetes, Gestational, 162, 175, 240, 279 Diabetic Foot, 161, 167, 240 Diabetic Ketoacidosis, 6, 8, 71, 132, 157, 161, 162, 170, 171, 240 Diabetic Retinopathy, 24, 33, 39, 42, 47, 64, 116, 120, 121, 156, 158, 166, 167, 173, 240, 276 Diagnostic procedure, 111, 129, 182, 240 Dialyzer, 240, 253 Diaphoresis, 137, 240 Diarrhea, 164, 240 Diastolic, 240, 255 Diencephalon, 240, 256, 293 Dietary Fats, 60, 240 Diffusion, 240, 241, 259 Digestion, 7, 132, 176, 219, 226, 227, 240, 249, 259, 263, 291 Digestive system, 109, 163, 240 Digestive tract, 225, 229, 240, 288 Dihydrotestosterone, 240, 284 Dilatation, 221, 240, 280, 298 Dilatation, Pathologic, 240, 298 Dilation, 32, 38, 228, 241, 298 Dilution, 51, 241, 277 Diploid, 221, 241, 268, 277, 296 Direct, iii, 19, 26, 36, 41, 60, 114, 185, 233, 241, 284 Disaccharides, 7, 241 Discrimination, 154, 157, 241 Disease Progression, 14, 61, 241 Dislocation, 241, 290 Disorientation, 235, 238, 241 Disparity, 40, 241 Disposition, 41, 241 Distal, 140, 237, 241, 275, 281 Diuretic, 241, 289 Diurnal, 5, 78, 241 Dizziness, 154, 164, 241 Dopamine, 223, 233, 241, 276, 286

306

Hyperglycemia

Dorsal, 36, 101, 241, 278, 290 Dorsum, 241, 248 Dosage Forms, 142, 241 Drive, ii, vi, 97, 157, 163, 167, 168, 171, 173, 175, 241, 259 Drug Interactions, 186, 242 Drug Tolerance, 242, 294 Duct, 230, 234, 242, 246, 286 Duodenum, 130, 226, 242, 249, 260, 273, 291 Dyskinesia, 223, 242 Dyslipidemia, 10, 22, 24, 51, 54, 60, 69, 79, 112, 124, 162, 174, 197, 202, 242 Dysmenorrhea, 141, 242 Dysphoric, 239, 242 Dyspnea, 238, 242 Dystonia, 223, 242 Dystrophy, 138, 242 E Eating Disorders, 124, 154, 163, 242 Eclampsia, 242, 279 Ectopic, 36, 242 Edema, 11, 127, 141, 142, 238, 240, 242, 269, 279, 297 Effector, 65, 217, 234, 242, 270, 276 Efficacy, 9, 11, 14, 35, 40, 51, 54, 59, 61, 70, 80, 108, 176, 242 Elasticity, 224, 237, 242 Elastin, 144, 234, 242, 246 Electrocoagulation, 234, 242 Electrolyte, 11, 239, 242, 247, 261, 267, 271, 279, 289, 297 Electrons, 222, 226, 242, 260, 264, 273, 283 Electrophoresis, 62, 243 Electrophysiological, 33, 36, 243, 298 Elementary Particles, 242, 243, 264, 270, 281 Embolus, 243, 258 Embryo, 227, 231, 243, 247, 257, 266, 279, 290 Embryo Transfer, 243, 279 Emollient, 243, 251, 271 Emphysema, 153, 154, 233, 243 Empirical, 54, 243 Encapsulated, 129, 243, 263 Encephalocele, 243, 270 Endemic, 232, 243, 290 Endocrine System, 243, 270 Endocrinology, 63, 74, 80, 85, 87, 88, 89, 93, 94, 96, 98, 127, 167, 243 Endocytosis, 230, 243 Endometrial, 88, 243, 272

Endometrium, 238, 243, 266, 296 Endonucleases, 39, 243 Endopeptidases, 244, 281 Endothelial cell, 24, 26, 31, 33, 52, 55, 72, 79, 102, 244, 293 Endothelium, 15, 19, 32, 44, 61, 62, 80, 244, 271, 277 Endothelium, Lymphatic, 244 Endothelium, Vascular, 19, 244 Endothelium-derived, 44, 244, 271 Endotoxic, 244, 262 Endotoxin, 61, 244, 296 End-stage renal, 18, 40, 233, 244, 278 Energetic, 22, 244 Energy balance, 46, 147, 244, 261 Energy Intake, 43, 88, 244 Enhancer, 142, 143, 244 Enteric-coated, 108, 244 Environmental Health, 190, 192, 244 Enzymatic, 19, 53, 55, 153, 228, 230, 235, 244, 245, 254, 285 Enzyme Inhibitors, 244, 277 Eosinophils, 244, 252, 262 Epidemic, 183, 244, 290 Epidemiological, 14, 15, 38, 66, 125, 245 Epidermis, 245, 260, 282 Epigastric, 245, 273 Epinephrine, 26, 218, 241, 245, 260, 271, 296 Epithelial, 16, 58, 70, 75, 95, 100, 218, 232, 238, 245, 261 Epithelial Cells, 70, 75, 100, 232, 245, 261 Epithelium, 226, 244, 245, 249 Epitopes, 13, 37, 245 Equipment and Supplies, 165, 245 Erectile, 121, 156, 162, 173, 245 Erection, 245 Erythrocytes, 221, 227, 245 Erythromycin, 84, 245 Escalation, 44, 245 Esophagus, 240, 245, 253, 291 Esterification, 50, 245 Estradiol, 245 Estrogens, 245, 252 Estrone, 102, 245 Ether, 86, 100, 246 Eukaryotic Cells, 246, 257, 272 Evacuation, 235, 246, 249, 261 Evoke, 246, 291 Excrete, 223, 246, 261 Exercise Therapy, 175, 246 Exhaustion, 50, 131, 222, 246

