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

DIABETES MELLITUS 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 ©2003 by ICON Group International, Inc. Copyright ©2003 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., 1960Diabetes Mellitus: 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: 0-597-83884-4 1. Diabetes Mellitus-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 diabetes mellitus. 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 DIABETES MELLITUS ................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Diabetes Mellitus .......................................................................... 8 E-Journals: PubMed Central ....................................................................................................... 69 The National Library of Medicine: PubMed ................................................................................ 74 CHAPTER 2. NUTRITION AND DIABETES MELLITUS ..................................................................... 121 Overview.................................................................................................................................... 121 Finding Nutrition Studies on Diabetes Mellitus....................................................................... 121 Federal Resources on Nutrition ................................................................................................. 125 Additional Web Resources ......................................................................................................... 126 CHAPTER 3. ALTERNATIVE MEDICINE AND DIABETES MELLITUS ............................................... 129 Overview.................................................................................................................................... 129 The Combined Health Information Database............................................................................. 129 National Center for Complementary and Alternative Medicine................................................ 130 Additional Web Resources ......................................................................................................... 136 General References ..................................................................................................................... 141 CHAPTER 4. DISSERTATIONS ON DIABETES MELLITUS ................................................................. 143 Overview.................................................................................................................................... 143 Dissertations on Diabetes Mellitus............................................................................................ 143 Keeping Current ........................................................................................................................ 152 CHAPTER 5. CLINICAL TRIALS AND DIABETES MELLITUS ............................................................ 153 Overview.................................................................................................................................... 153 Recent Trials on Diabetes Mellitus............................................................................................ 153 Keeping Current on Clinical Trials ........................................................................................... 176 CHAPTER 6. PATENTS ON DIABETES MELLITUS ............................................................................ 179 Overview.................................................................................................................................... 179 Patents on Diabetes Mellitus ..................................................................................................... 179 Patent Applications on Diabetes Mellitus ................................................................................. 205 Keeping Current ........................................................................................................................ 236 CHAPTER 7. BOOKS ON DIABETES MELLITUS ............................................................................... 237 Overview.................................................................................................................................... 237 Book Summaries: Federal Agencies............................................................................................ 237 Book Summaries: Online Booksellers......................................................................................... 240 The National Library of Medicine Book Index ........................................................................... 243 Chapters on Diabetes Mellitus................................................................................................... 244 CHAPTER 8. MULTIMEDIA ON DIABETES MELLITUS ..................................................................... 247 Overview.................................................................................................................................... 247 Video Recordings ....................................................................................................................... 247 Audio Recordings....................................................................................................................... 253 Bibliography: Multimedia on Diabetes Mellitus........................................................................ 255 CHAPTER 9. PERIODICALS AND NEWS ON DIABETES MELLITUS .................................................. 257 Overview.................................................................................................................................... 257 News Services and Press Releases.............................................................................................. 257 Newsletters on Diabetes Mellitus .............................................................................................. 259 Newsletter Articles .................................................................................................................... 260 Academic Periodicals covering Diabetes Mellitus ..................................................................... 260 CHAPTER 10. RESEARCHING MEDICATIONS ................................................................................. 263 Overview.................................................................................................................................... 263 U.S. Pharmacopeia..................................................................................................................... 263

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Commercial Databases ............................................................................................................... 265 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 269 Overview.................................................................................................................................... 269 NIH Guidelines.......................................................................................................................... 269 NIH Databases........................................................................................................................... 271 Other Commercial Databases..................................................................................................... 276 APPENDIX B. PATIENT RESOURCES ............................................................................................... 277 Overview.................................................................................................................................... 277 Patient Guideline Sources.......................................................................................................... 277 Finding Associations.................................................................................................................. 294 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 297 Overview.................................................................................................................................... 297 Preparation................................................................................................................................. 297 Finding a Local Medical Library................................................................................................ 297 Medical Libraries in the U.S. and Canada ................................................................................. 297 ONLINE GLOSSARIES................................................................................................................ 303 Online Dictionary Directories ................................................................................................... 305 DIABETES MELLITUS DICTIONARY..................................................................................... 307 INDEX .............................................................................................................................................. 405

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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 diabetes mellitus 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 diabetes mellitus, 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 diabetes mellitus, 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 diabetes mellitus. 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 diabetes mellitus, 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 diabetes mellitus. 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 DIABETES MELLITUS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on diabetes mellitus.

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

Association Between Hepatitis C Virus Infection and Type 2 Diabetes Mellitus: What Is the Connection? (editorial) Source: Annals of Internal Medicine. 133(8): 650-652. October 17, 2000. Contact: Available from American College of Physicians. American Society of Internal Medicine. 190 North Independence Mall West, Philadelphia, PA 19106-1572. Website: www.acponline.org. Summary: Chronic hepatitis C virus (HCV) infection and type 2 diabetes mellitus cause devastating long term complications in a significant minority of patients affected with these diseases. This editorial explores the potential link between these two disorders, noting that chronic HCV infection may cause cirrhosis (liver scarring), which, through insulin resistance, predisposes patients to diabetes mellitus. The author reviews a dozen

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studies that look at this connection, then introduces a research study published in the same journal issue as the editorial, which provides strong evidence for the association between HCV infection and type 2 diabetes mellitus. This latter study demonstrates that persons with HCV infection were more than three times more likely to have type 2 diabetes mellitus than those without HCV infection. Alcohol abuse did not seem to link the two disorders in this study. The editorial author addresses some of the potential limitations to this study, and suggests additional research that may further clarify the connection between the two diseases. The editorial concludes that the association between chronic HCV infection and type 2 diabetes mellitus seems genuine. However, numerous questions must still be addressed, most notably those regarding the nature of the link between the disorders. 19 references. •

High Prevalence of Celiac Disease Among Patients with Insulin-Dependent (Type I) Diabetes Mellitus Source: American Journal of Gastroenterology. 92(12): 2210-2212. December 1997. Contact: Available from Williams and Wilkins. 351 West Camden Street, Baltimore, MD 21201-2436. (800) 638-6423 or (410) 528-8555. Summary: Diagnosis of unrecognized celiac disease is potentially important, due to its association with an increased risk of malignancy and its complications by other conditions such as osteoporosis, infertility, and neurologic disorders (problems that may be averted with gluten restriction). The prevalence of celiac disease in patients with type 1 diabetes (insulin-dependent diabetes mellitus) is uncertain. This article reports on a study of the prevalence of celiac disease in a stratified random sample (n=101) of adults with type 1 diabetes and in an control group matched for age and sex (n=51). Screening was by anti-endomysial antibody, measured by indirect immunofluorescence using sections of human umbilical cord. Celiac disease had not been suspected in any patient at the time of screening. Eight patients tested positive for anti-endomysial antibody; each had a distal duodenal biopsy performed. Five patients had histologic evidence of celiac disease. One patient with negative histology was receiving immunosuppressive therapy for a renal-pancreas transplant. Of the five patients with abnormal histology, two improved on gluten restriction, one was unable to comply, one refused treatment, and one was lost to followup. No control subject tested positive for endomysial antibody. The authors conclude that patients with type 1 diabetes have an increased prevalence of celiac disease. Because most cases are clinically unrecognized, consideration should be given to screening all patients with type 1 diabetes. 1 table. 17 references. (AA-M).

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Risk Factors for Hepatocellular Carcinoma: Synergism of Alcohol with Viral Hepatitis and Diabetes Mellitus Source: Hepatology. 36(5): 1206-1213. November 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Risk factors associated with hepatocellular carcinoma (HCC, liver cancer) are well documented, but the synergisms between these risk factors are not well examined. This article reports on a hospital-based, case-control study that included 115 HCC patients and 230 non-liver cancer control patients. Odds ratios were 15.3 for anti-HCV antigen, 12.6 for hepatitis B surface antigen (HBsAg), 4.5 for heavy alcohol consumption, and 4.3 for diabetes mellitus. Synergistic interactions on the additive model were observed between heavy alcohol consumption and chronic hepatitis virus infection and

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diabetes mellitus. Independent of the effect of HCV, HBV, and diabetes mellitus, heavy alcohol consumption contributes to the majority of HCC cases (32 percent), whereas 22 percent, 16 percent, and 20 percent were explained by HCV, HBV, and diabetes mellitus, respectively. The authors conclude that the significant synergy between heavy alcohol consumption, hepatitis virus infection, and diabetes mellitus may suggest a common pathway for hepatocarcinogenesis (development of liver cancer). 3 tables. 38 references. •

Celiac Sprue and Diabetes Mellitus. (editorial) Source: Journal of Clinical Gastroenterology. 16(1): 4-5. January 1993. Summary: The frequent association of celiac sprue (CS) and insulin-dependent diabetes mellitus (IDDM) that may be the result of interplay between genetic, hormonal, and immunologic factors has obvious therapeutic implications. So contend the authors of this article that explores the association between CS and IDDM. Topics include hormones produced by the small bowel mucosa; the causal relationship between IDDM and CS; and the role of enteroglucagon. The authors hypothesize that a state of chronic hyperglucagonemia associated with low insulin levels may exist in CS patients, predisposing them to develop IDDM. The authors stress that a gluten-free diet may improve the diarrhea in some patients with IDDM where the reason for diarrhea is underlying celiac sprue; the diet may also improve control of DM by normalizing the serum hormonal profile. 32 references.

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Risk Factors for Diabetes Mellitus in Chronic Pancreatitis Source: Gastroenterology. 119(5): 1324-1332. November 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: The influence of disease progression and pancreatic surgery on the appearance of diabetes mellitus in patients with chronic pancreatitis is unknown. This article reports on a prospective cohort study of 500 consecutive patients with chronic pancreatitis (alcoholics, 85 percent); patients were followed over a mean period of 7.0 years (plus or minus 6.8 years) in a medical surgical institution between 1973 and 1996. Analysis of risk factors for diabetes mellitus was performed after the exclusion of 47 patients. Patients who underwent elective pancreatic surgery (n = 231; 51 percent) were compared with patients who never underwent surgery (n = 222; 49 percent). The cumulative rate of diabetes mellitus was 83 percent (plus or minus 4 percent) 25 years after the clinical onset of chronic pancreatitis (insulin requirement, 54 percent). The prevalence of diabetes mellitus did not increase in the surgical group overall but was higher 5 years after distal pancreatectomy (a surgical procedure that removes 50 to 70 percent of the distal pancreas; 57 percent of the patients) than after pancreaticoduodenectomy (36 percent), pancreatic drainage (36 percent), or cystic, biliary, or digestive drainage (24 percent), without difference in the latter ones. Pancreatic drainage did not prevent the onset of diabetes mellitus. Distal pancreatectomy and early onset of pancreatic calcifications were the only independent risk factors for diabetes mellitus. The authors conclude that the risk of diabetes mellitus is not influenced by elective pancreatic surgical procedures other than distal pancreatectomy in patients with chronic pancreatitis. This risk seems to be largely caused by progression of the disease because it increased by more than 3 fold after the onset of pancreatic calcifications. 4 figures. 4 tables. 55 references.

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Disturbances in Anorectal Function in Patients With Diabetes Mellitus and Faecal Incontinence Source: European Journal of Gastroenterology and Hepatology. 8(10): 1007-1012. August 1996. Contact: Available from Rapid Science Publishers. 400 Market Street, Suite 750, Philadelphia, PA 19106. (800) 552-5866 or (215) 574-2210. Summary: This article reports on a study designed to document the anorectal dysfunctions in patients with diabetes and fecal incontinence. Multiport anorectal manometry and electromyography were done in 11 patients with diabetes and fecal incontinence, and in 20 healthy controls. Basal and squeeze pressures were reduced in the patients with diabetes compared with the control subjects. During basal recording, six patients showed regular oscillations in anal electrical activity and pressure. Nine patients also exhibited spontaneous transient anal relaxations, and in six of them, leakage occurred as the anal pressure fell below the rectal pressure. None of the control subjects showed oscillation or spontaneous relaxations. In patients there was a greater tendency for repetitive rectal contractions in response to rectal distension and reduced rectal compliance. During rectal distension, four patients showed no anal relaxation, and in the remainder relaxation occurred at an abnormally high threshold. The authors conclude that the etiology of fecal incontinence in patients with diabetes is multifactorial, and that instability of the internal sphincter probably plays a major role. 2 figures. 1 table. 40 references. (AA-M).

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Costs Associated with the Primary Prevention of Type 2 Diabetes Mellitus in the Diabetes Prevention Program Source: Diabetes Care. 26(1): 36-47. January 2003. 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 describes the costs of the Diabetes Prevention Program (DPP) interventions that are designed to prevent or delay type 2 diabetes. The authors describe the direct medical costs, direct nonmedical costs, and indirect costs of the placebo, metformin, and intensive lifestyle interventions over the 3 year study period of the DPP. Resource use and cost are summarized from the perspective of a large health system and society. Research costs are excluded. The data showed metformin and lifestyle interventions are associated with modest incremental costs compared with the placebo intervention. The evaluation of costs relative to health benefits will determine the value of these interventions to health systems and society. 7 tables. 24 references.

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Gestational Diabetes Mellitus Source: Diabetes Care. 26(2): 385-389. February 2003. 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 undertaken to examine anxiety levels of women diagnosed with gestational diabetes mellitus (GDM) and to compare these with glucose-tolerant (GT) women at similar stages of pregnancy. The prospective longitudinal study was conducted on 50 women with GDM and 50 GT women. All women completed the Mental Health Inventory (MHI-5) forms and the Speilberger

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State-Trait Anxiety Inventory (STAI) at the beginning of the third trimester, antepartum, and 6 weeks postpartum. Women with GDM, compared with GT women, had a higher level of anxiety (state rather than trait) at the time of the first assessment. However, before delivery and in the postpartum period, there were no significant differences in anxiety scores between the two groups. Women in both groups were positive about being tested for GDM and wished to be tested during future pregnancies. The authors conclude that there were no sustained increased levels of anxiety for women diagnosed with GDM. Concerns expressed about causing sustained maternal anxiety by testing for GDM could not be substantiated. 3 tables. 20 references. •

Risk of Dementia Among Persons With Diabetes Mellitus: A Population-Based Cohort Study Source: American Journal of Epidemiology. 145(4): 301-308. 1997. Summary: This journal article describes a populations-based, historical cohort study, supported by the National Institute on Aging, which examined the risk of dementia among people with adult onset diabetes mellitus (AODM). The study population consisted of all people with AODM residing in Rochester, Minnesota, on January 1, 1970, plus all people who were diagnosed in Rochester or who moved to Rochester with a diagnosis of AODM between January 1, 1970 and December 31, 1984. All patients were followed from AODM diagnosis until onset of dementia, emigration, death, or January 1, 1985. The diagnosis of a dementing illness was made retrospectively through a review of the patients' complete medical records, using standardized criteria. Of the 1,455 cases of AODM followed for 9,981 person-years, 101 developed dementia, including 77 who met criteria for Alzheimer's disease (AD). The risk of dementia for the Rochester residents with AODM was 1.66 times that for residents without dementia. The authors conclude that this study revealed an increased risk of dementia for people with AODM and refuted the hypothesis that AODM is a protective for AD. 2 figures, 2 tables, 35 references. (AA-M).

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Diabetes Mellitus and the Risk of Dementia: The Rotterdam Study Source: Neurology. 53: 1937-1942. December 1999. Summary: This journal article examines the influence of type 2 diabetes mellitus on the risk of dementia and Alzheimer's disease (AD). Data were obtained from a prospective, population-based study of elderly residents of Rotterdam, Netherlands. The sample consisted of 6,370 participants without dementia who were examined at baseline for the presence of type 2 diabetes. Participants were followed for an average of 2.1 years, and incident dementia was diagnosed using a three-step screening and comprehensive diagnostic workup, or review of medical files for those who could not be reexamined. At baseline, 692 (10.9 percent) of the participants had diabetes. During the follow-up, 126 participants developed dementia, of whom 89 had AD. After adjusting for age and sex, diabetes mellitus nearly doubled the risk of dementia (relative risk 1.9) and AD (relative risk 1.9). Patients treated with insulin were at the highest risk of dementia (relative risk 4.3). The fraction of incident dementia attributable to diabetes was 8.8 percent, suggesting that diabetes may play a role in the pathogenesis of dementia in a substantial proportion of cases. 4 tables, 38 references.