Index 307

Exocrine, 246, 273 Exogenous, 43, 58, 113, 115, 118, 128, 229, 246, 249, 296 Expiration, 246, 285 External-beam radiation, 246, 283 Extracellular, 13, 42, 55, 65, 87, 235, 243, 246, 247, 289, 293 Extracellular Matrix, 13, 42, 55, 65, 87, 235, 246, 247 Extracellular Matrix Proteins, 55, 246 Extracellular Space, 246 Extraction, 142, 246 Extrapyramidal, 219, 223, 241, 246 Extremity, 162, 246, 286 Exudate, 142, 246 Eye Infections, 218, 246 F Faecal, 143, 247 Family Planning, 191, 247 Fatigue, 137, 247, 253 Fatty Liver, 46, 247 Feces, 235, 247, 291 Fertilization in Vitro, 247, 279 Fetal Blood, 247, 277 Fetal Development, 247, 270 Fetus, 32, 35, 43, 69, 160, 247, 277, 290, 291, 297 Fibrillation, 76, 247 Fibrin, 227, 247, 277, 293, 294 Fibrinogen, 247, 277, 293 Fibroblasts, 75, 235, 247, 259 Fibronectins, 246, 247 Fibrosis, 23, 247, 286 Filtration, 58, 64, 247, 261 Fluid Therapy, 11, 247, 271 Fold, 25, 45, 56, 62, 247, 266 Food Habits, 177, 247 Food Preferences, 247, 248 Foot Care, 155, 161, 162, 168, 175, 248 Foot Ulcer, 162, 240, 248 Forearm, 8, 44, 227, 248 Forskolin, 33, 248 Fractionation, 27, 248 Fructosamine, 100, 248 Fructose, 28, 248, 252, 259, 295 Functional magnetic resonance imaging, 64, 248 Fungi, 246, 248, 266, 267, 300 Fungistatic, 226, 248 G GABA, 248, 251, 288 Galanin, 71, 248

Gallbladder, 118, 217, 226, 240, 248, 273 Gallstones, 134, 226, 248 Gamma Rays, 248, 283 Ganglia, 217, 225, 248, 269, 275, 292 Ganglion, 36, 101, 248, 272 Gangrene, 114, 217, 249 Gas, 220, 229, 240, 249, 255, 271, 291 Gastric, 7, 9, 82, 84, 101, 225, 229, 241, 249, 253, 254 Gastric Emptying, 7, 9, 84, 101, 249 Gastric Mucosa, 82, 249 Gastrin, 249, 254 Gastritis, 180, 249 Gastrointestinal, 131, 154, 162, 198, 228, 229, 245, 249, 287, 289, 290, 291, 299 Gastrointestinal tract, 249, 287, 289, 290 Gastroparesis, 156, 249 Gavage, 247, 249 Gene Expression, 18, 20, 24, 30, 39, 47, 50, 57, 58, 69, 119, 249 Gene Targeting, 21, 249 Genetic Code, 249, 271 Genetic Counseling, 162, 249 Genetic Engineering, 227, 233, 249 Genetic Markers, 49, 249 Genetics, 16, 29, 45, 51, 62, 145, 153, 249 Genital, 225, 233, 249 Genotype, 249, 276 Geriatric, 89, 162, 249 Germ Cells, 145, 249, 272, 289, 293 Gestation, 29, 32, 35, 43, 249, 275, 277, 290 Gestational, 29, 32, 35, 43, 48, 57, 73, 82, 88, 98, 129, 156, 157, 160, 166, 180, 200, 202, 250 Gestational Age, 29, 250 Gland, 70, 127, 146, 167, 218, 250, 255, 264, 273, 277, 281, 286, 287, 291, 294 Gliclazide, 121, 250 Glipizide, 11, 121, 180, 250 Glomerular, 12, 58, 64, 65, 66, 250, 259, 261, 284 Glomerular Filtration Rate, 64, 250, 261 Glomeruli, 47, 65, 250 Glomerulosclerosis, 121, 250 Glomerulus, 58, 250 Glottis, 250, 275 Glucocorticoid, 17, 56, 71, 250 Glucokinase, 41, 148, 250 Gluconeogenesis, 18, 55, 56, 107, 127, 137, 250 Glucose Clamp Technique, 56, 125, 250

308

Hyperglycemia

Glucose Intolerance, 23, 32, 35, 49, 240, 250 Glucose Tolerance Test, 6, 38, 98, 112, 125, 129, 250, 251 Glucose-6-Phosphatase, 102, 128, 251 Glutamate, 70, 251 Glutamate Decarboxylase, 70, 251 Glutamic Acid, 251, 280 Glutamine, 28, 251 Glutathione Peroxidase, 44, 251 Glyburide, 121, 251 Glycerol, 51, 251, 276 Glycerophospholipids, 251, 276 Glycine, 226, 251, 287 Glycogen, 18, 41, 82, 115, 120, 132, 141, 144, 251, 276 Glycogen Storage Disease, 82, 251 Glycogen Synthase, 115, 251 Glycolysis, 33, 251 Glycoprotein, 247, 252, 261, 264, 293, 296 Glycosaminoglycans, 246, 252 Glycoside, 241, 252, 286 Glycosidic, 252, 276 Glycosuria, 88, 169, 252 Glycosylation, 28, 37, 65, 72, 153, 252 Gonad, 252 Gonadal, 108, 252, 290 Gonadorelin, 252, 262 Gonadotropin, 25, 252, 262 Governing Board, 252, 279 Gp120, 252, 274 Grade, 24, 160, 197, 252 Graft, 252, 254, 257, 267, 269 Grafting, 89, 90, 237, 252, 257 Granulocytes, 252, 268, 288, 299 Growth factors, 18, 57, 66, 138, 166, 252 Guanylate Cyclase, 252, 271 H Habitual, 231, 253 Headache, 137, 154, 253 Headache Disorders, 253 Health Care Costs, 60, 253 Health Expenditures, 253 Health Services, 14, 239, 253 Heart attack, 146, 173, 229, 253 Heart failure, 53, 83, 253 Heartburn, 164, 253 Helix-loop-helix, 31, 253 Hemodialysis, 18, 168, 240, 253, 261 Hemodynamics, 34, 253 Hemoglobin, 4, 6, 10, 133, 155, 156, 166, 173, 174, 221, 245, 253