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

Project Title: A RANDOMIZED TRIAL OF LIAISON PSYCHIATRY IN PRIMARY CARE Principal Investigator & Institution: Katon, Wayne J.; Professor; Psychiatry and Behavioral Scis; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-JUL-1987; Project End 31-AUG-2005 Summary: (Applicant Abstract): Rationale - The overall goal is to integrate an organized program of improved care of depression into the management of other chronic diseases in primary care. Diabetes mellitus was selected for study because of its prevalence and its large impact on patients and society. If a Depression Care Program (DCP) improves disability and/or disease outcomes among diabetics, it would help establish the core importance of recognition and management of depression for chronic disease management in primary care. Research goals - (1) We will develop population-based data in a managed care setting concerning the effects of depression on the societal impacts of diabetes and on the quality of diabetes (self)-management. By (self)management we refer to both patients' and providers' roles in ongoing care of a chronic illness. (2) We will evaluate a generalizable and economically feasible Depression Care Program (DCP) for population-based management of depression among patients with diabetes mellitus. These goals will be achieved by two related studies. Aims of Study 1: Study 1 will assess the impact and management of depressive illness among diabetic patients, in an epidemiologic study, which will include patients with and without depression. Study 1 will assess the effects of major depression on societal impacts of diabetes (health care costs and disability) and on the quality of diabetes (self) management. These analyses will control for medical co-morbidity and baseline severity of diabetes. Aims of Study 2: We will evaluate whether a Depression Care program (DCP) for major depression in adult patients with Type 2 diabetes mellitus improves depression outcomes, disability outcomes, and glycemic control (as measured by HemoglobinA1C). Secondary process and outcome measures will include adherence to antidepressant and to diabetic medications, severity of symptoms related to diabetes, self-efficacy in managing diabetes, adherence to diabetes (self) management regimens

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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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(diet, exercise, glucose monitoring and medications), and health care utilization and costs. We will assess the cost-effectiveness of the DCP relative to care as usual. Data collection: We will carry out these studies by assessing diabetes and depression status in 4500 diabetic patients. Among Type 2 diabetics with major depression, 290 eligible and willing patients will be randomly assigned to a Depression Care Program or to Usual Care, We will evaluate the effectiveness of the Depression Care Program using selfreport data collected at baseline, 3, 6, 12 and 24 months, and by HbA1C values assessed at baseline, 6, 12 and 24 months. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADHERENCE TO IDDM REGIMEN IN URBAN YOUTH Principal Investigator & Institution: Ellis, Deborah; Psychiatry & Behav Neuroscis; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Studies of medical treatment adherence suggest that substantial percentages of persons do not comply with recommendations given to them for the treatment of acute and chronic health conditions. Insulin dependent diabetes mellitus (IDDM) is a chronic health conditions with a highly complex medical regimen. Substantial data exist that suggest that improving treatment adherence and metabolic control in persons with IDDM can delay the onset of diabetes complications. Unfortunately, those adolescents with IDDM with the poorest diabetes self-management and metabolic control are often the most resistant to hospital-based health care and traditional educational/supportive interventions. They are also faced with multiple barriers to improved adherence, including lack of knowledge about diabetes, family disorganization and conflict, high levels of stress and limited social support and access to community resources. Multisystemic Therapy (MST) is a family and communitybased treatment model which has previously been used with adolescents presenting with serious mental health problems. MST has been shown to be both "effective" and highly transportable to the types of community settings where care is most often provided. Preliminary data suggest that MST is a promising approach for adolescents with IDDM as well. The objective of the present study is to utilize MST to improve the treatment adherence and metabolic control of urban adolescents with IDDM and a glycoslated hemoglobin of 11 percent or above. Additional aims are to determine the stability of MST's effects on treatment adherence and metabolic control over a two year interval, to test hypotheses about mediators of MST treatment effects and to assess the cost-effectiveness of MST when compared to the costs of short-term diabetes complications such as diabetic ketoacidosis (DKA). The experimental design for the present study is a randomized controlled trial with a sample of 100 adolescents, 50 of whom will receive MST in addition to their standard care and 50 of whom will receive only standard care of their IDDM. If successful, MST will provide immediate assistance to a vulnerable population at high risk for diabetes complications and quality of life and may also result in substantial health care savings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALPHA AND BETA CELL FUNCTION IN NORMAL AND DIABETIC MAN Principal Investigator & Institution: Gerich, John E.; Professor of Medicine; Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-DEC-1986; Project End 31-DEC-2002

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Summary: (Adapted from Applicant's Abstract): Hypoglycemia is a common and potentially serious problem for diabetic patients regardless of whether they are treated with insulin or oral agents. Conventional risk factors (wrong insulin doses, skipped or delayed meals, exercise) explain only a small percentage of episodes. However, hypoglycemia unawareness and abnormal glucose counterregulation have recently been identified as likely explanations for many cases. The overall goal of this grant is to delineate the mechanisms responsible for hypoglycemia unawareness and for abnormal glucose counterregulation in diabetic patients. The Specific Aims of the grant application are: A) To establish the mechanisms responsible for hypoglycemia unawareness in insulin dependent Type I diabetes. The investigators will; 1) establish the normal threshold for induction of hypoglycemia unawareness by hypoglycemia and test the hypothesis that in diabetic patients the threshold is reduced; 2) test the hypothesis that hypoglycemia unawareness in diabetic individuals involves diminished beta adrenergic sensitivity; 3) test the hypothesis that hypoglycemia per se reduces beta adrenergic sensitivity; 4) test the hypothesis that there are two types of hypoglycemia unawareness - an acute reversible type due to recurrent hypoglycemia and another chronic irreversible type related to duration of diabetes, possibly representing an encephalopathic complication of diabetes. B) To assess the mechanisms responsible for impaired glucose counterregulation in noninsulin dependent diabetes mellitus. The investigator will test the hypotheses that 1) reduced glucagon responses are due to increased plasma free fatty acid levels; 2) that increased catecholamine responses are secondary (e.g. compensatory) to reduced glucagon responses; 3) that increased catecholamine responses are in part the result of poor metabolic control; 4) that subnormal increase in glucose production during hypoglycemia results from impaired glucagon responses; 5) that enhanced suppression of glucose utilization results from the effects of increased catecholamine responses on muscle; and 6) that increased muscle glycogenolysis provides gluconeogenic precursors and promotes the compensatory increase in glucose production observed during hypoglycemia. To achieve these aims the investigator will use a combination of glucose clamp, isotope and limb balance techniques in conjunction with pharmacologic interventions in normal volunteers and in research subjects having either Type I or Type II diabetes. Better understanding of the pathogenesis of hypoglycemia unawareness and abnormal glucose counterregulation should make treatment of diabetes safer and improve the chances of achieving optimal glycemic control. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AN ALTERED PEPTIDE LIGAND TO PREVENT TYPE 1 DIABETES Principal Investigator & Institution: Marks, Jennifer B.; Medicine; University of MiamiMedical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2001; Project Start 29-SEP-2001; Project End 31-AUG-2008 Summary: (provided by applicant) Type 1 diabetes mellitus occurs in genetically predisposed individuals as a consequence of the progressive, selective destruction of the pancreatic beta-cells mediated by autoreactive T-cells. Our long-range goals are to understand the natural history of Type 1 diabetes and to participate in the evaluation of potential new approaches to prevent or ameliorate this disease. The objectives of this application are threefold: 1) to complete the ongoing Diabetes Prevention Trial-Type 1 (DPT-1), 2) to be involved in the design and implementation of new intervention strategies and, 3) to propose a novel intervention strategy, to test the effects of an altered peptide ligand (APL), NBI-6024 (Neurocrine Biosciences), in individuals at risk for clinical Type 1 diabetes. The central hypothesis of this proposed study is that

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administration of this APL, containing two natural L-amino acid substitutions from the insulin B-chain (9-23) region, will temper the destructive autoimmune process leading to Type 1 diabetes, preserving beta-cells and their insulin-secreting capacity. The rationale for this study is that, if treatment with this APL is safe and effective at stopping or slowing disease progression in a population at defined risk, it could be tested at an earlier stage of diabetes development, in those with less well-defined risk, and possibly result in large-scale prevention. We will test the central hypothesis of our proposed study and accomplish the objectives as a TriaINet Clinical Center by pursuing the following three Specific Aims: 1. Complete the DPT-1 protocols and achieve their objectives, 2. Establish a network of collaborating investigators to participate in the design and conduct of future studies to evaluate new approaches to prevent or ameliorate Type 1 diabetes, 3. Evaluate the effects of intervention with an APL on progression to clinical diabetes in individuals at risk for Type 1 diabetes. It is our expectation that the DPT-1 protocols will be successfully completed, and that insulin administration will alter the destructive immune response in the beta-cells, and attenuate beta-cell autoimmunity, thereby preventing or delaying the development of Type 1 diabetes. The data collected will also better characterize the natural history of Type 1 diabetes disease development. It is also our expectation, based on our Clinical Center performance in the DPT-1, and on the expertise of our investigators, that our contribution to the Diabetes TriaINet will help to ensure its successful implementation and facilitate its functioning as envisioned in future intervention trials. Additionally, we will test the hypothesis that our innovative intervention plan based on the administration of APL NBI-6024 will prevent or reduce disease progression. If not prevented, a treatment effect that preserves beta-cell function in those who do develop diabetes will provide an important clinical benefit. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANS HYPOGLYCEMIA INDUCED GLUCAGON SECRETION IN DIABETES Principal Investigator & Institution: Havel, Peter J.; Nutrition; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2001; Project Start 26-APR-1997; Project End 31-MAR-2002 Summary: (Adapted from applicant's abstract): The objective of the studies outlined in this proposal is to investigate four fundamental aspects of the physiology and pathophysiology of autonomic regulation of glucagon secretion during hypoglycemia in nondiabetic animals and in animal models of diabetes. Hypoglycemia is a common and serious complication of insulin-treated diabetes mellitus in humans which limits the ability to attain improved glycemic control. The Diabetes Control and Complications Trial found a dramatic decrease of diabetic retinopathy and nephropathy with intensive therapy, but at a cost of a three-fold increase of severe hypoglycemia. Increased secretion of glucagon is a primary factor for recovery from insulin-induced hypoglycemia in nondiabetic humans. Activation of the autonomic nervous system has been demonstrated to make an important contribution to hypoglycemia-induced glucagon secretion in several species including dogs and rats, however, the role of the autonomic nervous system in humans is controversial and experiments of this type in nonhuman primates as models of human physiology have not been previously conducted. In diabetic humans, the glucagon and certain autonomic responses to hypoglycemia are often impaired. The etiology and time of onset of this impairment is poorly understood. Potential factors that may be involved include, but are not limited to, hypoglycemia-associated autonomic failure and autonomic neuropathy. Autonomic

12

Diabetes Mellitus

and glucagon responses to hypoglycemia are also known to be impaired in some animal models of diabetes, including diabetic rats, although few mechanistic studies have been conducted to examine the underlying etiology, nor has it been determined if pharmacological interventions can to prevent or decrease the counterregulatory defects. To address these deficits in the understanding of t he regulation of hypoglycemiainduced glucagon secretion: 1) Experiments will be conducted to examine the autonomic contribution to hypoglycemia-induced glucagon secretion in a nonhuman primate (rhesus monkeys) in the absence of diabetes. 2) To define the timing of the onset of impaired autonomic activation and glucagon secretion during hypoglycemia in rhesus monkeys with chemically-induced (streptozotocin) diabetes and the effects of different levels of metabolic control on the deficits. 3) A series of mechanistic studies will conducted in streptozotocin diabetic rats to investigate whether defects in of autonomic activation or reduced A-cell secretory responses to autonomic stimulation could contribute to impaired glucagon secretion and to determine the effects of different treatment regimens, designed to maximize chronic hyperglycemia or induce antecedent hypoglycemia, on autonomic responses and glucagon secretion. 4) Autonomic and glucagon responses to hypoglycemia will be examined in streptozotocin diabetic rats treated with pharmacologic agents that have been shown to ameliorate neural dysfunction in diabetic rats. Collectively, these experiments will lead to greater understanding of the pathophysiology and treatment of impaired hypoglycemic counterregulation in diabetes and the greater use of animal models for this area of investigation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTI-APOPTOTIC ALLOTRANSPLANTATION

GENE

THERAPY:

Principal Investigator & Institution: Giannoukakis, Nick; Children's Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 15213

ISLET Hosp

Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2003 Summary: (provided by applicant) Type 1 diabetes mellitus, also termed insulindependent diabetes mellitus (IDDM) is an autoimmune disease that specifically targets the pancreatic beta cells of the islets of Langerhans in a T-lymphocyte-mediated destruction. While insulin replacement therapy corrects the hyperglycemia, it is not a cure, since most IDDM patients eventually succumb to the complications associated with imprecise glucose homeostasis. One approach that can restore tight glycemic control is the replacement of beta cells in the form of islet allografts or xenografts. The latter may not become a clinical reality anytime soon primarily because of concerns for zoonoses. Allografts are ethically acceptable, yet they face both alloimmune rejection as well as autoimmune destruction following transplantation. It appears that three distinct death effector pathways are responsible for beta cell destruction: 1) Fas, 2) tumor necrosis factor alpha and 3) perforin/granzyme B. Similar to autoimmune destruction, it appears that Fas, TNFa and perforin/granzyme B are important death effectors in allograft rejection of islets. Genetic engineering of islets to produce inhibitors of these pathways may facilitate allogeneic islet transplantation and may result in long-term survival. In the non-obese diabetic (NOD) mouse model, engineering islets ex vivo to express a variety of immunoregulatory cytokines and proteins has resulted in significant, but not indefinite, prolongation of allogeneic islet transplant survival. One important reason why long-term or indefinite allograft survival has not been achieved is the nature of the gene delivery vectors, most of which are of viral origin and highly immunogenic or toxic to islet cells. Recent engineering of lentiviruses including human

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immunodeficiency virus (HIV-1), feline immunodeficiency (FIV) and equine infectious anemia viruses (EIAV), has resulted in vectors that are able to infect non-dividing cells, are non-immunogenic in vivo and can stably integrate into the host cell. These desirable characteristics of lentiviral vectors as gene delivery vehicles for islets ex vivo, are in contrast to the highly immunogenic, transient and toxic nature of vectors that have been recently used in islet gene transfer strategies (adenovirus, herpes simplex). While HIVbased lentiviral vectors have been demonstrated to readily infect human islets, the nature of the virus strain is a significant impediment for clinical applications. EIAV, on the other hand, offers the same characteristics as HIV and is not pathogenic in humans. The focus of this proposal is to demonstrate that soluble antagonists of Fas, TNF and granzyme B can protect islets in culture from apoptosis activation and to further develop the EIAV lentiviral system as an efficient gene delivery vector of cDNAs encoding inhibitors of Fas, TNFa and perforin/granzyme B-dependent death effector pathways, alone or in combinations. This may be a desirable approach to facilitate allogeneic islet transplantation as a possible therapy for IDDM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIBODIES TO RECOMBINANT AUTOANTIGENS: PREDICTION Principal Investigator & Institution: Eisenbarth, George S.; Executive Director; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 01-MAY-1996; Project End 31-JUL-2005 Summary: (provided by applicant): The OPT -1 trial, whose clinical component is sponsored by the National Institutes of Health, is testing the hypothesis that parenteral or oral insulin administration will delay the development of type 1 diabetes amongst cytoplasmic ICA positive relatives of patients with diabetes. The trial represents the largest evaluation of first degree relatives ever undertaken with more than 80,000 relatives screened, and more than 100,000 sera samples analyzed for cytoplasmic ICA, GAO65 and ICA512 (IA-2) autoantibodies and 3,000 analyzed for insulin autoantibodies (micro-lAA assay) under the aegis of this grant. A supplement to this grant has allowed limited one time "staging" of a subset of relatives with "biochemical" autoantibodies but lacking cytoplasmic ICA. Preliminary results indicate: One half of cytoplasmic ICA positive individuals lack all biochemical autoantibodies and have a low probability of being eligible on Staging for the OPT -1 trial. Approximately one fourth of relatives expressing multiple autoantibodies are cytoplasmic ICA negative. Expression of "biochemical" autoantibodies is related to relationship to proband and HLA status. A new micro-insulin autoantibody assay (micro-lAA) has a higher correlation with multiple autoantibody expression compared to the standard anti-insulin assay. A subset of DaB 1 *0602 positive individuals progress to overt diabetes. We believe from the preliminary data that "biochemical" autoantibody determination will be essential for future trials of type 1 A diabetes prevention. Nevertheless specific predictive paradigms cannot yet be precisely specified (too few determinations of micro-IAA (insulin autoantibody), and too little follow up of ICA negative biochemical autoantibody positive relatives). It is now essential to take advantage of the cohorts already assembled and new screenees over the next several years to obtain adequate prospective metabolic and immunologic evaluation. Newer assays (including epitope specific assays and subclass specific assays) combined with the unique OPT clinical study, will be important both for the practical development of "biochemical" autoantibody prediction and understanding of the "natural history" and pathogenesis of type 1A diabetes and response to "insulin" therapy. The current grant seeks support to continue to determine

14

Diabetes Mellitus

GAO65 and ICA512 (IA-2) autoantibodies on new samples and to apply new assays, to measure with the recently developed high-throughput insulin autoantibody assay all samples, to prospectively evaluate on an annual basis cytoplasmic ICA negative, biochemical autoantibody positive individuals, to analyze genetic determinants of autoantibody phenotype and metabolic progression, as well as further analyze the wealth of accumulating data. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIGAD MAB POLYMER CONJUGATES FOR DIABETES TREATMENT Principal Investigator & Institution: Kim, Sung W.; Professor; Pharmaceutics/Pharmaceutl Chem; University of Utah 200 S University St Salt Lake City, Ut 84112 Timing: Fiscal Year 2001; Project Start 15-APR-1997; Project End 31-MAR-2003 Summary: (Adapted from the applicant's abstract) Insulin dependent diabetes mellitus (IDDM Type I) is the result of autoimmune destruction of insulin producing beta cells. Disease progression is evidenced by multiple autoantibodies responding in a cascade mechanism, wherein the first antigen induces the activation of the immune system, leading to destruction of beta cells and consequently, exposure of other antigens and autoantibodies. Glutamic acid decarboxylase (GAD) is a primary autoantigen involved in the cascade. One underlying hypothesis of this study is that injected anti-GAD derivatives and conjugates will bind to the GAD antigen, blocking the antigenic determinant and preventing immune recognition by lymphocytes. The applicants' laboratory routinely isolates anti-GAD-IgG and has tested it to prevent IDDM onset in nonobese diabetic (NOD) mice. At 32 weeks of age, a significant decrease in the incidence of diabetes was observed in the anti-GAD treatment group (85 percent) (p<0.05). Treatment efficacy was correlated to the age of initial treatment. The extent of lymphocyte cell infiltration (insulitis) in the test group was less than controls, indicating the therapeutic benefit of anti-GAD-IgG in delaying diabetes. Other data supports the fact that anti-GAD has a direct effect on the immune system by inducing lymphocyte proliferation in vitro. The proposal will also investigate the effect of chemically coupled poly(ethylene glycol) (PEG) to anti-GAD. PEGylated proteins and antibodies are well recognized for their improved pharmacokinetic, pharmacodynamic, and immunological properties. Anti-GAD-PEGs representing different degrees of PEG modification will be synthesized. Anti-GAD-IgG and Anti-GAD-PEG conjugates will be compared in their pharmacological actions, their role in immune regulation, and ultimately in their ability to delay the onset of diabetes. These compounds will be compared and correlated to the previous results to produce an optimal molecule for the prevention of diabetes in NOD mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANTIPSYCHOTIC MEDICATION Principal Investigator & Institution: Newcomer, John W.; Associate Professor; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 20-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant) Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia than in the general population. Type 2 diabetes mellitus is characterized by disturbances in insulin action on skeletal muscle, liver and adipose tissue. Diabetes causes increased morbidity and mortality due to acute (e.g.,

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diabetic ketoacidosis) and long-tenn (e.g., cardiovascular disease) complications. The combination of hyperglycemia, dyslipidemia and abdominal adiposity is even more strongly associated with increased cardiovascular morbidity and mortality. The association of type 2 diabetes and hyperglycemia with schizophrenia was first noted prior to the introduction of antipsychotic medications, suggesting that these patients may be at increased risk. Since then, however, additional glucoregulatory abnormalities (e.g., new Onset diabetes), dyslipidemia, and increased weight and adiposity have all been associated with antipsychotic medications. Concern about antipsychotic effects on glucose, lipids and adiposity has increased recently, focusing on the widely-used newer medications, clozapine and olanzapine. Increased abdominal adiposity can secondarily decrease insulin sensitivity and antipsychotics can increase adiposity. However, medication effects on glucose control and insulin action may also occur independent of differences in adiposity. This project aims to a) evaluate the effects of selected antipsychotic medications on insulin action in skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (whole-body lipolysis), b) evaluate the effects of selected antipsychotic medications on abdominal adipose tissue mass, total body fat and total fat-free mass, and c) explore the longitudinal effects of treatment with selected ant:ipsychotics on glucose tolerance, lipid profiles, abdominal adipose tissue mass, total body fat and total fat-free mass. These hypotheses will be evaluated by measuring 1) whole-body glucose and lipid kinetics with the use of gold-standard stable isotopetracer methodology, 2) body composition using dual energy x-ray absorptiometry and magnetic resonance imaging, and 3) longitudinal changes in glucose tolerance and lipid profiles. The aims will be addressed in non-diabetic schizophrenia patients chronically treated with risperidone, olanzapine, clozapine, or haloperidol, and untreated healthy controls. Re-evaluations will also be performed in patients treated with olanzapine and risperidone (from groups above), crossed over to treatment with the other agent for 6 months. Relevant data is critically needed to target basic research, identify long-term cardiovascular consequences, and plan therapeutic interventions. 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 2001; Project Start 01-APR-1998; Project End 31-MAR-2002 Summary: Adapted from applicant's abstract): Atherosclerosis is common in humans with diabetes. The underlying mechanisms are not completely clear. Common genetic conditions such as heterozygous LPL deficiency could potentiall be involved. However, the exact role of LPL and atherosclerosis, especially in diabetic patients is uncertain. The long term objective of the application is to understand the mechanisms of premature atherosclerosis in diabetic patients The applicants have generated a mouse with heterozygous LPL deficiency. These heterozygous mice have been crossed with low density lipoprotein receptor knockout mice to generate double knockout mice. The investigators have demonstrated the feasibility of diet-induced atherosclerosis in these models, as well as the production of experimental diabetes. The studies proposed will test the hypothesis that genetic heterozygous LPL deficiency promotes atherosclerosis in diabetes. The application has the following Specific Aims: To determine the effects of the LPL deficient heterozygous state alone and in combination with the LDL receptor deficient phenotype on atherosclerosis in mice with streptozotocin-induced diabetes used as a model for Type-I diabetes. To define how the LPL deficient heterozygous state interacts with streptozotocin-induced diabetes to affect vascular wall gene expression

16

Diabetes Mellitus

and lipoprotein biology. To determine the effects of the LPL heterozygous deficient state alone and in combination with the LDL receptor knockout phenotype on atherosclerosis in mic with dietary-induced diabetes used as a model for Type-II diabetes. To define how the LPL heterozygous deficient state interacts with this model of diabetes to affect vascular wall gene expression and lipoprotein biology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BRAIN GLUCOSENSING NEURONS IN HEALTH AND DIABETES Principal Investigator & Institution: Levin, Barry E.; Professor and Acting Chair; U.S. Dept/Vets Affairs Med Ctr(E Orange) Affairs Medical Center East Orange, Nj 07019 Timing: Fiscal Year 2001; Project Start 01-JUN-1998; Project End 31-MAY-2005 Summary: The brain requires glucose for its normal physiologic function. It has evolved glucosensing neurons which both sense and regulate peripheral glucose metabolism and energy homeostasis. Glucose responsive (GR) neurons increase their firing rate as ambient glucose levels rise whereas glucose sensitive (GS) neurons lower their firing rate as glucose levels rise. Our previous studies have identified some of the physiologic functions of these neurons and their responses to pathological states such as type 1 and 2 diabetes mellitus. This proposal will continue those studies to further delineate the function of these neurons in health and disease. The specific aims follow 2 hypotheses. Hypothesis I: Glucosensing neurons represent a unique class of sensor-integratoreffector neurons involved in the regulation of energy homeostasis. Specific Aim I: Use Ca+2 imaging combined with single cell polymerase chain reaction (SC-PCR), as well as in situ hybridization and immunocytochemistry with c-fos expression, to characterize arcuate (ARC), ventromedial nucleus (VMN) and substantial nigra (SN) GR and GS neurons by their response to and/or expression of components of the glucosensing mechanism, glucose, sulfonylureas, potassium channel openers, neuropeptides and neurotransmitters. Specific Aim II: Characterize the response of SN DA neurons to systemic hyper- vs. hypoglycemia using microdialysis. Specific Aim III: Use Ca2+ imaging with SC-PCR, in situ hybridization plus immunocytochemistry and microdialysis to characterize the effects of type I and type II diabetes on the molecular and functional properties of glucosensing neurons. Hypothesis II: Because ARC GR neurons use glucose as a signaling molecule acting at the KATP channel to sense glucose, they are selectively vulnerable to conditions which limit energy substrates as a source of intracellular ATP and to toxins that selectively target GR neurons. Specific Aim IV: Verify that a single bout of hypoglycemia produces apoptosis in ARC neurons using other markers of apoptosis. Then demonstrate the phenotype of apoptotic cells and that functional markers of ARC glucosensing (c-fos expression to systemic hyper- or hypoglycemia) are attenuated in such animals. Finally, show that these changes cannot be prevented by lactate or pyruvate. Specific Aim V: Demonstrate that brain glucosensing neurons are the target of toxins known to destroy pancreatic beta-cells (alloxan) and ARC neurons (gold thioglucose) using molecular and functional tests. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELL HYPERTROPHY

CYCLE

DEPENDENT

MECHANISMS

OF

RENAL

Principal Investigator & Institution: Riley, Daniel J.; Medicine; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 15-MAY-2002; Project End 31-MAR-2007

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Summary: (Provided by applicant): Early in diabetic nephropathy glomerular mesangium and renal tubules hypertrophy. Mesangial hypertrophy is an important, perhaps reversible, step preceding glomeruloscierosis and overt nephropathy. Using unique transgenic mice overexpressing retinoblastoma protein (Rb) and mesangial cells expressing Rb from a tetracycline-confrollable promoter system, we have discovered that renal and glomerular mesangial cell hypertrophy occur with both diabetes mellitus and with over expression of hypophosphorylated Rb. Preliminary data has shown that when Rh is over expressed, neither kidneys nor mesangial cells hypertrophy further in diabetic conditions. Our hypothesis to explain these observations is that excess glucose results in specific, cyclin-dependent phosphorylation of Rb protein during early Gi phase, and that Rb is involved distally in a pathway of glomerular mesangial cell hypertrophy. To test this hypothesis, three Specific Aims are proposed: (1) Determine whether renal and glomerular hypertrophy caused by diabetes mellitus in vivo and mesangial cell hypertrophy caused by high glucose concentrations ex vivo are dependent on activation of specific C1 phase cyclin-cdk complexes and specific phosphorylations of Rb protein. (2) Determine how high glucose regulates cdk4-cyclin Dl activity and Rb phosphorylation in mesangial cells by examining patterns of gene regulation including transcription of the cyclin D1 gene itself and of events controlled by relevant transcription factors including AP-1. (3) Test the requirement for Cl cyclin dependent kinase activation and specific cdk4-dependent phosphorylations of Rb protein for diabetic renal hypertrophy in vivo and mesangial cell hypertrophy in culture. Transgenic mice with strategic phosphorylation sites in Rb inactivated by sitedirected mutagenesis will be generated and the effects of type 1 diabetes mellitus will be examined in them. Primary mesangial cells will also be cultured from the mice and more detailed studies on hypertrophy and GI cell cycle regulation by cdks and Rb conducted in vitro. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELL CYCLE PROTEINS IN RENAL GROWTH, INJURY, AND REPAIR Principal Investigator & Institution: Preisig, Patricia A.; Professor; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 15-AUG-2000; Project End 31-JUL-2005 Summary: Renal epithelial cells are normally quiescent, but can increase their growth rate. In some situations, such as following an acute renal injury, the cell growth is essential to repairing the damaged epithelium, and appears tightly regulated. In contrast, unregulated, and ultimately destructive, growth occurs in renal cancer, polycystic kidney disease, and the progressive loss of renal function associated with loss of renal mass, diabetes mellitus, and most forms of glomerular injury. The growth changes that occur involve both hyperplasia (resulting in an increase in cell number) and hypertrophy (resulting in an increase in cell size). Using in vitro systems, two mechanisms of renal epithelial cell hypertrophy have been characterized; One involves regulation of the cell cycle process (referred to as being cell cycle-dependent) and is mediated by growth factors and cytokines, and the other is independent of cell cycle processes and mediated by agents that alkalinize intravesicular compartments, such as NH4C1. Using in vivo renal growth models, we have shown that: 1) Compensatory renal growth following uninephrectomy is a hypertrophic growth process that involves primarily activation of cyclin D kinase, without an increase in BrdU incorporation, and is not affected by inhibiting ammoniagenesis, suggesting that a cell cycle-dependent mechanism is involved; 2) Diabetes-induced renal growth involves an initial

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Diabetes Mellitus

hyperplastic growth phase associated with activation of both G, kinase and an increase in BrdU incorporation, followed by a hypertrophic growth phase associated with continued activation of cyclin D kinase, inhibition of cyclin E kinase, and inhibition of BrdU incorporation; 3) The renal growth associated with chronic hypokalemia can be reversed when ammoniagenesis is inhibition by an alkaline diet, suggesting a cell cycleindependent mechanism of growth; and 4) In transgenic mice in which the endothelin B receptor has been knocked out, uninephrectomy does not lead to hypertrophy. Aim 1 will continue to characterize the role of cell cycle proteins in compensatory renal growth. Aim 2 will focus of diabetes-induced hypertrophy. Studies will examine the regulation of the cell cycle proteins in the switch between a hyperplastic and hypertrophic growth pattern. Studies will be done in 3 models of diabetes mellitus: streptozotocin-induced type I, in Nod mice (type I), and in db/db mice (type II). Studies will also be done to determine the role of the endothelin B receptor in diabetes-induced renal growth. Aim 3 will determine the mechanisms involved in the activation of cyclin D kinase and inhibition of cyclin E kinase in cell cycle-dependent hypertrophy. Aim 4 will determine if the endothelin B receptor plays a role in chronic metabolic acidosis and chronic potassium deficiency, models of renal hypertrophy thought to be mediated by the cell cycle-independent mechanism. Together these studies will afford us the opportunity to determine if direct regulation of cell cycle processes provides an avenue for therapeutic advances that will either improve upon the beneficial effects or reduce the detrimental sequelae of renal injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHARACTERIZING AND MAPPING OBESITY AND DIABETES GENES Principal Investigator & Institution: Naggert, Juergen K.; Staff Scientist; Jackson Laboratory 600 Main St Bar Harbor, Me 04609 Timing: Fiscal Year 2001; Project Start 15-SEP-1998; Project End 31-AUG-2004 Summary: Non insulin dependent diabetes mellitus (NIDDM) is a major health problem which affects an estimated 5-10 percent of the American population. Although NIDDM is highly heritable in humans, its inheritance does not follow simple Mendelian laws and is, therefore, thought to be caused by the simultaneous action of many genes. Because such polygenic inheritance is still very difficult to unravel, single gene mutant models offer significant advantages for gene identification and for detailed physiological studies. Five recently cloned single gene obesity mutations in mouse have provided exciting new insights into the etiology of obesity. In contrast, identification of NIDDM genes is delayed, because single gene mouse mutations for NIDDM are lacking. We have identified a new mouse model for maturity onset NIDDM, which apparently is due to a recessive single gene mutation, that has provisionally been named sugar baby (sub). The Tallyho-sub/sub mouse stock is characterized by glucose intolerance, hyperinsulinemia, chronic hyperglycemia, and increased body weight. We have carried out a preliminary outcross to a nondiabetic, nonobese mouse strain to map the sub diabetes mutation. In this cross, in addition to the sub locus which determines plasma glucose levels, we were able to map a second locus, nicknamed 'brother of sub' (bos), which controls body weight. We also found evidence that the two loci interact epistatically, i.e. homozygosity at the bos locus is necessary for sub/sub mice to become diabetic. In contrast, homozygous bos/bos mice without the sub gene do not become diabetic. Based on our preliminary results, we hypothesize that the Tallyho strain carries a major obesity susceptibility allele (bos) that interacts with the sub mutation to produce the obese/diabetic phenotype of Tallyho-sub/sub mice. To test this hypothesis, we