Hemorrhage, 89, 94, 179, 237, 242, 253, 269, 282, 291, 299 Hemostasis, 253, 287 Hepatocellular, 77, 254 Hepatocellular carcinoma, 77, 254 Hepatocyte, 83, 92, 254 Heredity, 249, 254 Heterozygote, 17, 254 High-density lipoproteins, 124, 254 Hirsutism, 254, 255 Histamine, 221, 223, 254 Histocompatibility, 148, 254, 267 Histocompatibility Antigens, 148, 254 Histology, 65, 254 Holidays, 156, 157, 168, 254 Homeostasis, 16, 20, 22, 41, 43, 55, 56, 108, 112, 130, 171, 254, 289 Homologous, 45, 145, 220, 238, 249, 254, 287, 292 Hormonal, 28, 55, 56, 125, 171, 224, 254 Hospital Mortality, 75, 85, 254 Host, 20, 119, 225, 254, 256, 257, 297, 299 Humulin, 99, 254 Hybrid, 225, 233, 254 Hybridomas, 254, 259 Hydrogen Peroxide, 90, 230, 251, 255, 262, 292 Hydrolysis, 67, 243, 255, 259, 262, 276, 278, 281 Hydrophilic, 113, 122, 239, 255 Hydrophobic, 130, 239, 251, 255, 262 Hydroxylysine, 234, 255 Hydroxyproline, 234, 255 Hygienic, 255, 288 Hyperalgesia, 36, 101, 255 Hyperandrogenism, 108, 255 Hypercholesterolemia, 19, 77, 87, 108, 112, 120, 124, 136, 144, 242, 255 Hyperlipidaemia, 255 Hyperlipoproteinemia, 255, 262 Hyperplasia, 45, 63, 87, 138, 145, 255 Hypersensitivity, 220, 239, 255, 286 Hypertriglyceridemia, 60, 69, 81, 83, 91, 100, 108, 112, 121, 124, 242, 255 Hypertrophy, 24, 42, 45, 63, 138, 226, 236, 255, 296 Hypoglycemic Agents, 114, 117, 120, 121, 137, 144, 162, 165, 166, 168, 175, 256 Hypolipidemic, 113, 142, 256 Hypoplasia, 46, 145, 256 Hypotension, 162, 223, 236, 256 Hypothalamic, 17, 108, 256

Index 309

Hypothalamus, 119, 147, 225, 240, 252, 256, 277, 289, 293 Hypothyroidism, 73, 256 Hypoxia, 62, 64, 77, 95, 239, 256 I Iatrogenic, 76, 256 Ice Cream, 163, 256 Id, 103, 197, 198, 199, 200, 201, 202, 203, 204, 205, 212, 214, 256 Idiopathic, 38, 137, 201, 256 Ileum, 256, 260 Imaging procedures, 256, 295 Imidazole, 134, 254, 256 Immune response, 222, 225, 236, 256, 257, 264, 291, 297, 299 Immune Sera, 256, 257 Immune system, 37, 222, 225, 226, 256, 257, 264, 275, 297, 299 Immunity, 17, 70, 256, 257, 295 Immunization, 70, 218, 256, 257 Immunoblotting, 27, 58, 257 Immunogenic, 257, 262 Immunoglobulin, 222, 257, 268 Immunologic, 14, 176, 218, 232, 250, 257, 283 Immunology, 67, 79, 81, 139, 153, 167, 218, 257 Immunosuppressive, 250, 257 Immunotherapy, 218, 226, 239, 257 Impairment, 16, 36, 41, 46, 50, 86, 115, 226, 238, 242, 246, 257, 266, 282 Implant radiation, 257, 259, 283 Implantation, 87, 235, 257, 272 Impotence, 156, 173, 245, 257 In situ, 39, 257 In Situ Hybridization, 39, 257 In vitro, 19, 20, 30, 33, 35, 38, 42, 44, 47, 56, 58, 62, 66, 67, 86, 102, 153, 243, 257 Incision, 228, 257, 259 Incontinence, 118, 257 Incubated, 33, 257 Incubation, 257, 275 Incubation period, 257, 275 Indicative, 23, 169, 257, 274, 298 Induction, 16, 24, 38, 40, 141, 221, 223, 257, 283, 288 Infancy, 258 Infantile, 79, 258 Infarction, 11, 25, 44, 53, 70, 75, 79, 83, 86, 94, 114, 121, 162, 181, 197, 237, 258, 266, 268, 285, 298

Infusion, 34, 45, 51, 63, 64, 76, 99, 107, 153, 165, 227, 250, 258, 269 Ingestion, 9, 18, 129, 130, 251, 258, 278, 293 Initiation, 25, 258, 295 Innervation, 258, 275, 286, 294 Inorganic, 218, 258 Insight, 19, 22, 52, 61, 258 Insulin-like, 38, 42, 108, 153, 166, 258 Intensive Care, 76, 84, 94, 258 Interindividual, 9, 258 Interleukin-1, 139, 258 Interleukin-2, 258, 259 Interleukin-6, 139, 259 Intermittent, 134, 247, 259, 263 Internal Medicine, 14, 31, 37, 40, 77, 98, 99, 101, 171, 243, 259 Internal radiation, 259, 283 Interstitial, 228, 236, 246, 259, 284 Intestinal, 7, 60, 70, 118, 130, 154, 230, 232, 251, 259 Intestine, 124, 135, 226, 228, 259, 261 Intracellular, 13, 30, 33, 39, 41, 47, 55, 67, 74, 117, 123, 258, 259, 265, 271, 279, 284, 286, 288 Intracellular Membranes, 259, 265 Intraindividual, 9, 259 Intramuscular, 259, 273 Intraocular, 248, 259 Intraocular pressure, 248, 259 Intravenous, 5, 8, 107, 171, 227, 258, 259, 273 Intrinsic, 219, 226, 259 Intubation, 230, 259 Inulin, 250, 259 Invasive, 27, 65, 156, 256, 259, 264 Invertebrates, 250, 259 Involuntary, 225, 232, 247, 259, 269, 288, 289 Ion Transport, 100, 259, 267 Ions, 225, 242, 255, 259, 267, 281 Ischemia, 25, 34, 85, 120, 141, 144, 224, 238, 260, 269, 285 Ischemic stroke, 80, 260 Islet, 20, 30, 34, 37, 40, 41, 46, 51, 57, 72, 98, 117, 126, 131, 132, 148, 166, 260 Isoenzyme, 237, 260 Isoproterenol, 33, 260 J Jejunum, 130, 260 Joint, 139, 143, 168, 260, 290, 292 Joint Capsule, 260, 292