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propose to carry out two specific aims. a.) to construct separate congenic lines of mice that carry either the bos and sub genes individually or in combination on a common genetic background and to use these lines to generate fine structure genetic maps for bos and sub in order to positionally clone these genes. b.) to physiologically characterize the Tallyho strain and the congenic lines and test the hypothesis that the sub gene can interact with obesity mutations other than bos to cause diabetes. At the successful conclusion of this work, we will have identified two new genes, bos and sub, that constitute an epistatic genetic system involved in the etiology of type II diabetes. Additionally, through examination of the mutations individually and in combination in a common genetic background, we will gain a better understanding of the pathways and physiological abnormalities that are necessary to cause diabetes. 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 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

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Diabetes Mellitus

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: CORE--MOUSE GENETICS Principal Investigator & Institution: Killeen, Nigel P.; Assistant Professor; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2003; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: (Provided by applicant): The primary objective of the DRTC Mouse Models Core is to create a shared resource for the establishment, maintenance and experimentation on mouse models of type 1 and type 2 diabetes and related disorders to assist DRTC investigators in meeting their research objectives. Specific aims of the core are: 1.Produce transgenic mice in standard laboratory strains; 2. Produce transgenic mice in the NOD mouse background; 3. Produce transgenic mice carrying bacterial artificial chromosomes (BACs), in standard and NOD backgrounds; 4. Provide standardized ES cells and assistance with producing gene targeted clones; 5. Establish gene-targeting procedures for targeting the NOD chromosomes in embryonic stem (ES) stern cell lines derived from NOD x 129 F1 mice, facilitating the generation of gene knockout and knock-in mice that can be rapidly inbred to homozygosity in NOD; 6. Produce gene targeted mice via blastocyst injection of standard and NOD ES cell clones; and 7. Provide liaison to the Stanford University Gene Trap Resource, facilitating the screening by DTRC members for mouse insertional mutations with phenotypes relevant to types I and II diabetes. To meet these aims, the core will operate in a fashion similar to most institutional transgenic and targeted mutagenesis cores. This facility will, however, emphasize and specifically support diabetes-related projects. For example, the core will establish routine microinjection and gene-targeting procedures using zygotes and embryonic stem (ES) cell lines from the NOD (and potentially other) mouse strains that are of key significance for diabetes research. The Core will import and maintain relevant mouse strains and ES cell lines relevant in diabetes research and it will establish the capability to derive new ES lines to complement external sources. In addition, the Core will subscribe to a regional consortium that is producing new mutations in the mouse through 'gene-trap' insertion technologies, so as to identify new mutant mice showing developmental or physiological phenotypes relevant to research of the UCSF DRTC in types I and II diabetes. A major focus of the core will be on establishing the capability to genetically manipulate the non-obese diabetic (NOD) mouse via transgenic and gene targeting experiments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--MOUSE METABOLISM Principal Investigator & Institution: Tecott, Laurence H.; Assistant Professor; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2003; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): The objectives of the Mouse Metabolism Core Laboratory will be to provide support and assistance for an extensive and integrated assessment of the impact of genetic, pharmacological and environmental manipulations on energy balance in the mouse. An important function of the Core Laboratory will be to provide investigators with direct assistance with these techniques to facilitate the timely and successful completion of experiments. The Core Laboratory will provide

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opportunities for investigators, fellows and students to receive training in a range of techniques relevant to the study of energy balance in the mouse. In addition, the Core Laboratory will monitor and implement advances in assay procedures, and engage in technology development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEFINING DIABETES IN YOUTH Principal Investigator & Institution: Hamman, Richard F.; Professor and Chairman; Preventive Med and Biometrics; 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-2005 Summary: (provided by applicant): There is very limited information about the epidemiology of Type 2 diabetes mellitus in youth, though it is believed that the prevalence is increasing rapidly. Risk factors similar to those in adults with Type 2 are thought to be important, (e.g., obesity, insulin resistance, diet, physical activity, positive family history), however, there are no reliable epidemiological studies of these risk factors in youth with type 2 diabetes using appropriate controls. In addition, risk factors such as low birth weight lack of breast-feeding, maternal diabetes during pregnancy and family dysfunction and depressive symptoms have received little epidemiological study in populations other than American Indians. This application addresses the lack of such studies. The Defining Diabetes in Youth (DDY) project will focus on type 2 diabetes in youth aged 10-19, drawing upon the CDC funded SEARCH diabetes registry project in Colorado and South Carolina. The SEARCH project will ascertain all cases of diabetes in youth, collect immunologic, clinical, and metabolic information, and classify cases as Type 1 or 2 diabetes. DDY will only have to recruit appropriate controls aged 10-19 from three ethnic backgrounds including African Americans (AA), Hispanics (H), and nonHispanic whites (NHW) to test specific etiologic hypotheses in the cases classified by SEARCH as Type 2 diabetes. It will also explore cardiovascular risk factor differences in youth with Type 2 diabetes and controls, and will evaluate insulin resistance and secretion differences among controls by level of obesity and other factors. The primary design is a case-control study, through which risk factors for diabetes, selected complications and CVD risk factors will be evaluated. The current application is an approved SEARCH ancillary study. Collaborating investigators bring expertise in multiple areas relevant to diabetes in youth, and experience in large epidemiological studies of diabetes (both type 1 and 2) in minority populations. Given the low prevalence of Type 2 in Youth, DDY is an efficient design, since case ascertainment and typing will be conducted by SEARCH, and only control recruitment, addition of new measures, and analysis are requested. The biostatistical analysis, data management and central laboratory will be the same as used in SEARCH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM Principal Investigator & Institution: Newgard, Christopher B.; Professor; Biochemistry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: The goal of this P01 application is to develop novel therapies for the treatment of non insulin-dependent diabetes mellitus (NIDDM). We seek to team senior members for the Marjorie Touchstone Diabetes Center (Project 1, Unger and Project 2, Newgard) with colleagues from the Molecular Cardiology Center for Biomedical

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Diabetes Mellitus

Inventions (Project 3, Johnston and Project 4, Kodadek) here at the University of Texas Southwestern Medical Center in Dallas (UTSWMC). These principal investigators will be complemented buy key co-investigators that will provide expertise in molecular biology (Mangelsdorf, Meidell), nuclear magnetic resonance (NMR) analysis of metabolism (Sherry, Jones), and physical methods for gene targeting (Grayburn). The proposal contains plans for basic biology research relating to the mechanics of hepatic, cardiovascular, and islet dysfunction in obesity and NIDDM (Projects 1 and 2). It also contains proposals for development of novel technologies for gene targeting, controlled regulation of gene expression by small molecules, and manipulation of protein/protein interactions (Projects 3 and 4). Several points of integration of the biology and technology development programs have been identified and will be exploited. The fundamental motivation for assembling a team of this type is that no comprehensive and complete therapy for NIDDM currently exists. Given the complexity of the disease and the alarming rise in its incidence towards epidemic proportions, a focused effort for creation of new therapeutic strategies is required. Integration of biological research with technology development as we are proposing here may allow achievement of this difficult goal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES RESEARCH AND TRAINING CENTER Principal Investigator & Institution: Granner, Daryl K.; Professor of Medicine & Biochemistry; Molecular Physiol & Biophysics; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2001; Project Start 13-FEB-1996; Project End 31-MAR-2002 Summary: The Diabetes Research and Training Center (DRTC) at Vanderbilt is one of a network of Core Centers established by the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) to conduct research and training in diabetes mellitus and related endocrine and metabolic disorders consistent with the National Diabetes Mellitus Research and Education Act, the report of the National Commission on Diabetes, and the Administrative Guidelines for DRTCs, as promulgated by the NIDDK. The Vanderbilt DRTC is a multi-disciplinary program with 81 participating faculty members distributed among 14 departments in 2 schools and 3 colleges of the University. The Biomedical Research Component consists of a research base of 64 investigators in the following interest areas: In vivo metabolism, Signal transduction, Etiology and complications, Gene regulation, Beta cell function, Demonstration and education. These investigators are supported by a Surgical and Analytical Services Core that is comprised of Hormone Assay, Amino Acid Assay and Animal Services subcores, and by the Cell and Molecular Biology Services Core that consists of DNA Chemistry, Media/Reagents, Cell Imaging and Transgenic Mouse/ES Cell subcores. A Pilot and Feasibility Studies Program helps new investigators initiate their research programs. The Demonstration/Education Component includes a Model Demonstration Unit that serves as the training laboratory for students in the health professions and it maintains a cohort of patients with diabetes who serve as volunteers for approved clinical research programs. The MDU also provides professional, technical and administrative support for Center investigators who conduct research in the General Clinical Research Center. This component also includes the Education/Evaluation Core that initiates and supports education research and instructional development activities. The Center coordinates three NIH-sponsored training programs that provide education and laboratory training in diabetes/endocrinology to medical students and graduate students and postdoctoral training for MDs and PhDs. An enrichment program provides continuing education

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through a Diabetes Research Day, a seminar series and annual symposia. The Administrative Component provides both scientific and administrative leadership for the total program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETIC NEUROPATHIC FOOT ULCER: WHO WILL HEAL? Principal Investigator & Institution: Margolis, David S.; Associate Professor; Dermatology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2003 Summary: (adapted from the application) Lower extremity ulcers are a serious complication of diabetes mellitus. More than 16 million people in the US have diabetes mellitus and 15% of them can expect to develop a foot ulcer at some point in their life. Annually more than 50% of all non-traumatic amputations occur in patients with diabetes, thereby making diabetes the leading cause of lower extremity non-traumatic amputation. Lower extremity chronic wounds precede more than 85% of these amputations. In diabetics, the etiologies of these wounds are believed to be lower-limb arterial insufficiency, neuropathy, or a combination of both. The patients with diabetic neuropathy are often managed medically while those with arterial insufficiency are treated by vascular surgical intervention. Previous studies have shown that both poor lower-limb arterial blood flow and diabetic neuropathy are associated with the risk of developing a foot ulcer and eventually an amputation. However, very little has been published on the risk factors or prognostic factors associated with the failure of a patient with a diabetic neuropathic foot ulcer to heal. This is problematic, since new medical treatments recently approved by the FDA were specifically labeled for the treatment of diabetic neuropathic foot ulcers. Without knowledge of risk and prognostic factors, it is difficult for health care practitioners to make informed decisions with respect to whom they should treat with standard care and it is very difficult for a clinical investigator to plan well designed clinical trials. Using the largest wound care specific database and multivariable regression techniques, we will conduct a series of cohort studies to create explanatory and prognostic models. The explanatory models will be used to estimate the association of a risk factor on the likelihood that a wound will heal (or require an amputation) by the 20th week of standard therapy. The prognostic models will be used to estimate the probability that an individual with a neuropathic foot ulcer will heal with standard therapy. Ultimately, parsimonious clinically friendly models will be developed from complex models, so that a healthcare provider can discriminate between those wounds that will heal (or require an amputation) with standard care and those wounds that will not heal (or require an amputation). These models will not only be useful to health care providers, but they will also be useful to clinical investigators trying to design clinical trials on patients that might maximally benefit from a new treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DNA IMMUNIZATIONS WITH GAD65 TO INDUCE TOLERANCE Principal Investigator & Institution: Morel, Penelope A.; Associate Professor; None; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2003 Summary: Type 1 diabetes is an autoimmune disease characterized by T cell- mediated destruction of the insulin-producing cells of the islets of Langerhans. The murine model of insulin dependent diabetes mellitus (IDDM), the non-obese diabetic (NOD) mouse

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Diabetes Mellitus

has served as a useful model of the human disease since many of the features of the disease are shared. In both mouse and human the development of diabetes is preceded by heavy islet infiltration with lymphoid cells, including CD4+, CD8+ T cells, dendritic cells and monocytes. Recently it was found that T cell responses to the neuronal enzyme glutamic acid decarboxylase 65 (GAD65) were among the first to be detected in the spleen of young NOD mice, with responses being detected as early as 4 weeks. In addition it was found that if NOD were made tolerant to GAD65, by intra-thymic or intravenous injection, diabetes was prevented. We have recently shown that treatment of NOD mice with dendritic cells pulsed with a single GAD65 peptide can prevent diabetes and that this occurs through the initiation of a GAD65-specific Th2 response. Genetic immunization using either plasmid DNA, depending on the route of immunization, can lead to either a Th1 or Th2 response. We have preliminary evidence in a non-diabetes model that the cellular localization of the transfected protein also profoundly influences the nature of the immune response. Strong Th1 responses, with CTL, are obtained when the protein is cytoplasmic, whereas a Th2 dominated response is seen when the protein is secreted following gene gun immunization of ovalbumin (OVA) cDNA. Genetic immunization can thus be tailored to induce the desired response. In the case of diabetes in the NOD mouse, it has been shown that the induction of Th2 responses to specific GAD65 peptides can lead to a halt in the destructive insulitis and the prevention of diabetes. In this proposal are: 1) To construct GAD65 cDNA plasmids which will allow expression of GAD65 in the cytoplasm, as a secreted protein and as a transmembrane protein; 2) To characterize the immune response initiated following immunization of NOD and non diabetes-prone strains with the three GAD65 constructs; 3) To determine whether DNA immunization GAD65 constructs prevent the initiation of diabetes and insulitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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

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myocardium where it likewise positively influences lipid metabolism. This study will, therefore, provide evidence to support this hypothesis. It will assess the effect of captopril on myocardial lipid metabolism of the diabetic-hypertensive rat. Specifically, it will assess the effect of this agent on myocardial levels of cholesterol, triglycerides and long chain acyl carnitines and CoAs. These lipids and lipid intermediates accumulate in the diabetic heart and are strongly implicated in its depressed contractile performance. The male spontaneously hypertensive rat (SHR) will be the animal model. It will be made diabetic with a single tail vein injection of streptozotocin (60 mg/kg). Captopril will be administered in the drinking water (100 mg/kg) 3 days after diabetes induction. Rats will be sacrificed after 6 weeks of diabetes with sodium pentobarbital (75 mg/kg, i.p.). This study will present new findings about captopril therapy during diabetes plus hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOTHELIAL CELL DYSFUNCTION IN OXIDATIVE STRESS MODELS Principal Investigator & Institution: Caldwell, Robert W.; 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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Diabetes Mellitus

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: ENDOTHELIN-1-CARDIOMYOPATHY

A

NEW

PLAYER

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DIABETIC

Principal Investigator & Institution: Schwartz, Dean D.; Vet Microbiology and Pathology; Auburn University at Auburn Auburn University, Al 36849 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2003 Summary: Applicant's Abstract Diabetes mellitus is a metabolic disorder recently identified as a strong independent risk factor for cardiovascular disease. Both Type 1 and 2 diabetes mellitus have been linked to a marked increase in the incidence of heart failure and mortality associated with coronary heart disease. Diabetic cardiomyopathy, an independent clinical syndrome, is characterized by diastolic dysfunction, abnormalities in systolic function and histological changes that occur with or without coronary artery disease. The specific etiological mechanism(s) responsible for the cardiormyopathy observed in diabetic patients and experimental models of diabetes has not been clearly defined. However, the direct effects of abnormal carbohydrate metabolism and excessive fatty acid oxidation have been implicated as important proximate causes in diabetic cardiomyopathy. We propose that another factor contributing to altered cardiac energy metabolism and function associated with diabetic cardiomyopathy is the bioactive peptide, endothelin-1 (ET-1). In this application, we present preliminary data demonstrating that diabetic rats have elevated plasma and tissue levels of ET-1, decreased cardiac mechanical function and decreased tissue fructose-2,6-bisphosphate (F26P2) levels compared to vehicle-treated rats eight weeks after induction with streptozotocin. Furthermore, in isolated ventricular myocytes. ET-1 inhibits glucose uptake, glycolysis and F26P2 production, possibly by a protein kinase C (PKC)-dependent mechanism. We therefore hypothesize that the progressive decline in cardiac metabolism and function observed in the diabetic patient is due in part to the metabolic effects of ET-1, which augment the already altered cardiac metabolism produced by insulin deficiency/resistance and subsequent elevations in free fatty acid levels. To test this hypothesis, the following specific aims will be examined in