310

Hyperglycemia

K Kb, 190, 260 Keratin, 260, 287 Keratitis, 236, 260 Keratoconjunctivitis, 236, 260 Ketone Bodies, 132, 217, 240, 260 Ketosis, 148, 240, 260 Kidney Failure, 132, 137, 168, 244, 250, 261 Kidney Failure, Acute, 261 Kidney Failure, Chronic, 261 Kidney stone, 261, 297 Kidney Transplantation, 168, 261 Kinetic, 51, 68, 261 L Labile, 234, 261 Laminin, 226, 246, 261 Large Intestine, 240, 259, 261, 284, 288 Larynx, 250, 261, 295 Latent, 261, 279 Laxative, 219, 261, 289 Lectin, 261, 265 Lens, 16, 75, 123, 230, 261, 299 Leprosy, 248, 261 Leptin, 22, 30, 41, 55, 99, 100, 124, 147, 261 Lesion, 64, 76, 145, 237, 248, 262, 263, 292 Lethal, 14, 262 Lethargy, 256, 262 Leukemia, 92, 262 Leukocytes, 24, 226, 227, 231, 232, 244, 252, 262, 296 Leuprolide, 25, 262 Library Services, 212, 262 Life cycle, 157, 248, 262 Ligament, 262, 281, 290 Ligands, 55, 262 Ligation, 53, 262 Linkage, 20, 22, 49, 70, 249, 262 Lipid A, 17, 41, 49, 144, 262 Lipid Peroxidation, 62, 262, 273 Lipolysis, 26, 41, 118, 262 Lipophilic, 131, 262 Lipopolysaccharide, 17, 61, 262 Lipoprotein, 15, 51, 54, 60, 67, 98, 112, 135, 136, 158, 242, 262, 263 Lipoprotein Lipase, 15, 67, 262 Lipoprotein(a), 51, 262 Liposomal, 129, 263 Liposome, 129, 263 Lipoxygenase, 31, 65, 224, 263 Lithium, 223, 263 Liver, 8, 18, 22, 41, 46, 56, 69, 72, 91, 112, 115, 117, 118, 119, 124, 126, 127, 132,

135, 137, 140, 141, 148, 217, 219, 224, 226, 229, 240, 247, 248, 250, 251, 253, 254, 263, 284 Liver Cirrhosis, 141, 263 Localization, 67, 263 Localized, 47, 243, 254, 258, 261, 263, 277 Longitudinal study, 22, 61, 263 Long-Term Care, 174, 263 Loop, 147, 263 Lovastatin, 263, 288 Low-density lipoprotein, 124, 242, 262, 263 Lubricants, 263, 275 Luciferase, 39, 58, 263 Lumbar, 101, 225, 264, 286, 294 Lumen, 244, 264 Luteal Phase, 25, 264 Lymph, 37, 70, 244, 264, 273 Lymph node, 37, 70, 264, 273 Lymphatic, 244, 258, 264, 266, 278, 289, 290, 294 Lymphatic system, 264, 289, 290, 294 Lymphocyte, 69, 222, 264, 265 Lymphoid, 70, 222, 237, 264 Lysine, 65, 68, 255, 264 Lytic, 204, 264 M Macrophage, 47, 139, 258, 264 Macrophage Colony-Stimulating Factor, 139, 264 Magnetic Resonance Imaging, 21, 74, 264 Magnetic Resonance Spectroscopy, 65, 264 Major Histocompatibility Complex, 29, 254, 264 Malformation, 180, 264 Malignant, 89, 218, 224, 264, 269, 283, 293 Malnutrition, 219, 224, 228, 265 Mammary, 237, 262, 265 Manic, 223, 263, 265, 282 Manifest, 23, 47, 53, 265 Meat, 240, 265 Meat Products, 240, 265 Meatus, 265, 296 Medial, 224, 265, 272, 294 Mediate, 16, 18, 57, 65, 180, 241, 265 Mediator, 55, 259, 265, 287 Medicament, 127, 265 MEDLINE, 191, 265 Megakaryocytes, 227, 265 Melanin, 265, 276, 296 Melanocytes, 265

Index 311

Melanoma, 95, 100, 265 Membrane, 16, 25, 28, 33, 57, 66, 67, 230, 231, 232, 235, 239, 240, 243, 246, 252, 261, 265, 272, 276, 277, 279, 285, 288, 292, 295, 296, 299 Membrane Fluidity, 16, 265 Membrane Proteins, 16, 230, 265 Memory, 21, 70, 87, 141, 221, 238, 239, 265 Meninges, 231, 237, 265 Menopause, 25, 266, 278, 279 Menstrual Cycle, 25, 264, 266, 280 Menstruation, 220, 238, 242, 264, 266, 271 Mental Disorders, 109, 266, 282 Mental Health, iv, 12, 109, 190, 192, 266, 282 Mentors, 68, 266 Mesenchymal, 264, 266 Mesenteric, 70, 266 Mesentery, 266 Mesoderm, 266, 296 Mesolimbic, 223, 266 Meta-Analysis, 76, 266 Metabolic disorder, 125, 136, 251, 266 Metabolite, 245, 263, 266, 280 Metastasis, 266 Metastatic, 42, 266 Metastatic cancer, 42, 266 MI, 53, 78, 123, 144, 156, 180, 183, 215, 266 Mice, Transgenic, 65, 266 Microbe, 266, 295 Microbiology, 218, 224, 266 Microcirculation, 19, 263, 267, 277 Microorganism, 234, 267, 299 Microscopy, 19, 27, 226, 267 Migration, 31, 267 Milligram, 159, 267 Mineralocorticoids, 167, 218, 267 Minor Histocompatibility Antigens, 254, 267 Minority Groups, 59, 267 Mitochondria, 44, 47, 61, 67, 135, 267, 269, 272 Mitochondrial Swelling, 267, 269 Mitosis, 223, 267 Mitotic, 145, 267 Mobility, 58, 267 Modeling, 4, 267 Modification, 16, 38, 70, 122, 131, 249, 267, 283 Molecular Structure, 176, 267 Monitor, 6, 27, 34, 158, 173, 237, 267, 271 Monoclonal, 13, 37, 254, 257, 268, 283

Monoclonal antibodies, 13, 37, 257, 268 Monocyte, 31, 48, 88, 264, 268 Monogenic, 46, 87, 268 Mononuclear, 47, 264, 268, 296 Monosomy, 221, 268 Monotherapy, 3, 7, 51, 74, 177, 268 Morphology, 39, 230, 268 Motility, 118, 156, 268, 287 Motion Sickness, 268, 269 Motor Activity, 236, 268 Movement Disorders, 223, 268 Mucinous, 249, 268 Muscular Dystrophies, 242, 268 Musculature, 268, 290 Mutagenesis, 39, 62, 268 Mutagens, 268 Mydriatic, 241, 268 Myeloid Cells, 140, 268 Myocardial Ischemia, 120, 144, 221, 268 Myocardial Reperfusion, 268, 269, 285 Myocardial Reperfusion Injury, 269, 285 Myocardium, 53, 221, 266, 268, 269 N Natriuresis, 63, 269 Nausea, 154, 164, 198, 222, 223, 241, 249, 260, 269, 297 NCI, 1, 109, 189, 233, 269 Necrosis, 25, 38, 223, 258, 266, 268, 269, 285 Neonatal, 32, 35, 43, 57, 162, 198, 269 Neonatal period, 43, 269 Neoplasm, 102, 269, 296 Nephron, 250, 269 Nephrosis, 269 Nephrotic, 141, 269 Nephrotic Syndrome, 141, 269 Nervous System, 141, 159, 218, 225, 231, 233, 251, 265, 269, 270, 275, 292 Neural, 180, 218, 243, 270 Neural tube defects, 180, 270 Neuroendocrine, 102, 270 Neuroendocrinology, 167, 270 Neuroleptic, 89, 219, 222, 233, 270 Neurologic, 38, 243, 270 Neuromuscular, 138, 217, 270, 297 Neuronal, 77, 233, 270 Neurons, 239, 248, 270, 271, 292 Neuropeptide, 141, 270 Neuropsychological Tests, 21, 270 Neurosis, 270, 276 Neurotransmitters, 270, 289 Neutralization, 13, 270

312

Hyperglycemia

Neutrons, 220, 270, 283 Neutrophil, 88, 99, 100, 270 Niacin, 51, 270, 296 Nicotine, 75, 271 Nitric Oxide, 26, 32, 44, 55, 62, 63, 64, 271 Nitrogen, 7, 219, 221, 246, 251, 261, 271, 296 Norepinephrine, 218, 241, 271 Nuclear, 58, 74, 79, 92, 124, 225, 242, 246, 248, 269, 271, 283 Nuclei, 220, 242, 249, 264, 267, 270, 271, 272, 281 Nucleic acid, 68, 70, 119, 249, 257, 268, 271, 282 Nucleus, 223, 225, 226, 232, 238, 239, 243, 244, 246, 248, 266, 268, 270, 271, 281, 289, 291 Nutritional Status, 156, 271 Nutritional Support, 42, 203, 271 O Occult, 198, 271 Ocular, 16, 48, 162, 236, 271 Ointments, 241, 271, 288 Oligomenorrhea, 271, 278 Oliguria, 261, 271 Opacity, 230, 239, 271 Opsin, 272, 285 Optic Chiasm, 256, 272 Optic Disk, 240, 272 Optic Nerve, 272, 285 Organelles, 238, 265, 272 Organizational Culture, 157, 272 Orthostatic, 223, 272 Osmosis, 272 Osmotic, 36, 123, 219, 267, 272 Osteoporosis, 127, 138, 272 Outpatient, 87, 272 Ovaries, 255, 272, 278, 293 Ovary, 116, 245, 252, 272, 291 Overexpress, 30, 65, 272 Overweight, 30, 68, 88, 103, 272 Ovulation, 222, 264, 272 Ovum, 238, 250, 262, 272, 280, 296, 300 Ovum Implantation, 272, 296 Oxidation, 17, 26, 30, 41, 47, 55, 68, 134, 217, 222, 223, 240, 251, 262, 272, 273, 274 Oxidative Stress, 16, 22, 30, 31, 32, 39, 44, 47, 53, 61, 62, 81, 84, 86, 273 Oxygen Consumption, 273, 285 Oxygenation, 95, 273 P Palliative, 273, 293

Pancreas Transplant, 40, 273 Pancreas Transplantation, 40, 273 Pancreatectomy, 40, 273 Pancreatic cancer, 23, 273 Pancreatitis, 79, 91, 273 Parathyroid, 167, 273, 293 Parathyroid Glands, 273 Parenteral, 76, 128, 198, 244, 273 Parenteral Nutrition, 76, 198, 273 Parkinsonism, 223, 273 Paroxysmal, 221, 253, 274, 275, 299 Partial remission, 274, 284 Particle, 263, 274, 289, 295 Partnership Practice, 274, 280 Patch, 33, 274 Pathogenesis, 6, 19, 29, 33, 36, 37, 42, 58, 65, 66, 68, 77, 85, 92, 115, 153, 171, 274 Pathologic, 37, 42, 65, 132, 143, 217, 223, 237, 255, 274 Pathologic Processes, 42, 223, 274 Pathologies, 22, 47, 53, 274 Pathophysiology, 40, 50, 55, 58, 155, 156, 161, 170, 171, 176, 274 Patient Care Team, 153, 160, 163, 274 Patient Education, 152, 160, 166, 174, 176, 196, 210, 212, 215, 274 Patient Selection, 152, 274 Pelvic, 274, 281 Penicillin, 222, 274 Pentosephosphate Pathway, 274, 295 Peptide, 34, 37, 115, 125, 140, 141, 232, 244, 260, 261, 274, 278, 281, 294 Peptide T, 35, 274 Perfusion, 36, 62, 101, 250, 256, 274 Pericytes, 24, 33, 274 Perinatal, 49, 57, 84, 100, 203, 274 Periodontal disease, 42, 159, 275 Perioperative, 89, 90, 275 Peripheral Nervous System, 9, 36, 275, 289, 291 Peripheral Neuropathy, 9, 36, 38, 175, 275 Peripheral Vascular Disease, 10, 95, 112, 162, 275 Peroneal Nerve, 275, 286 Perspiration, 240, 275 Pertussis, 71, 275, 299 Petroleum, 100, 275 Phagocyte, 264, 275 Pharmaceutical Solutions, 241, 275 Pharmacist, 168, 275 Pharmacologic, 17, 41, 157, 174, 198, 221, 275, 295

Index 313

Pharmacotherapy, 51, 275 Phenotype, 24, 37, 38, 44, 51, 66, 276 Phenyl, 124, 127, 276 Phenylalanine, 276, 296 Phobia, 163, 276 Phobic Disorders, 276 Phosphodiesterase, 116, 121, 276 Phospholipases, 276, 288 Phospholipids, 31, 247, 262, 265, 276 Phosphorus, 228, 273, 276 Phosphorylase, 120, 144, 276 Phosphorylate, 44, 135, 276 Phosphorylating, 38, 276 Phosphorylation, 17, 28, 37, 41, 62, 67, 79, 135, 218, 276 Photocoagulation, 234, 276 Physical Examination, 11, 24, 250, 276 Physical Fitness, 183, 246, 276 Physiologic, 17, 21, 26, 44, 55, 62, 219, 226, 247, 259, 266, 277, 284, 296 Physiology, 24, 63, 78, 96, 100, 145, 167, 169, 171, 229, 243, 277 Pigment, 100, 226, 265, 277 Pilot study, 54, 277 Pituitary Gland, 141, 167, 248, 252, 277 Placenta, 62, 245, 246, 247, 277, 280 Placental Circulation, 62, 277 Placental tissue, 57, 277 Plants, 219, 229, 250, 252, 259, 261, 268, 271, 277, 286, 295 Plaque, 13, 144, 277 Plasma cells, 140, 222, 277 Plasma protein, 147, 219, 244, 277, 281 Plasma Volume, 267, 277 Plasmin, 277, 294, 297 Plasminogen, 51, 72, 277, 294, 297 Plasminogen Activators, 277 Platelet Activation, 74, 278, 288 Platelet Aggregation, 141, 143, 221, 248, 271, 278 Platelets, 117, 223, 271, 278, 293, 294 Platinum, 263, 278 Plexus, 278, 286 Poisoning, 239, 269, 278 Polycystic, 116, 134, 255, 278 Polycystic Ovary Syndrome, 116, 134, 255, 278 Polymerase, 72, 278 Polymers, 113, 122, 278, 281 Polymorphic, 45, 278 Polymorphism, 50, 63, 94, 278