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streptozotocin (STZ)- and vehicle-treated rats: 1) Determine the cellular effects of ET-1 on cardiac glucose uptake and utilization in isolated ventricular myocytes; 2) Examine endothelin-insulin myocardial receptor signaling crosstalk in isolated ventricular myocytes and the effect of protein kinase C activation on this crosstalk; and 3) Determine the time course for the pathological effects of ET-1 on cardiac metabolism, PKC activation and function in vivo in diabetic rats using the endothelin receptor antagonist bosentan. In summary, this application will delineate the connections between altered intracellular signaling between ET-1 and insulin as they relate to glucose utilization, protein kinase C activation and myocyte function, and examine the relation between altered energy metabolism and myocardial function in diabetes mellitus. (End of Abstract) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPIDEMIOLOGY OF ISLET CELL AUTOIMMUNITY IN NIDDM Principal Investigator & Institution: Pietropaolo, Massimo T.; Assistant Professor; Children's Hosp Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 15213 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: Several lines of evidence indicate that Type 2 (non-insulin-dependent) diabetes mellitus is a heterogeneous disease that results from a combination of abnormalities in both insulin secretion and insulin action. The causes of decreased insulin secretion in Type 2 diabetes are still not completely understood, but in a subgroup of Type 2 diabetic patients they may be related to an autoimmune destruction of the pancreatic beta cells. A pronounced activation of the acute-phase response, that was found to be associated with islet cell autoimmunity in the Preliminary Studies, may in part explain the defect in insulin secretion seen in Type 2 diabetes. There have been no extensive investigations, particularly in the U.S., with regard to the prevalence and clinical significance of islet cell autoimmunity particularly in elderly patients with Type 2 diabetes. Two of the most widely used markers for the diagnosis and prediction of autoimmune diabetes, namely GAD65 and IA-2 autoantibodies, along with inflammatory markers of activation of the acute phase response, will be applied in a well-characterized population of Type 2 diabetic patients over the age of 65 from the Cardiovascular Health Study (CHS). The CHS is a longitudinal study, which was proposed to identify and evaluate factors, such as diabetes mellitus, related to the incidence and the natural history of Coronary Heart Disease (CHD) and stroke in noninstitutionalized adults 65 years and older. The identification of individuals at risk of developing autoimmune Type 2 diabetes is of public health interest because immunomodulatory strategies could potentially be instituted early enough to prevent the complications related with hyperglycemia and, possibly, the time of onset of insulin requirement. A more appropriate characterization of a subgroup of Type 2 diabetic patients of autoimmune pathogenesis will be of benefit to future research into the etiology, natural history as well as treatment of Type 2 diabetes mellitus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FAMILY STUDIES OF NIDDM--AFRICAN AMERICANS AND HISPANICS Principal Investigator & Institution: Guze, Carol D.; Professor; California State UnivDominguez Hills Carson, Ca 90747 Timing: Fiscal Year 2001; Project Start 30-SEP-1992; Project End 31-MAR-2005

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Summary: The objective of this pilot study is to generate empiric counseling risks for use in counseling patients and families as well as to identify risk factors that contribute to the development and course of type 2 diabetes (DM-2) in African Americans and Hispanics in Central Los Angeles. Type 2 diabetes mellitus is a common disorder usually of middle-aged individuals and, if untreated, complications can arise. DM-2 is one of the top ten health problems in the United States and the prevalence in African Americans is estimated to be 10% and in Hispanics, 15%. These communities are also at greater risk for developing long-term complications of diabetes such as retinopathy (including blindness). An alarming new trend is an increase in DM-2 among young people especially Hispanics and African Americans. DM-2 has also been shown to have a disproportionate impact among ethnic seniors. We plan to use family studies gathered by personal interviews and questionnaires to obtain the necessary informati on from our DM-2 patients. 100 adult African American patients and 100 adult Hispanic patients in diabetes clinics at King Drew Medical Center and its outlying clinics will be interviewed. Interviews of non English speaking Hispanics will be conducted in Spanish. The specific aims of our project are 1. To develop empiric counseling risks using the information gathered from the family history studies and 2. to explore within our families those risk factors which in other studies have not been looked at in detail. These include the regions of origin in Mexican-Americans; acculturation factors; maternal pregnancy factors; birth weight; birth order; obesity in the family members. We anticipate that the information gathered from our pilot study will suggest testable hypothesis for future more focused studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE REGULATION OF ATHEROSCLEROSIS IN DIABETIC ANIMALS Principal Investigator & Institution: Leboeuf, Renee C.; Professor; Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 01-FEB-1997; Project End 31-AUG-2006 Summary: (provided by applicant): Our long term goal is to identify molecular mechanisms for the onset of accelerated atherosclerosis in diabetes mellitus. This will be accomplished by studying animal models susceptible to both diabetes and atherosclerosis. During the previous grant period, we developed new mouse models, which show remarkable changes at the artery wall due to diabetes. BALB and BALB.LDLR-/- mice develop vascular lesions which are accelerted by hyperglycemia but are independent of changes in plasma lipids. In contrast, C57BL/6 and C57BL/6.LDLR-/- develop lesions which are not reflective of hyperglycemia. We use this genetic difference to test the hypothesis that hyperglycemia modulates the expression and/or function of specific genes causing diabetic macrovascular disease, in three aims: Aim 1: Identify major gene(s) determining the increased atherosclerosis in response to hyperglycemia. We use microarray technology coupled to mouse genetics for validation to identify such genes. Aim 2: Determine the role of specific candidate gene pathways in diabetic vascular disease. We study candidate proteins of perlecan, MMP-9 and MMP-13, and connexins 43 and 45 in our mouse system. Aim 3: Determine whether interventions aimed at reducing oxidative stress or protease activity can protect BALB from diabetic vascular disease. Anti-oxidant diets and diets containing synthetic protease ihibitors are used to test the general role of these pathways in diabetic vascular disease. Together, this information will provide potential gene targets for future prediction and treatment of diabetic macrovascular disease in humans Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE THERAPY FOR BLADDER HYPERACTIVITY IN DIABETIC RATS Principal Investigator & Institution: Christ, George J.; Professor; Urology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2003 Summary: (provided by applicant) Diabetes mellitus affects more than 100 million people worldwide. Neuronal alterations, as a consequence of diabetes mellitus can cause bladder dysfunction ranging from mild to severe in scope. In fact, urinary incontinence occurs in up to 80 percent of diabetic patients, and the manifestations include decreased bladder sensation, increased residual urine or detrusor instability (i.e., bladder overactivity or hyperactivity). These conditions have a severely adverse effect on the quality of life of the individual, at great monetary as well as emotional expense. These diabetes-related changes in bladder function are permanent and require medical therapy to reverse the symptoms. Current medical therapies lack both efficacy and specificity. To this end, we propose to evaluate the efficacy of K channel gene therapy to ameliorate the bladder hyperactivity associated with the most commonly used animal model of diabetic neuropathy (as determined by reference citations), that is, the streptozotocin (STZ)-diabetic rat. We shall study the effects of STZ-induced diabetes on bladder function in vivo in MALE and FEMALE rats. In Specific Aim #1 we will utilize the micturition reflex to study bladder function in conscious and freely moving rats, and thereby identify those animals exhibiting STZ-induced bladder overactivity. Rats with documented bladder hyperactivity will receive a single injection of the hSlo/pcDNA, which encodes the alpha subunit of the human maxi-K (potassium) channel. In Specific Aim #2 we will utilize in situ hybridization techniques to establish the relationship between recombinant transgene expression (i.e., hSlo/pcDNA expression) and bladder function in the same animal. Such studies will permit us to firmly establish the relationship between transfection efficiency and organ function in vivo in the same animal. In Specific Aim #3, we will utilize microarray gene chip analysis to study the effects of STZ-Diabetes on gene expression in the bladder of rats that have already been characterized with respect to the degree of bladder dysfunction in vivo. Moreover, we will also examine the effects of hSlo gene therapy on gene expression. As such, we anticipate being able to establish definite relationships between the degree of transgene expression, and the effects of these molecular changes on bladder function in vivo. In year 2 of this proposal we will study the prophylactic ability and duration of this gene therapy approach. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENERATING NEPHROPATHY

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DIABETIC

Principal Investigator & Institution: Breyer, Matthew D.; Professor; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (Provided by Applicant): Diabetic nephropathy (DN) is a disease of monumental proportions both in terms of human suffering and public health expenditures. Approximately six percent of the U.S. population has diabetes mellitus, 10-20% of which develop DN, ultimately progressing to end stage renal disease (ESRD). The factors contributing to DN remain obscure. While hyperglycemia is a necessary trigger, alone, it is insufficient to cause DN. Sibling studies suggest a strong genetic component, however defining the specific genetic loci contributing to DN in man has

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Diabetes Mellitus

been confounded by the heterogeneous causes of diabetes, and by the diversity of human genetic background. In contrast, the wide availability of genetically homogenous mouse strains, coupled with advances in transgenic technology, make mice uniquely amenable to dissection of the molecular mechanisms of disease. As in man, most mice do not develop diabetic nephropathy, and the array of genes that confer susceptibility to DN to this minority, have not been characterized. This proposal is to generate a robust murine model of DN that closely parallels the human disease; that is genetically defined; and can be easily transferred between mouse strains. To achieve these goals we propose to identify specific genes that convert the "nephropathy resistant" C57BL/6 strain to one that develops DN. We will take two approaches. The first will use a "candidate gene" approach. In man, patients susceptible to DN exhibit worse hypertension and dyslipidemia than those resistant to nephropathy. Treatment of these conditions slows the progression of nephropathy. Polymorphisms in Angiotensinogen (Atg) eNOS and ApoE alleles have been described in susceptible patients. The first specific aim will examine the effect of superimposing the hypertensive human Atg transgenic, eNOS-/or hyperlipidemic ApoE-/- alleles on two different models of diabetes, insulin deficient HN6 transgenic mice and insulin resistant db/db mice. The second approach will attempt to identify novel dominant modifiers that predispose to DN. Diabetic HNF6 or db/db C57BL/6 mice will be mutagenized with ethylnitrosourea (ENU) and G 1 offspring screened for DN (renal insufficiency and/or proteinuria). These studies should not only yield a well-defined mouse model of DN, but also provide important new information regarding genes that contribute to the development of DN. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENES FOR NON-INSULIN-DEPENDENT DIABETES MELLITUS Principal Investigator & Institution: Bell, Graeme I.; Professor; Biochem and Molecular Biology; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2001; Project Start 30-SEP-1993; Project End 31-AUG-2004 Summary: Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from an absolute or relative deficiency of insulin. The chronic hyperglycemia of diabetes is associated with long-term tissue damage, especially of the eyes, kidneys, nerves, heart and blood vessels. Type 2 or non-insulin-dependent diabetes mellitus is the most common form of diabetes, affecting about 15 million people in the United States. Genetic factors play an important role in the development of type 2 diabetes and the overall aim of this application is to identify the genes that are responsible for type 2 diabetes and then to determine how they contribute to the pathogenesis of this disorder. During the present funding period, research carried out under the auspices of this grant has shown that linkage studies using affected sib pairs without parents can be used to localize genes for type 2 diabetes. We have mapped the major type 2 diabetes susceptibility gene in Mexican Americans (gene symbol, NIDDM1), a gene which may account for 30 percent of the familial clustering of type 2 diabetes in this population, to the region of the markers D2S125-D2S140. Our studies also provided evidence for other susceptibility genes of smaller effect than NIDDM1. This is a continuation of collaborative studies between investigators at The University of Chicago, the University of Texas Health Science Center at Houston and Virginia Mason Research Center to identify genes for type 2 diabetes. The aim in the first funding cycle was to map the genes for type 2 diabetes. We have made major progress toward reaching this goal and now propose to make the natural transition from genetic linkage studies to identification and functional characterization of NIDDM1 and other type 2 diabetes genes. Studies being carried out at the University of Chicago will focus on

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NIDDM1 whereas those at the University of Texas Health Science Center at Houston and Virginia Mason Research Center will involve other regions containing putative type 2 diabetes genes. The identification and characterization of the genes for type 2 diabetes will lead to a better understanding of the molecular basis of this disorder, thereby providing the basis for new approaches for prevention and treatment based on the nature of the underlying molecular defect. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC AND PATHOLOGIC ALTERATIONS IN MURINE DIABETES Principal Investigator & Institution: Quigg, Richard J.; Professor; Medicine; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 31-MAY-2002 Summary: A number of experimental models of diabetes mellitus (DM) exist in mice. The non-obese diabetic strain (NOD/Lt) develops insulin-dependent DM with immunologic pancreatic beta cell destruction and insulinopenia inherited in a polygenic fashion. The Leprdb strain develops non-insulin dependent DM characterized by obesity and insulin resistance due to a single nucleotide substitution in the leptin receptor gene (Lepr). There is evidence that the renal functional and morphological changes occurring in both strains of diabetic mice parallel much of what is seen clinically in humans, including the development of albuminuria and glomerular matrix accumulation. A great deal of effort and technological advancements have allowed the continual identification and sequencing of expressed genes, some related to known gene families and some novel. For the most part, these gene sequences are in accessible data bases. To determine the relevance of these gene products in various circumstances, he technique of massively parallel DNA analysis is being developed by a number of groups. This approach allows the determination of which genes are expressed in a given tissue at a particular time. In these studies, groups of NOD/Lt and Leprdb mice will be followed longitudinally. At different times, selected animals will be sacrificed for detailed evaluation of renal pathological changes relevant to human diabetic nephropathy. The expression of mRNA for genes potentially altered in Dm will be determined. Genes chosen based on logic detailed in the application will be evaluated using the technique of massively parallel DNA analysis. mRNA from diabetic and control glomeruli will be differentially labeled and hybridized with cDNA-containing microchips. A relative increase or decrease in the expression of these genes will be determined. The strategy will permit identification of known and novel genes that may be affected in experimental insulin- and noninsulin- dependent DM and correlate these with renal functional and pathological changes. Furthermore, successful completion of these pilot studies will justify additional work to: 1) identify analogous genes potentially altered in human diabetic nephropathy; 2) determine the importance of identified gene products in experimental diabetic nephropathy; and, 3) study additional genes and organ systems affected in DM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC SUSCEPTIBILITY TO END STAGE RENAL DISEASE Principal Investigator & Institution: Iyengar, Sudha K.; Associate Professor; Epidemiology and Biostatistics; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 01-SEP-1998; Project End 31-JUL-2003

32

Diabetes Mellitus

Summary: (Adapted from applicant's abstract) End-stage renal disease (ESRD) is a lateonset multi-factorial disease that primarily occurs in a subset of patients with diabetes mellitus, hypertension or chronic glomerulonephritis. End-stage renal disease incidence ins rising with an annual mortality of about 20% in incident cases. End-stage renal disease clusters in families and familial aggregation is a more powerful predictor of whether an individual with diabetes mellitus, hypertension or chronic glomerulonephritis will develop ESRD. However, no particular genetic mechanism responsible for the renal function damage that ultimately leads to ESRD as yet been identified. We will recruit 150 affected sib pairs concordant for ESRD and Type 2 diabetes and 200 sib pairs discordant for ESRD (but concordant for Type 2 diabetes mellitus) and 200 additional family members from hemodialysis, peritoneal dialysis and transplant centers as part of a study to identify genetic risk factors for ESRD. We will collect extensive family history and medical history as related to ESRD, on all members of the family recruited into the study. Blood will be obtained from consenting family members. The DNA will be extracted from lymphocytes and candidate genes and other markers will be genotyped. More than half the candidate genes/regions being examined are novel candidates and have not been evaluated for linkages with ESRD before. These include the receptors for the growth factors and the human regions syntenic to ESRDrelated loci in rat or mouse models of ESRD. We will also examine regions of human chromosomes 7 and 16, where a genome scan in the Pima Indians shows suggestive evidence for diabetic nephropathy loci. Data will be analyzed using model-free linkage analysis. This dataset is expected to be complex and will have to sub-divide the data by race/ethnicity for analysis. We anticipate that this study will lead to identification of gene(s) for ESRD. This application is intended to provide a core for further, more extensive, acquisition of ESRD phenotype and genotype data. We intend to expand the entire project to include a genome scan and have designed subject collection to accommodate this goal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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 2001; Project Start 01-AUG-1995; Project End 31-JUL-2003 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 virus-induced 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