Polypeptide, 72, 220, 234, 247, 277, 278, 281, 289, 300 Polysaccharide, 222, 278, 281 Pons, 226, 278 Posterior, 141, 220, 225, 226, 232, 241, 273, 278 Postmenopausal, 272, 278 Postnatal, 42, 278 Postoperative, 90, 199, 278 Postprandial Blood Glucose, 7, 279 Postsynaptic, 279, 288, 292 Post-translational, 28, 279 Postural, 162, 279 Potassium, 5, 8, 11, 94, 267, 279, 288 Potentiate, 38, 279 Potentiation, 279, 288 Practice Guidelines, 192, 197, 200, 202, 205, 279 Precipitating Factors, 4, 11, 170, 253, 279 Preclinical, 35, 40, 279 Precursor, 52, 105, 221, 224, 241, 242, 244, 271, 276, 277, 279, 280, 281, 296 Predisposition, 45, 63, 279 Preeclampsia, 62, 279 Pregnancy in Diabetics, 240, 279 Pregnancy Outcome, 32, 35, 49, 93, 279 Pregnancy Tests, 250, 279 Premenopausal, 25, 279 Prevalence, 5, 13, 21, 60, 91, 125, 183, 279 Private Practice, 48, 280 Probe, 68, 280 Problem Solving, 156, 280 Prodrug, 126, 280 Progeny, 20, 139, 280 Progesterone, 280, 290 Progression, 7, 15, 18, 24, 30, 38, 49, 51, 61, 133, 139, 145, 221, 280 Proinsulin, 50, 70, 128, 153, 280, 282 Proline, 234, 255, 280 Promoter, 20, 39, 50, 56, 58, 280 Prone, 29, 68, 148, 280 Prophylaxis, 143, 280, 285, 297 Prospective Studies, 7, 280 Prospective study, 30, 263, 280 Prostaglandins, 64, 82, 224, 280 Prostaglandins A, 64, 280 Prostaglandins D, 280 Prostate, 118, 226, 281 Prostatic Hyperplasia, 281 Protease, 60, 180, 234, 281, 294 Protease Inhibitors, 60, 281

314

Hyperglycemia

Protein C, 84, 219, 220, 223, 225, 260, 262, 281 Protein Conformation, 220, 260, 281 Protein Kinases, 65, 281 Protein S, 18, 20, 23, 62, 70, 128, 169, 227, 245, 249, 281, 286 Proteinuria, 49, 58, 250, 269, 279, 281 Proteoglycans, 54, 144, 226, 246, 281 Proteolytic, 220, 234, 247, 277, 281, 294, 297 Prothrombin, 13, 281, 293 Protocol, 27, 35, 45, 49, 63, 281 Protons, 220, 255, 264, 281, 283 Protozoa, 267, 281 Proximal, 241, 281 Proxy, 89, 282 Psychiatric, 21, 34, 53, 266, 282 Psychiatry, 34, 88, 89, 91, 92, 95, 96, 100, 282 Psychic, 270, 282, 287 Psychomotor, 21, 238, 243, 270, 282 Psychosis, 222, 250, 282 Public Health, 15, 54, 59, 69, 99, 147, 192, 202, 203, 282 Public Policy, 191, 282 Publishing, 7, 8, 71, 114, 151, 153, 154, 158, 159, 161, 163, 166, 282 Pulmonary, 11, 23, 138, 227, 235, 236, 261, 282, 298 Pulmonary Artery, 227, 282, 298 Pulmonary Edema, 261, 282 Pulmonary Embolism, 11, 282 Pulmonary hypertension, 236, 282 Pulse, 128, 267, 282 Pupil, 236, 241, 268, 282 Purified Insulins, 280, 282 Purines, 282, 287 Purpura, 201, 282 Purulent, 282, 298 Putrefaction, 249, 283 Pyridoxal, 251, 283 Q Quality of Life, 27, 152, 283 R Race, 45, 59, 63, 267, 283 Radiation, 36, 80, 95, 198, 221, 229, 243, 246, 248, 259, 283, 300 Radiation therapy, 198, 229, 246, 248, 259, 283 Radioactive, 60, 255, 257, 259, 268, 271, 283 Radioactivity, 16, 283

Radiography, 250, 283 Radioisotope, 283, 295 Radiolabeled, 227, 283 Radiological, 139, 283 Radiology, 34, 100, 283 Radiotherapy, 228, 283 Randomized, 25, 51, 60, 68, 73, 87, 98, 108, 242, 283 Reabsorption, 141, 283 Reactive Oxygen Species, 26, 30, 33, 38, 39, 44, 283 Reagent, 263, 284 Receptors, Serotonin, 284, 287 Recombinant, 50, 70, 81, 107, 108, 147, 284, 298 Recombination, 145, 249, 284 Rectum, 228, 240, 249, 257, 261, 281, 284 Recurrence, 233, 284 Reductase, 75, 121, 123, 135, 219, 263, 284, 288 Refer, 1, 175, 234, 241, 248, 263, 270, 282, 284 Regeneration, 46, 284 Regimen, 114, 132, 174, 182, 242, 275, 284 Regurgitation, 253, 284 Relaxant, 248, 284 Remission, 139, 284 Renal failure, 18, 40, 58, 137, 141, 239, 284 Renal Plasma Flow, 45, 63, 284 Renin, 37, 45, 61, 62, 64, 221, 229, 284 Renin-Angiotensin System, 37, 45, 62, 229, 284 Reperfusion, 25, 83, 85, 86, 269, 284, 285 Reperfusion Injury, 25, 285 Reproduction Techniques, 279, 285 Reproductive cells, 249, 285 Research Design, 21, 285 Research Support, 49, 285 Respiration, 100, 229, 232, 267, 285 Respiratory distress syndrome, 11, 285 Retina, 47, 65, 83, 119, 123, 232, 235, 240, 261, 272, 285, 286, 299 Retinal, 24, 33, 39, 64, 66, 79, 100, 240, 241, 272, 285 Retinal Vessels, 33, 285 Retinoids, 285 Retinol, 60, 285 Retinopathy, 10, 24, 34, 39, 47, 64, 84, 112, 114, 116, 175, 219, 240, 285 Reversion, 30, 285 Rheumatism, 139, 285, 286 Rheumatoid, 42, 139, 142, 286

Index 315

Rheumatoid arthritis, 42, 139, 142, 286 Ribose, 72, 286 Ribosome, 286, 295 Rickettsiae, 286 Risk factor, 4, 7, 10, 19, 23, 25, 51, 57, 59, 60, 70, 84, 95, 124, 156, 158, 173, 174, 175, 280, 286 Risperidone, 91, 286 Rod, 233, 286 Rosiglitazone, 74, 117, 120, 121, 286 S Saline, 8, 171, 286 Saliva, 286 Salivary, 70, 130, 240, 273, 286 Salivary glands, 240, 286 Salivation, 142, 286 Saphenous, 237, 286 Saphenous Vein, 237, 286 Saponins, 286, 291 Schizophrenia, 95, 286 Sciatic Nerve, 36, 275, 286, 294 Sclerosis, 85, 138, 224, 286 Screening, 23, 49, 69, 119, 158, 183, 204, 233, 286 Sebaceous, 286, 287 Sebaceous gland, 287 Sebum, 143, 286, 287 Sedentary, 183, 287 Segmental, 250, 287 Segregation, 284, 287 Seizures, 113, 122, 154, 239, 274, 287, 290 Self Care, 8, 157, 160, 163, 217, 287 Sella, 241, 277, 287 Semen, 281, 287 Senile, 272, 287 Sensibility, 220, 255, 287 Sepsis, 86, 287 Sequence Homology, 274, 287 Serine, 17, 244, 287, 294 Serotonin, 121, 223, 233, 276, 284, 286, 287, 296 Serous, 244, 287 Sexually Transmitted Diseases, 164, 287 Shock, 287, 296 Side effect, 88, 121, 131, 132, 144, 148, 163, 175, 176, 185, 218, 219, 223, 226, 229, 288, 295 Signal Transduction, 18, 28, 62, 65, 67, 230, 288 Signs and Symptoms, 155, 170, 284, 288, 297 Simvastatin, 81, 181, 288

Skeletal, 20, 40, 46, 68, 69, 81, 115, 135, 138, 140, 221, 233, 237, 260, 268, 288, 289 Skeleton, 139, 260, 288 Skin Care, 162, 165, 288 Skull, 237, 243, 270, 288, 293 Small intestine, 46, 226, 233, 242, 254, 256, 259, 260, 288, 299 Smallpox, 288, 298 Sneezing, 275, 288 Soaps, 288 Social Behavior, 141, 288 Social Environment, 283, 289 Socioeconomic Factors, 45, 62, 289 Sodium, 64, 157, 267, 269, 283, 288, 289 Soft tissue, 227, 288, 289 Solid tumor, 221, 289 Solitary Nucleus, 225, 289 Solvent, 217, 251, 272, 275, 289 Soma, 289 Somatic, 145, 267, 275, 289 Somatostatin, 68, 76, 289 Sorbitol, 123, 219, 289 Sound wave, 235, 289 Spasm, 145, 237, 289, 293 Spasmodic, 275, 289 Spatial disorientation, 241, 289 Specialist, 175, 206, 241, 289 Specificity, 50, 115, 140, 219, 224, 244, 290 Sperm, 221, 232, 285, 290, 293 Spina bifida, 270, 290 Spinal cord, 231, 232, 248, 265, 269, 270, 275, 286, 290, 292 Spinal Nerves, 275, 290 Spleen, 37, 70, 119, 264, 273, 290 Spondylolisthesis, 204, 290 Spontaneous Abortion, 279, 290 Sporadic, 23, 132, 290 Sprains and Strains, 164, 290 Stabilization, 14, 290 Stasis, 102, 290 Statistically significant, 59, 125, 290 Status Epilepticus, 93, 290 Steatosis, 22, 247, 290 Steel, 233, 290 Stent, 87, 290 Sterile, 273, 290 Steroid, 127, 226, 237, 286, 288, 290 Stillbirth, 279, 291 Stimulant, 254, 260, 291 Stimulus, 25, 70, 235, 241, 258, 276, 291, 293 Stool, 257, 261, 291

316

Hyperglycemia

Strand, 278, 291 Stroma, 62, 236, 291 Stromal, 227, 291 Stromal Cells, 227, 291 Subacute, 17, 258, 291 Subarachnoid, 89, 179, 253, 291 Subclinical, 258, 287, 291 Subcutaneous, 5, 11, 42, 129, 218, 242, 273, 291, 299 Subspecies, 290, 291, 298 Substance P, 245, 266, 287, 291 Substrate, 22, 25, 26, 39, 68, 135, 244, 291 Substrate Specificity, 68, 291 Suction, 247, 291 Sulfur, 246, 291 Superoxide, 19, 26, 32, 44, 47, 52, 61, 62, 63, 68, 72, 291, 292 Superoxide Dismutase, 19, 61, 68, 292 Supplementation, 99, 102, 292 Suppression, 14, 25, 42, 51, 70, 81, 94, 126, 143, 292 Survival Rate, 53, 292 Sympathetic Nervous System, 225, 292 Sympathomimetic, 241, 245, 260, 271, 292 Symphysis, 281, 292 Symptomatic, 137, 240, 273, 279, 292 Synaptic, 271, 288, 292 Synaptic Transmission, 271, 292 Synergistic, 58, 74, 116, 292 Synovial, 139, 260, 292 Synovial Fluid, 139, 292 Synovial Membrane, 140, 260, 292 Systemic, 34, 36, 147, 168, 171, 186, 223, 227, 239, 245, 253, 258, 283, 292, 295, 296, 298 Systolic, 10, 255, 292 Systolic blood pressure, 10, 292 T Tardive, 223, 292 Telencephalon, 225, 293 Temporal, 15, 29, 253, 265, 293 Teratoma, 76, 293 Testicles, 293 Testicular, 46, 145, 293 Testis, 45, 245, 293 Testosterone, 284, 293 Tetany, 273, 293 Therapeutics, 22, 82, 83, 95, 186, 293 Thermal, 27, 88, 270, 293 Thigh, 23, 293 Third Ventricle, 256, 293 Thoracic, 85, 89, 225, 293, 300