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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: GENETICS OF DIABETIC RETINOPATHY Principal Investigator & Institution: Hanis, Craig L.; Professor; Human Genetics Center; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: (Applicant's Abstract) Diabetic retinopathy substantially contributes to the morbidity of type 2 diabetes mellitus and is a strong predictor of subsequent, often early, mortality in those with diabetes. Susceptibility to type 2 diabetes has long been known to have a substantial genetic component. Not only does diabetes aggregate in families, but so do its complications. Preliminary results demonstrate an 8.3 fold increased risk for retinopathy in diabetic siblings of a diabetic with no retinopathy. It is likely that diabetes susceptibility alleles impact the clinical courses of the disease and development of retinopathy. It is also plausible that other genes influence susceptibility to retinopathy, but exert their influence only after the development of diabetes. To determine the contribution of genetic factors to diabetic retinopathy, 1,000 Mexican Americans with type 2 diabetes distributed in 750 sibling pairs will undergo detailed eye examinations on 2 occasions (2.5 years apart). Examinations will include stereoscopic fundus photography and scoring according to standard protocols. Except for the retinal examinations, these individuals have been and are being characterized in ongoing studies in Starr County, Texas. These characterization includes genotypes at markers spanning the entire genome at an average distance of 8 to 10 centi-Morgans. All marker data will be available prior to the completion of the first round of retinal examinations. Documentation of the presence and severity of diabetic retinopathy in this sibling pair genotype resource and an additional confirmatory set of 200 individuals with diabetes will permit: 1) Determining the sibling pair concordance for retinopathy, 2) Localizing retinopathy susceptibility loci based on two-point and multi- point sibling pair linkage analysis, and 3) Identification of variation by DNA sequence scanning of genes in linked regions impacting on the presence and development of retinopathy. The end result will be improved understanding of mechanisms and exploitable pathways for moving retinopathy treatment from palliative to preventive. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETICS OF OBESITY AND DIABETES Principal Investigator & Institution: Attie, Alan D.; Professor; Biochemistry; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2006 Summary: (Scanned from the Applicant's Description): The majority of persons with non-insulin-dependent diabetes mellitus (NIDDM) are obese. Nevertheless, although

34

Diabetes Mellitus

most obese people have insulin resistance, the great majority never develop NIDDM. There are essentially no biochemical clues that allow us to predict which obese individuals will develop diabetes, much less why they develop diabetes. In addition, there is limited mechanistic information to help us understand why obesity is so intimately related to diabetes. The objective of this project is to identify genes that link obesity and diabetes in mice. We have mapped two gene loci that determine whether or not an obese mouse will develop Type 2 diabetes. We have also mapped two loci that strongly affect body weight in a population of obese hyperphagic mice. The aims of this project are to: 1) Create interval-specific congenic strains for each mapped locus. 2) Refine the obesity and diabetes phenotypes. 3) Use a positional candidate strategy to identify the genes responsible for the mapped traits. Identification of obesity and diabetes susceptibility genes will provide clues to novel pathways and biochemical mechanisms underlying complex disease problems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEART FAILURE IN THE COMMUNITY Principal Investigator & Institution: Roger, Veronique L.; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2003; Project Start 15-JAN-2003; Project End 31-DEC-2006 Summary: (provided by applicant): Heart failure (HF) is designated as an emerging epidemic. Yet, it is not fully characterized. Most data, derived from hospital discharges, cannot measure incidence, have uncertain validity and cannot capture the full burden of HF because of the shift towards outpatient care. Regarding its etiology, the respective role of hypertension and coronary heart disease (CHD) is controversial. Moreover, the prevalence of obesity and diabetes mellitus is increasing, both conditions linked to HF via several mechanisms such that their contribution to HF could conceivably be increasing but remains to be examined. Finally, while the existence of diastolic HF is recognized, its diagnosis is exclusionary based on symptoms of HF in the absence of LV systolic dysfunction. This approach is unsatisfactory, thus the contribution of DHF to HF remains contentious. These striking gaps in knowledge underscore the necessity of a rigorous investigation of the HF epidemic. Through surveillance of the Olmsted County community, we demonstrated the postponement of CHD towards older ages and the decline over time in the severity of hospitalized MI and the incidence of HF after MI. This implies that, if CHD is the main cause of HF, HF should be postponed towards older ages and its incidence rate relatively stable. During the same period, preliminary findings on HF surveillance suggest that the incidence of first clinical diagnosis of HF may not be increasing as much as implied by hospital discharges and that adverse trends may be occurring preferentially among younger ages. These data from the same community are challenging to reconcile with the concept of an ongoing major contribution of CHD to an epidemic of HF, thereby underscoring the need to rigorously study the epidemiology of HF, which is the focus of this application. We propose 3 specific aims and a community surveillance approach, integrated with our ongoing work on CHD surveillance to investigate the HF epidemic in Olmsted County by characterizing its magnitude and determinants and studying prospectively the contribution of DHF. Aim 1 will estimate the secular trends in the incidence and in the outcome of validated HF to test the hypotheses that there has been an increase in the incidence of HF, which differs by age and sex and that the survival of HF improved while hospitalization for HF has increased. Aim 2 will use a case-control approach to characterize the etiology of HF and its changes over time to test the hypotheses that CHD and hypertension confer an excess risk of HF, the magnitude of which is declining

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over time, that obesity and diabetes mellitus confer an excess risk of HF the magnitude of which is increasing and that the population attributable risk of CHD and hypertension for HF is declining, while that of obesity and diabetes mellitus is increasing over time. Aim 3 will prospectively characterize the contribution of DHF to HF using brain natriuretic peptide (BNP) among persons with HF and define the prognostic value of BNP in all cases of HF. Thus, the completion of these aims will provide important insights into the epidemiology of HF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HISTORY OF DIABETES MELLITUS Principal Investigator & Institution: Feudtner, John C.; Pediatrics; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2003 Summary: (provided by applicant): Despite the importance of diabetic mellitus to the 6% of Americans (or more) who live with this disease, or to the US healthcare system which treats their disease and its many complications, we do not yet have a historical account that places this aliment and the technology that has come to surround it in their evolving social, cultural, and ethical contexts. The proposed book will provide a rich historical account of the pre- and post-insulin history of type I diabetes mellitus, aiming to: describe a new paradigm of disease change, whereby medical interventions transmute acutely lethal diseases into chronic and often debilitating illnesses; adopt the "patient's perspective" and analyze how this process of disease transmutation affected the lives of patients with diabetes over the course of decades; explore the social, cultural, and ethical implications of diabetes history for other areas of health and healthcare. The book will be based on a dissertation and previously-authored articles, carefully rewritten for the educated lay audience, addressing the concerns of patients and their families, practicing physicians, healthcare policy analysts, and medical historians. Not only will the book "tell the story of diabetes" more accurately than any other account, it will strive to create a new perspective on the role of medical technology in our lives. If funded, I would specifically aim to complete the revision of an originally 614 page dissertation, producing a polished book manuscript of approximately 350 pages, and bringing this manuscript into print the Social Medicine series of the University of North Carolina Press early in the year 2002. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUNCTION

HYPOGLYCEMIA

AND

AUTONOMIC

NERVOUS

SYSTEM

Principal Investigator & Institution: Freeman, Roy; Associate Professor of Neurology; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2008 Summary: The Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study have documented unequivocally that improved glycemic control decreases the incidence and progression of microvascular complicatons of diabetes. The implementation of regimens to rigorously control blood sugar in diabetic patients has led to an increased incidence of severe iatrogenic hypoglycemic events that have limited glycemic management of diabetes mellitus. Recent antecedent iatrogenic hypoglycemia impairs the neuroende:rine and autonomic response to subsequent hypoglycemia - a disorder known as hypoglycemia associated autonomic failure - thus increasing the predisposition to severe hypoglycemia. It is not known whether

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Diabetes Mellitus

antecedent hypoglycemia has more general effects on autonomic nervous system function. Impaired autonomic function is associated with increased mortality and morbidity in individuals with diabetes mellitus. If hypoglycemia induces generalized autonomic dysfunction it may further increase the mortality and morbidity associated with diabetes mellitus. The goal of this research is to understand the mechanisms of hypoglycemia associated autonomic failure. The proposed studies test the hypothesis that antecedent hypoglycemia not only impairs the counterregulatory response to subsequent hypoglycemia but also impairs cardiovascular autonomic function in nonhypoglycemic individuals. These studies will examine those markers of cardiovascular autonomic function that, when impaired, are associated with increased morbidity and mortality in patients with diabetes. Furthermore, we hypothesize that antecedent hypoglycemia causes a rise in serum cortisol and that cortisol activation of glucocorticoid receptors mediates the development of hypoglycemia associated autonomic failure. The specific aims for the proposal are to assess autonomic control of cardiovascular function following antecedent euglycemia and hypoglycemia. In addition, we will determine whether administration of a glucocorticoid receptor antagonist, mifepristone, prior to antecedent hypoglycemia improves the autonomic and neuroendocrine response to subsequent hypoglycemia in healthy men and women. Thus, the broad long term objectives of the proposal are to fully understand the mechanisms and consequences of hypoglycemia associated autonomic failure with the ultimate goal of finding an efficacious treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDENTIFYING GENES FOR TYPE 2 DIABETES: FUSION Principal Investigator & Institution: Boehnke, Michael L.; Professor; Biostatistics; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Type 2 diabetes (T2DM) is a major cause of morbidity and mortality in the USA and around the world. While disease prevalence varies, it has been estimated that 6.6 percent of the US population aged 20-74 years suffers from T2DM; similar rate has been observed in Finland. In the US, it has been estimated that diabetes is responsible for nearly 1/7 of all health care expenditures. There is substantial evidence of a genetic component in the etiology of T2DM. The Finnish population provides an ideal basis for studies of complex genetic diseases such as T2DM due to its relative genetic homogeneity, excellent data sources, and a population strongly supportive of medical research. The goal of the Finland-United States Investigation of NIDDM Genetics (FUSION) study is to identify genetic variants that predispose to T2DM (formerly non-insulin-dependent diabetes mellitus or NIDDM) and are responsible for variability in T2DM-related quantitative traits. As part of FUSION, a total of 4852 individuals have been sampled, including 855 families ascertained through T2DM-affected sibling pairs and 231 independent elderly normoglycemic controls and their families. Genome scans on two independent sets of T2DM Finnish families have been completed, and fine mapping of several chromosomal regions has begun. In the next five years, FUSION investigators will sample and/or phenotype approximately 1700 additional members of the FUSION families, carry out limited additional phenotyping of current FUSION samples, obtain independent samples of about 600 T2DM cases and about 800 controls, fine map regions of chromosomes 22, 20, and 11, and seek to identify the relevant T2DM-predisposing variants. FUSION investigators will continue and expand collaborations with other

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investigators seeking to map and clone variants for T2DM, through continued involvement in the International T2DM Linkage Analysis Consortium and other new and established collaborations. The proposed research builds logically on the investigators' past work, and will likely result in identification of one or more T2DMpredisposing variants during the coming project period. These efforts should contribute in a significant way to improved understanding of the etiology of T2DM, and point the way to novel methods of treatment and prevention. Methods developed and lessons learned in FUSION will also be useful in the study of other complex genetic diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IL-2 IN AUTOIMMUNE DIABETES Principal Investigator & Institution: Flavell, Richard A.; Professor and Chairman; Immunobiology; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Type 1 insulin-dependent diabetes mellitus is caused by an autoimmune attack on the islets of Langerhans. The susceptibility to this disease is determined both genetically and by environmental events. The elucidation of the underlying mechanisms of this disease has been greatly facilitated by the mapping of genes conferring susceptibility or resistance to diabetes in humans. Further, the availability of animal models, including the non-obese diabetic (NOD) mouse has made it possible to perform fine mapping of the corresponding mouse genes. Idd3 is a critical diabetes-susceptibility gene, which has profound effects on development of disease. NOD mice carrying an Idd3 gene from the diabetes-resistant B6 mouse show a substantially reduced incidence of insulitis and diabetes as well as greatly retarded kinetics of disease development. The Idd3 locus has been mapped to a 780 kb region of chromosome 3. The most likely candidate gene in this region is the IL-2 gene. This gene shows several structural differences between alleles that are derived from resistant or susceptible strains of mice. However, definitive evidence for or against a role of IL-2 has not yet been obtained, since it has not been possible until recently to target genes in the NOD genetic background. In this study we will establish gene knock-in technology on the NOD genetic background by using NOD/129 F1 ES (embryonic stem) cells, which we have recently found to be very effective in all the steps of gene targeting. Specifically, to establish or refute a role of IL-2 in T1 DM, we will use gene targeting to replace the IL-2 gene of the NOD mouse with the IL-2 gene of the diabetes-resistant B6 mouse. We hypothesize that the NOD allele of IL-2 confers susceptibility to diabetes in one of two ways. First, IL-2 is required for antigen induced cell death (AICD) and we propose that AICD in NOD mice is deficient as a result of a defective IL-2 gene. Our second hypothesis proposes that suppressor (also called regulatory) T-cells, which are IL-2 dependent, are defective in the NOD mouse as a result of an IL-2 deficiency in this strain. We will utilize our IL-2 knock-in mice to test these two mutually nonexclusive hypotheses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMPAIRED BETA CELL GENE EXPRESSION IN A MODEL OF NIDDM Principal Investigator & Institution: Griffen, Steven C.; Assistant Professor; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 31-JAN-2004

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Diabetes Mellitus

Summary: (provided by applicant): Understanding the pathogenesis of type 2 diabetes mellitus (DM-2) is critical for both prevention and the development of new treatments for the disease. Two defects, insulin resistance and a failure of the pancreatic beta-cell to adequately compensate for increased insulin demands by increasing insulin production and secretion, characterize this disease. The nature of this beta-cell defect is unknown for the majority of people with DM-2, although there is evidence that a defect in betacell gene expression may be involved. Recently, we have identified a defect in beta-cell gene expression in an animal model of DM-2, the ZDF rat. Although not yet fully characterized, our data demonstrate that the defect results in impaired insulin gene transcription by altering the function of several key promoter regulatory elements. Ultimately, the defect results in measurably lower insulin mRNA levels, but is insufficient to cause diabetes by itself. Only when combined with increased insulin resistance does the beta-cell defect result in diabetes, similar to human DM-2 The experiments proposed in this application will investigate the nature of the beta-cell defect in the ZDF rat. First, we will test for candidate transcription factors that may be responsible for the defect in beta-cell gene expression. Secondly, we will evaluate the mechanism by which insulin resistance unmasks the beta-cell defect, resulting in diabetes. We will specifically test the role of elevated free fatty acids on ZDF rat beta-cell function. We expect the studies proposed will identify the defect in beta-cell function that contributes to the development of DM-2 and identify the process by which insulin resistance unmasks defects in beta-cell function to result in overt diabetes. These studies will provide critical information regarding the interaction of the beta-cell and the insulin resistant state in the pathogenesis of DM-2, and identify candidates for human mutations causing type 2 diabetes mellitus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN PRODUCING VECTORS FOR GENE THERAPY OF DIABETES Principal Investigator & Institution: Ripps, Michael E.; Laboratory Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 15-FEB-1999; Project End 31-DEC-2003 Summary: Strong impetus exists for developing improved modes of insulin delivery for the treatment of diabetes mellitus. The insertion of appropriately regulated insulin genes into non-islet tissues is a potential strategy for the treatment of type I diabetes, in which islet cells are destroyed by autoimmune mechanism. The objective of the proposed project is to explore an approach to gene therapy for diabetes for engineering glucose regulated insulin production in extra-pancreatic sites. Our approach will be to target insulin expression to hepatocytes and intestinal epithelial cells in vivo using an insulin gene construct driven by the liver-type pyruvate kinase (L-PK) promoter. Since L-PK promoter activity is stimulated by glucose and blocked by glucagon and cyclic AMP, we expect that insulin synthesis and secretion will increase after a carbohydrate meal, and that possible over-production of insulin leading to severe hypoglycemia may be prevented by the cAMP-mediated actions of glucagon and epinephrine. Since the LPK promoter requires permissive amounts of insulin to be active, a second gene construct expressing insulin from a modified metallothionein promoter will be transferred along with the L-PK/insulin gene to provide a basal level of insulin. Double gene cassettes will be packaged into adeno-associated virus vectors and transferred in vivo to mice rendered diabetic by ablation of pancreatic beta cells using the drug streptozotocin. The time course of L-PK/insulin gene activation and repression will be determine after glucose loads and during insulin-induced hypoglycemia. Possible

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amelioration of the diabetic state will be assessed by oral glucose tolerance tests and measurement of glycohemoglobin levels. New initiatives in gene therapy will undoubtedly require the development of control systems to achieve the desired expression level for varying physiological or therapeutic circumstances. This project will assess a new therapeutic approach to diabetes and may also serve as a model for future attempts to engineer control systems for gene transfer. Furthermore, the Research Center Award will enhance my development as a physician-scientist and allow me to reach my long-term goal of an independent research career in academic medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ISOLATION/DISTRIBUTION OF HUMAN PANCREATIC ISLETS Principal Investigator & Institution: Naji, Ali; Professor; Surgery; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (Provided by applicant): The transplant program at the University of Pennsylvania (UP)has had a long-standing interest in the application of pancreatic islet transplantation in the treatment of diabetes mellitus. The program has continued basic investigations of the biological barriers to islet transplantation, with emphasis on the induction of immunological tolerance. Insights gained from experimental islet transplantation have led to recent successful applications of this therapy and achievement of euglycemia in patients with Type I diabetes mellitus. Based on these advances, a comprehensive islet transplantation program was established at the UP integrating a multidisciplinary team of investigative scientists and clinicians with recognized expertise in diabetes research and transplantation. Since the inception of the program in 1999, significant progress has been made in building its critical components: 1) construction of an Food and Drug Administrative (FDA)-compliant current good manufacturing practices (cGMP) facility devoted exclusively to islet processing; 2) recruitment and training of personnel qualified to perform islet isolation and assignment of dedicated transplant surgeons for on-site recovery of cadaveric pancreata; 3) establishment of a strong collaboration with the local organ procurement organization, which has led to a marked increase in the procurement of the human cadaveric pancreata; 4) distribution of isolated pancreatic islets to regional and national investigators engaged in diabetes research; and 5) development of a standardized islet quality index. In the present application, this strong infrastructure will serve as the mechanism for increasing the availability of human cadaveric pancreata suitable for preparation of isolated islets. This goal will be accomplished by procurement of pancreata from an expanded donor pool, including non-heart-beating organ donors. Another emphasis for the program will be the refinement of the islet quality index, based on physiological, biochemical, and morphological parameters, for correlation with the outcome of islet transplantation. With this strong platform in place, the program is poised to realize its goal of generating large quantities of highly purified and qualitycontrolled human islets for transplantation into Type I insulin-dependent diabetic patients. 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 2001; Project Start 01-JUN-2001; Project End 31-MAR-2004

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Diabetes Mellitus

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 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: MAPPING GENES FOR NIDDM NEPHROPATHY IN AFRICAN AMERICANS Principal Investigator & Institution: Bowden, Donald W.; Professor; Biochemistry; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2003 Summary: The purpose of this study is to identify genes causing non- insulindependent diabetes mellitus (NIDDM)-associated nephropathy (NIDDM-NEPH) in high risk African American families. At most, 30 percent of diabetic patients are susceptible to nephropathy with it's invariable progression to end-stage renal disease (ESRD) and high mortality rate. African American and Native American populations are known to be at higher risk for developing NIDDM and it's associated Nephropathy, relative to whites. However, in all populations, select diabetic families demonstrate multi-generational clustering of renal disease. An inherited basis for NIDDM-NEPH is also supported by reports that racial differences in the prevalence and severity of diabetes mellitus and hypertension, socioeconomic status and access to health care fail to fully account for the excess risk of NIDDM-NEPH observed in African Americans, relative to whites. In order to identify genes causing NIDDM- NEPH we will continue to identify, clinically characterize, and collect DNA from NIDDM affected sibling pairs concordant and discordant for NIDDM-NEPH. This phase of the project employs the unique "Family History of ESRD" database, independently compiled by the federallyfunded ESRD Network 6 (Southeastern Kidney Council). This registry currently

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contains family history data from 7,600 incident patients with ESRD and contains data from more than 13,000 patients as of September, 1996 (60 percent of patients are African American; more than 35 percent have NIDDM-associated Nephropathy). Candidate genes will be screened for linkage to NIDDM-NEPH and a systematic genome wide survey for novel loci causing NIDDM-NEPH will be carried out. This effort will be formally linked to, and interact with, a parallel search for chromosome locations with evidence of linkage to insulin dependent diabetes associated nephropathy (IDDMNEPH) in Caucasians through an interactive IRPG. The goal of this initial phase of the study is to locate chromosome regions with evidence of linkage to NIDDM-NEPH. The identification of NIDDM- NEPH genes would form a genetic basis for detection of high risk individuals and lead to development of intervention and treatment strategies for prevention of diabetic nephropathy, the most common etiology of ESRD in the U.S. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM OF ARSENIC-INDUCED DIABETES Principal Investigator & Institution: Styblo, Miroslav; Pediatrics; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2003 Summary: (provided by applicant) This project examines the role of arsenicals in the induction of diabetes mellitus. Inorganic forms of arsenic (iAs) are highly toxic and are classified as human carcinogens. Drinking water contaminated with iAs, along with industrial emissions, are major sources of exposure to iAs for populations worldwide. Numerous epidemiological studies have linked environmental exposures to iAs to increased incidences of various types of cancer and noncancerous diseases. Among diseases associated with chronic exposure to iAs, diabetes mellitus remains a significant problem especially in arsenic-endemic areas with large populations exposed to this metalloid from drinking water (e.g., Taiwan and Bangladesh). The adverse health effects associated with chronic exposure to iAs are also being intensively studied in the U.S. where hundreds of thousands of residents drink water with iAs levels that exceed the current maximum contaminant level (MCL) of 50 milligrams of arsenic per liter of water. Mechanisms by which iAs induces cancer, diabetes mellitus or other noncancerous disease are unknown. iAs species that contain trivalent arsenic (iAs-III) are potent oxidants that induce oxidative stress in laboratory animals and cultured cells. iAs-III species are also inhibitors of numerous enzymes and receptors involved in key metabolic and cell signaling pathways. Interactions of iAs-III with catalytically-active thiols have been shown to underlie these effects. In humans, iAs is metabolized to yield methylarsenic (MAs) and dimethylarsenic (DMAs) metabolites. Because of the redox nature of the metabolic reactions, both trivalent and pentavalent arsenicals (iAs-III, iAsV, Mas-V, DMAs-III, DMAs-V) are intermediates of final metabolites in this pathway. Recent reports from this and other laboratories have shown that trivalent methylated metabolites (Mas-III and DMAs-III) are more potent cytotoxins and enzyme inhibitors than iAs-III. The thioredoxin reductase/thioredoxin (TR/Trx) system that plays a key role in numerous regulatory mechanisms in the cell (e.g., antioxidant defense, activation of transcriptional factors and cellular receptors, cytokine expression or insulin excretion by B cells) has been shown to be a primary target for MAs-III in intact cells. In addition, unlike iAs-III, Mas-III and DMAs-III can damage DNA in intact cells. The investigators have shown that both Mas-III and DMAs-III are produced by human hepatic cells exposed to iAs and are present in the urine of individuals chronically exposed to iAs from drinking water. Thus, Mas-III and DMA-III, toxic products of iAs metabolism in humans, can significantly contribute to adverse affects associated with exposure to iAs.

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This pilot project is designed to examine effects of trivalent arsenicals, especially Mas-III and DMAs-III, on basic mechanisms that regulate utilization of glucose: (1) production of insulin in the pancreas and (2) metabolism of glucose in peripheral tissues. Effects of arsenicals will be examined in cultured cells (pancreatic B cell lines, adipocytes and skeletal muscle cells) and in mice. Induction of oxidative stress and inhibition of TR/Trx activities will be examined as possible mechanisms underlying the induction of diabetic symptoms. Arsenic metabolites responsible for these effects will be identified. In addition, the role of cellular and nutritional antioxidants in protection against arsenicinduced diabetes will be examined, providing information that may be critical for prevention and/or treatment of diabetes in arsenic-exposed individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM OF DIABETIC CARDIOMYOPATHY Principal Investigator & Institution: Buttrick, Peter M.; Professor of Medicine and Physiology; Medicine; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: This project will investigate cellular events that lead to the development of left ventricular dysfunction in experimental animals and patients with diabetes mellitus. Diabetes mellitus is associated with a cardiomyopathy characterized in part by impaired diastolic relaxation. In previous animal studies, we have defined biochemical features of this myopathy that suggest that chronic protein kinase C activation and subsequent phosphorylation of the thin filament protein, troponin I, is central to the maladaptation and also that this process can be abrogated by treatment with an AT1 receptor antagonist. The present application will extend these observations. Two parallel lines of investigation are proposed: 1. Studies in diabetic rats and mice will be performed to establish the effects of transcriptional and post-translation modification of thin myofilament proteins on the relaxation properties and contraction kinetics of isolated fibers. These will include troponin I exchange experiments in skinned fibers to establish the functional of significance of TnI phosphorylation and also studies in transgenic mice expressing TnI protein with a mutated PKC site. 2. Studies will be performed on cardiocytes isolated from the myocardium of patients with diabetes in order to establish whether the same biochemical and mechanical abnormalities are present in human heart disease. It is hoped that this pronged approach will allow the extension of a fundamental experimental observation to clinical practice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS AND EFFECT OF DECREASED GLUCOSE INSULIN SENSITIVITY IN PREGNANT WOMEN Principal Investigator & Institution: Catalano, Patrick M.; Professor; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2002 Summary: The long term objectives of this grant proposal are to investigate the mechanisms and effect of pregnancy on glucose insulin sensitivity in women with normal glucose tolerance (NGT) and gestational diabetes (GDM). The specific aims of this proposal are to: 1) determine the relationship between the changes in glucose insulin sensitivity and level of expression of post receptor insulin signaling intermediates in skeletal muscle in lean and obese women with NGT and GDM in late gestation and postpartum, 2) to determine the role of tumor necrosis factor alpha

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(TNFalpha) modulation of insulin receptor beta (IRbeta) and insulin receptor substrate I (IRS-1) in skeletal muscle in late pregnancy and 3) to characterize the effect of pregnancy on glucose metabolism, i.e. insulin sensitivity and pancreatic beta cell response postpartum in women with NGT and GDM. Specific aim #1 will evaluate longitudinally 12 women with NGT (6 lean and 6 obese) matched with 12 women with GDM (6 lean and 6 obese) at 30-36 weeks and 16 weeks postpartum. All subjects will be evaluated using the euglycemic clamp with infusion of [66/2/H2] glucose and have Bergstrom needle skeletal muscle biopsies. The specific methodology will allow us to estimate insulin sensitivity using Western blotting to measure changes in protein expression and competitive PCR to compare differences in mRNA expression during and after pregnancy. Specific aim #2 will evaluate 16 women at the time of elective cesarean delivery (8 NGT) and gynecologic surgery (8 CTL). All subjects will have densitometry and rectus muscle biopsies at the time of surgery. Skeletal muscle will be used to immunoprecipitate IRbeta and IRS-1. IRS-1 from pregnant NGT will be incubated with IRbeta from non pregnant CTL and insulin added to phosphorylate IRbeta. This will allow us to evaluate if the rise in TNF- alpha in late pregnancy induces serine phosphorylation of IRS-1 and converts IRS-1 to an inhibitor of IRbeta tyrosine kinase activity. Specific aim #3 will evaluate 24 women; 8 women (4 NGT and 4GDM) who do not plan to conceive (at yearly intervals), and 16 women (8 NGT and 8 GDM) planning to conceive (prior to conception, at 30-36 weeks and post partum. All subjects will be evaluated using densitometry, an intravenous glucose tolerance test, indirect calorimetry and the euglycemic clamp with infusion of [6-6/2H2] glucose. These data will allow us to evaluate the effect of pregnancy on pancreatic beta cell function and insulin sensitivity in women with NGT and GDM, in contrast to changes in thee measurements ascribed to time alone. The information obtained from these studies will allow us to begin to understand the mechanisms involved in the alterations in insulin sensitivity during pregnancy, and the potential genetic factors responsible for decreased glucose insulin sensitivity in women with GDM. 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 2001; 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

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Diabetes Mellitus

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 •

Project Title: MECHANISMS OF ENHANCED VASCULAR SMC GROWTH IN DIABETES Principal Investigator & Institution: Mcnamara, Coleen A.; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2001; Project Start 30-SEP-1995; Project End 31-JUL-2006 Summary: Patients with diabetes mellitus have increased rates of atherosclerotic vascular disease as well as restonosis following percutaneous coronary interventions. Smooth muscle cell (SMC) proliferation plays a key role in atherosclerosis and restonosis following vascular injury. The long-term goal of this project is to identify the molecular mechanisms regulating the accelerated SMC proliferation in diabetic states in response to injury. Previous studies and our preliminary data suggest that Id3 is an important regulator of enhanced SMC growth in response to injury in diabetic conditions. The studies outlined in this proposal will utilize our culture system to further define the molecular mechanisms whereby glucose regulates Id3-induced SMC growth enhancement (Aim 1). We will collaborate with Dr. Nadler to determine if 12LO is an important mediator in this process. The in vitro studies will be complemented by important in vivo studies. We will determine the pattern of expression and function of Id3 in vivo in 3 diabetic animal models (the obese vs. lean Zucker and ZDF rats, streptozotocin-induced diabetes with our without hyperlipidemia in the swine, and streptozotocin-induced and genetic diabetes in the mouse). (Aims 2 and 3). Each model will allow for unique approaches to test the central hypothesis that glucose-induced enhancement of SMC growth is mediated at least in part through the HLH factor Id3. The Zucker rat will provide for data on expression of Id3, Id3a and p21 in a model of insulin-resistance. The ZDF rat is a diabetic model with hyperglycemia and thus will allow us to test the hypothesis that Id3 mediates accelerated SMC growth in hyperglycemic states in vivo. The rat studies will be performed in collaboration with Dr. Nadler and these animals/tissues will be shared between projects 1 and 3. Aim 2 will provide further in vivo data to determine if Id3 is essential for enhancement of SMC proliferation and if this effect is mediated by 12LO using gene delivery of hammer head ribozymes (in collaboration with Drs. Gu, Rossi, and Nadler in project 1). The swine model from our core allows for confirmation of the expression data in the rodents in a novel pig model of accelerated diabetic vascular disease at baseline and in response to stent deployment. The STZ-induced diabetic mouse and the db/db/ApoE-/- will allow for genetic analysis of the mechanisms of accelerated SMC proliferation and vascular lesion formation in diabetes with and without hyperlipidemia. The Id3-/- mouse will also allow for a genetic approach to determine the importance and function of Id3 in the accelerated lesion formation in diabetic mice. A major strength of this proposal is that it combines in vitro mechanistic studies with in vivo studies and genetic approaches to gain an overall broader understanding of the role of Id3 in the enhanced SMC proliferation in diabetic states.