Thorax, 217, 264, 293 Threonine, 274, 287, 293 Threshold, 24, 39, 44, 255, 293 Thrombin, 13, 247, 278, 281, 293 Thrombocytes, 278, 293 Thrombocytopenia, 46, 145, 293 Thrombolytic, 277, 293 Thrombomodulin, 281, 293 Thrombosis, 13, 88, 141, 145, 281, 291, 294 Thrombus, 237, 258, 260, 268, 269, 278, 293, 294 Thymus, 257, 264, 294 Thyroid, 167, 256, 273, 294, 296 Thyroid Gland, 167, 273, 294 Thyroid Hormones, 294, 296 Thyrotropin, 73, 256, 294 Thyroxine, 219, 276, 294 Tibial Nerve, 286, 294 Tin, 98, 154, 275, 278, 294 Tissue Plasminogen Activator, 51, 80, 294 Tocolysis, 48, 294 Tolazamide, 121, 144, 294 Tolerance, 23, 32, 35, 38, 40, 43, 57, 59, 69, 70, 73, 81, 102, 108, 113, 116, 121, 122, 129, 148, 156, 169, 170, 176, 217, 240, 250, 279, 294 Tooth Preparation, 218, 294 Topical, 114, 255, 288, 294 Torsion, 258, 294 Total pancreatectomy, 273, 294 Toxaemia, 279, 294 Toxic, iv, 16, 62, 108, 134, 256, 270, 271, 295 Toxicity, 28, 30, 50, 229, 242, 295 Toxicology, 26, 101, 192, 295 Toxins, 222, 258, 268, 294, 295 Trace element, 102, 232, 294, 295 Tracer, 25, 295 Trachea, 118, 228, 261, 294, 295 Trachoma, 236, 295 Traction, 233, 295 Transaldolase, 18, 295 Transcription Factors, 31, 51, 295 Transduction, 55, 288, 295 Transfection, 37, 41, 56, 227, 295 Transfer Factor, 257, 295 Transferases, 252, 295 Translation, 54, 205, 245, 295 Translational, 50, 60, 295 Translocation, 22, 28, 41, 245, 295 Transmitter, 217, 241, 265, 271, 295

Index 317

Transplantation, 40, 52, 92, 153, 166, 203, 233, 243, 254, 257, 264, 295 Trauma, 11, 74, 76, 84, 88, 203, 239, 269, 273, 296 Tremor, 137, 196, 273, 296 Tricuspid Atresia, 236, 296 Trigger zone, 223, 296 Triglyceride, 40, 46, 51, 61, 96, 123, 134, 159, 255, 296 Trisomy, 221, 296 Troglitazone, 117, 120, 121, 176, 296 Trophic, 66, 296 Trophoblast, 62, 227, 296 Tryptophan, 234, 287, 296 Tuberculosis, 127, 235, 296 Tumor Necrosis Factor, 17, 296 Tumour, 248, 296 Tympanic membrane, 27, 296 Tyrosine, 28, 52, 62, 79, 241, 296 U Ultralente Insulin, 99, 296 Ultrasonography, 250, 296 Unconscious, 221, 256, 297 Unresectable, 77, 297 Uracil, 297 Uraemia, 273, 297 Uremia, 261, 284, 297 Ureters, 261, 297 Urethra, 226, 281, 297 Uric, 75, 282, 297 Uridine Diphosphate, 89, 297 Urinary, 49, 118, 154, 164, 228, 257, 271, 294, 297 Urinary Plasminogen Activator, 294, 297 Urinary tract, 164, 297 Urinary tract infection, 164, 297 Urine Testing, 156, 162, 297 Uterine Contraction, 118, 294, 297 Uterus, 118, 238, 243, 266, 272, 280, 297, 298 V Vaccination, 34, 297, 298 Vaccine, 281, 297, 298 Vaccinia, 70, 298 Vaccinia Virus, 70, 298 Vacuole, 119, 298 Vagina, 239, 266, 298 Vaginitis, 164, 298 Variola, 298 Vascular endothelial growth factor, 58, 298 Vascular Resistance, 141, 298

Vasculitis, 273, 298 Vasoconstriction, 45, 63, 245, 298 Vasodilation, 32, 44, 80, 83, 118, 298 Vasodilator, 32, 45, 63, 228, 241, 254, 269, 298 Vasomotor, 19, 33, 298 Vector, 39, 65, 70, 119, 295, 298 Vein, 221, 224, 259, 271, 286, 298 Venous, 224, 238, 281, 296, 298 Ventricle, 224, 236, 282, 292, 293, 296, 298 Ventricular, 38, 86, 180, 236, 269, 296, 298 Ventricular Function, 86, 180, 298 Ventricular Remodeling, 38, 298 Venules, 227, 229, 244, 267, 298 Vertebral, 226, 290, 298 Veterinary Medicine, 191, 299 Vibrio, 232, 299 Vibrio cholerae, 232, 299 Villi, 130, 299 Villous, 62, 299 Viral, 14, 29, 236, 247, 295, 299 Virilism, 255, 299 Virulence, 224, 295, 299 Virus, 29, 70, 127, 225, 231, 237, 244, 249, 252, 277, 288, 295, 298, 299 Virus Diseases, 127, 299 Viscera, 266, 289, 299 Visceral, 68, 225, 299 Visceral Afferents, 225, 299 Visceral fat, 68, 299 Visually Impaired Persons, 155, 161, 299 Vitreous Body, 285, 299 Vitreous Hemorrhage, 240, 299 Vitreous Humor, 64, 299 Vitro, 20, 34, 35, 47, 57, 62, 66, 299 Vivo, 12, 14, 16, 18, 19, 20, 21, 22, 28, 31, 36, 38, 41, 47, 55, 56, 57, 62, 65, 67, 70, 71, 86, 126, 257, 299 W Weight Gain, 23, 89, 152, 299 White blood cell, 222, 257, 262, 264, 268, 270, 277, 299 Whooping Cough, 275, 299 Windpipe, 294, 300 Womb, 297, 300 Wound Healing, 146, 300 X Xenograft, 221, 300 X-ray, 248, 271, 283, 300 Y Yeasts, 248, 276, 300

318

Z

Hyperglycemia

Zymogen, 281, 300

Index 319

320

Hyperglycemia

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