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

Project Title: MECHANISMS OF HYPOGLYCEMIC VULNERABILITY DUE TO ETHANOL Principal Investigator & Institution: Burge, Mark R.; Assistant Professor; Medicine; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: Hypoglycemia is the principal adverse event associated with the pharmacologic management of type 2 diabetes mellitus, and it frequently limits the effectiveness of therapy. Our preliminary studies suggest that sub-intoxicating doses of ethanol are an important mechanism for the development of sulfonylurea-associated hypoglycemia in elderly patients with type 2 diabetes. The purpose of this proposal is to provide rationale for expanded studies into the pathophysiologic effects of ethanol among individuals with type 2 diabetes. I hypothesize that moderate doses of ethanol predispose sulfonylurea-treated patients with type 2 diabetes to hypoglycemic vulnerability by altering one or more of the physiologic processes critical to the defense against hypoglycemia, including (1) direct suppression of counterregulatory hormone release, (2) direct or indirect suppression of hepatic glucose production, and/or (3) reduction of gastrointestinal function with a subsequent delay in carbohydrate absorption. Additionally, I hypothesize that (4) aging will exacerbate the prohypoglycemic effects of ethanol, and that (5) the timing of ethanol ingestion relative to meal ingestion will at least partially determine its hypoglycemic potential. To address these hypotheses, I plan to compare the effects of low doses of intravenously and orally administered ethanol on counterregulatory hormone release and recovery from insulininduced hypoglycemia to placebo among healthy subjects and subjects with type 2 diabetes. Additionally, the effects of administration of intravenous ethanol or its metabolite acetate on parameters of hepatic glucose turnover and lipolysis will be compared to placebo in subjects with type 2 diabetes. I will further examine parameters of gastric motility and function following intravenous and oral administration of ethanol or placebo in subjects with type 2 diabetes and will also compare the metabolic and hormonal responses to moderate doses of ethanol between young and elderly patients with type 2 diabetes mellitus matched for duration of disease. Finally, the effect of ethanol administration with a meal on parameters of overnight glucose homeostasis will be compared to ethanol administration 4 hours after meal ingestion in subjects with type 2 diabetes. These studies will explore clinically important questions that will enhance our understanding of hypoglycemia in type 2 diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF IMMUNOTHERAPY IN IDD PREVENTION TRIALS Principal Investigator & Institution: Atkinson, Mark A.; Professor; Pathology, Immunol & Lab Med; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2001; Project Start 01-MAY-1996; Project End 31-JUL-2005 Summary: Adapted from Investigator's abstract): The Diabetes Prevention Trial (DPT-1) was formed to test whether antigen specific therapies can prevent type 1 diabetes in persons at increased-risk for the disease. The trial involves autoantibody, genetic, and metabolic screening of non-diabetic relatives of type I diabetes patients to determine disease-risk, followed by randomized assignment of high-risk individuals to a daily prophylactic dose of subcutaneous insulin/annual intensive intravenous insulin therapy

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Diabetes Mellitus

and intermediate-risk persons to daily oral treatment (placebo or oral insulin). Both treatment arms have untreated control groups subject to identical follow-up analyses. Examination of changes in the immune response, including those against insulin, may yield valuable information as to the mechanism of (presumed) disease prevention. While such studies are (unfortunately) not part of the formal DPT-1 trial, we have received separate NIH support (R0l Al39250) to perform such investigations. This proposal represents an important continuation as well as an expansion of these studies aimed at addressing the question as to how insulin therapy effects the autoimmune response. Analysis of both therapy responders and non-responders may indicate: 1) a mechanism whereby subsequent trials may be improved, 2) identify those with the best chance of a positive therapeutic response, or 3) provide a more refined assessment of diabetes risk based on immunologic phenotypes. Finally, examination of high-risk individuals from the untreated parenteral arm, or placebo treated subjects, will further our understanding of the natural history of the cellular immune response in the prediabetic period. This proposal tests two hypotheses: 1) that CD1d-restricted T cells interact with dendritic cells (DC)and that this axis is dysfunctional in at-risk pre-diabetic individuals, and 2) that the development of disease correlates with parameters of T cell autoimmunity wherein Th1-like immunities against an expanded repertoire of beta cell antigens (afforded in-part by the aforementioned dysfunctions occurs in association with diminished Th2-like responses. These hypotheses will be tested through performance of four specific aims including: 1) monitoring T cell responses (blastogeneis, cytokine production) to islet cell antigens including insulin, 2) analysis of DC subsets and antigen presenting cell function, 3) determining the frequency of circulating CD1d-restricted T cells, and 4) analysis of the effector functions of CD1drestricted T cell clones. In sum, our purpose is to delineate the mechanism of disease prevention provided by prophylactic insulin therapy and to further understand the natural history of cellular immune responses in the prediabetic period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MENTORED DEVELOPMENT AW

PATIENT-0RIENTED

RESEARCH

CAREER

Principal Investigator & Institution: Gater, David R.; Assistant Professor; Phys Med and Rehabilitation; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 29-SEP-2000; Project End 31-AUG-2005 Summary: (Adapted from the applicant's abstract): SCI predispose to glucose intolerance and insulin resistance, presumably due to changes in body composition and skeletal muscle dysfunction, placing SCI individuals at greater risk for diabetes and coronary artery disease. In the able-bodied, marked improvements in glucose tolerance have been reported in response to aerobic exercise, with variable changes in insulin sensitivity. Resistance training has also improved glucose tolerance, and to a greater extent, insulin sensitivity in the able-bodied. Exercise responses in SCI have not been examined as extensively as they have in the general population, and yet this population has significantly more to gain than the able-bodied population by improving metabolic and functional abilities. The proposed hypothesis is that aerobic exercise, resistance training and/or a combination of aerobic exercise and resistance training will improve body composition and glucose tolerance, but only exercise which involves resistance training, and subsequent increases in muscle mass, will significantly improve insulin sensitivity in individuals with SCI. Twenty individuals with motor complete T6-L2 SCI will be recruited each year to participate in one of the following exercise protocols.

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Subjects will be randomly assigned to control or aerobic (Trial 1), resistance (Trial 2), and combined (Trial 3) exercise groups. Glucose tolerance, insulin sensitivity and body fat will be determined before and after each of the exercise interventions. If glucose intolerance and subsequently diabetes mellitus can be prevented in individuals with SCI by utilizing appropriately dosed exercise, significant savings in health care dollars and improved quality of life could be realized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METABOLIC ENGINEERING OF SURRGOATE BETA CELLS Principal Investigator & Institution: Lipes, Myra A.; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-JAN-1998; Project End 31-DEC-2002 Summary: (Adapted from applicant's abstract): The goal of this project is to provide a source of surrogate b-cells that will be suitable for treatment of insulin-dependent diabetes mellitus (IDDM). The applicant has recently targeted preproinsulin expression to the intermediate lobe (IL) of the pituitary in transgenic nonobese diabetic (NOD) mice, a model of human IDDM. The IL pituitary cells isolated from these mice secrete mature insulin via a regulated secretory pathway, similar to islet b-cells. However, in contrast to insulin producing islet b-cells, the insulin producing IL pituitary cells are not attacked by cells of the immune system when the cells are transplanted under the kidney capsule in NOD mice. Further, transplantation of the transgenic IL tissues into diabetic NOD mice resulted in restoration of near-normoglycemia and reversal of other diabetic symptoms. The absence of autoimmunity in intermediate lobe pituitary cells engineered to secrete bone fide insulin has suggested that these cells may have potential for treatment of IDDM. The major objective of the project is to introduce into the insulinsecreting IL tissues the ability to secrete insulin in response to glucose and other physiological secretagogues (e.g., meals). The requirements for glucose sensing will initially be tested utilizing a recombinant adenovirus gene delivery system. Subsequently, the optimal components will be stably expressed in the insulin secreting IL tissues of NOD mice using transgenic techniques. The applicant will then assess whether these bioengineered tissues, when transplanted into NOD mice, can lead to the long term normalization of glucose homeostasis and whether they can still avoid the autoimmune destructive process targeted against b-cells in IDDM. These strategies may create a novel source of 'artificial b cells' for diabetes treatment and provide important insights into the biochemical requirements for glucose sensing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR DETERMINANTS OF VASCULARIZATION IN ISLETS Principal Investigator & Institution: Powers, Alvin C.; Associate Professor of Medicine; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Pancreatic islets are extensively vascularized and this is likely important in their ability to sense the blood glucose and quickly secrete insulin. Although pancreatic islet function and vascularization are fundamentally linked, there are a number of unanswered questions and gaps in our knowledge about this process. For example, islets within the pancreas have a complex intraislet vascular network, but the factors that control the development of normal islet vasculature are incompletely defined. Furthermore, islet transplantation in humans has great promise as a treatment for type 1 diabetes, but islet isolation severs arterial and venous connections

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so transplanted islets must revascularize to obtain the nutrients and oxygen necessary for function and survival. Little is known about the sequence of molecular events and factors important for revascularization of transplanted islets and thus, interventions to improve islet revascularization are not known. Using a multidisciplinary approach involving developmental biology, transgenic technology and transplantation of murine and human islets, our team proposes two interrelated specific aims: 1) describe the molecules and fundamental events in islet vascularization and revascularization; 2) determine the role of two angiogenic factors, VEGF and Ang-1, in islet vascularization and revascularization of islets after transplantation. The studies will involve an in-depth analysis of the relationship between islet development and vascularization in genetically modified mice that allow for precise "marking" of endothelial cells and in transgenic mice that express angiogenesis factors or inhibitors. These powerful experimental techniques emphasize the utility of such mouse models to address mechanistic questions. However, human and mouse islet differ, so the proposed studies also will integrate parallel studies with human islets transplanted into a xenograft model. The proposed studies bring three distinguished investigators from the vascular biology area (Bader/Baldwin/Lin) to work with two investigators already working in the area of type 1 diabetes and islet biology (Gannon/Powers). In addition to bringing together scientists from different disciplines (Endocrinology, Cell Biology, Cardiology, Pediatrics, Cancer Biology), the proposed studies also seek to apply rapidly expanding knowledge about angiogenesis and neovascularization from the developmental biology and cancer biology fields to improve islet revascularization. A better understanding of normal islet vascularization will provide insights into normal islet development, architecture, and function. This information may be pertinent to efforts to proliferate and expand islet stem cells and islets, all of which must become vascularized. In addition, the rapidity and degree of revascularization of transplanted islets greatly influences the survival and function of transplanted islets and whether the surviving islet mass is sufficient to reverse diabetes. We anticipate that information about islet revascularization from these studies will be directly relevant to transplantation in humans and will be useful in planning future interventions in humans. 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. Surprisingly, the requirement for E2F 1 and E2F2 in preventing beta islet cell

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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: OBESITY, GLUCOSE METABOLISM AND DIET IN OLDER WOMEN Principal Investigator & Institution: Ryan, Alice S.; Associate Professor; Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2001; Project Start 01-SEP-1997; Project End 31-AUG-2003 Summary: The candidate is an Exercise Physiologist whose initial research and funded pilot projects focused on the effects of diet and exercise on obesity and glucose metabolism in sedentary normals and patients with diabetes. The proposed MRSDA will allow her to gain training in the areas of muscle and fat metabolism while investigating the interactions of aging and glucose metabolism in women with a high risk of developing diabetes. Research: Gestational diabetes mellitus (GDM) affects 90,000 women per yr in the U.S. Within 10-20 y of pregnancy, 40-65% of these women develop non-insulin dependent diabetes mellitus (NIDDM); a disease linked to obesity, physical inactivity and characterized by abnormalities in glucose and fatty acid metabolism. We hypothesize that women with a history of GDM who present with impaired glucose tolerance (IGT) or NIDDM after the menopause will be sedentary, have visceral obesity and abnormalities in their glucose, fat and muscle metabolism. A structured weight loss and aerobic exercise program (WL+AEX) will be more effective than weight loss (WL) alone in reducing visceral obesity and increasing aerobic capacity to 1) decrease free fatty acid (FFA) levels and increase fat oxidation; 2) increase muscle GLUT-4 protein and glycogen storage; and 3) enhance insulin sensitivity thereby improving glucose tolerance. This study will investigate glucose homeostasis in IGT or NIDDM (N=80) postmenopausal women (50-60 y) with a history of GDM. Measurements will be performed at baseline and after 6 months of WL or WL+AEX. Follow-up of patients will occur 1 yr after the intervention(s) to evaluate the patient's glucose tolerance, body composition and VO2max. Total and regional percent body fat, fat mass, lean tissue mass and hone mineral content will be determined by dual-energy x-ray absorptiometry. Computed tomography will quantify' intraabdominal and subcutaneous adipose tissue areas and mid-thigh muscle and adipose tissue area. VO2 max will be measured during a progressive treadmill test. Hyperinsulinemiceuglycemic clamps with tritiated glucose will assess glucose utilization, insulin sensitivity, and quantitate the role of the liver with respect to glucose production. During the clamp, plasma FFA levels and fat oxidation will be determined. Muscle biopsies of the vastus lateralis will be obtained for measurement of fiber characteristics, GLUT-4 transporters, and oxidative enzyme levels. The effects of WL or WL+AEX

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program on glucose homeostasis in IGT or NlDDM postmenopausal women with prior GDM are unknown. The projected study will contribute valuable information to help develop guidelines for the management of the metabolic control in the obese glucose intolerant and diabetic patient. Environment: Receipt of this MSRDA with the guidance of Drs. Goldberg and Nagey will allow the candidate to launch a career in gerontology studying disorders of glucose homeostasis in women at a high risk for NIDDM, and investigate the mechanisms by which WL or WL+AEX improve carbohydrate metabolism. The interdisciplinary environment in the School of Medicine provides excellent training and resources for advanced learning in gerontology and metabolism. The proposed work will provide the candidate with the requisite skills and training to embark on an independent research career. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OXIDATIVE STRESS AND DIABETIC CARDIOMYOPATHY Principal Investigator & Institution: Anversa, Piero; Professor and Director; Medicine; New York Medical College Valhalla, Ny 10595 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: Applicant's Abstract The long-term objective of this application is to identify whether hyperglycemia with diabetes upregulates the myocardial renin-angiotensin system (RAS), resulting in the synthesis and secretion of Ang II Hyperglycemiamediated enzymatic glycosylation of p53 may enhance transcription of angiotensinogen (Aogen) and AT1 receptor; Aogen is the limiting factor in the generation of Ang II and the AT1 effector pathway conditions cardiac cell death. Transmission of death signals by Ang II may involve an increase in cytosolic Ca2+ which, in turn, promotes the formation of reactive oxygen species (ROS), DNA damage and cell death. Ligand binding to AT1 receptor leads to phosphorylation of p53 by p38-MAP kinase, enhancing p53 function chronically and, thereby, the cellular production of Ang II, cytosolic Ca2+ and oxygen toxicity. ROS may induce DNA strand breaks and subsequently an interaction of injured DNA with p53. Autoproteolytic cleavage of p53 may occur and p53 fragments lacking the C-terminus, p50 (dC), or the N-terminus, p50 (dN), are formed. Since the C-terminus is required for cell death to take place, p50 (dC) may interact with single DNA strand breaks, upregulating p2l, inhibiting growth and inducing DNA repair. Conversely, p50 (dN) may bind to double DNA strand breaks, triggering apoptosis. These possibilities associated with the induction of diabetes by streptozotocin administration will be tested in a mouse model in which targeted mutation of the p66shc gene increases the resistance of cells to oxidative stress. In the p66shc-/- mouse, hyperglycemia may be characterized by an attenuated effect of ROS on DNA damage, leading to single DNA strand breaks, growth arrest and DNA repair. In the wild-type mouse, diabetes may result in extensive DNA injury, p50 (dN) activation and diffuse cell death. High levels of ROS are coupled with cell necrosis and lower levels with apoptosis. The initiation of cell death is largely dependent on the antioxidant defense mechanisms of cardiac cells. Because mitochondria comprise more than one third of the myocyte cytoplasm, large amounts of ROS may be generated in this cell population with hyperglycemia and its antioxidant enzymes may be less effective than in other cardiac cell types. Although, cells interact with each other in situ, making difficult to predict the cell population first injured by oxidative challenge with diabetes, myocytes constitute a reasonable initial target. To validate the primary role of hyperglycemia in the development of a decompensated diabetic myopathy, the experimental studies on insulin-dependent diabetes mellitus will be complemented and compared with studies of human hearts affected by noninsulin-dependent diabetes mellitus.

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

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. 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

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Project Title: PATHOGENESIS OF X-LINKED ALLERGIC AUTOIMMUNE DIABETES Principal Investigator & Institution: Chatia, Talal I.; Professor; Pediatrics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 31-JUL-2003 Summary: (provided by applicant): Insulin-dependent Diabetes Mellitus (IDDM) represents a significant public health issue in that it affects a large number of children and exacts a heavy price in morbidity and mortality. Susceptibility to this disorder is inherited, but the genes involved remain poorly characterized. Our long-term goal is to elucidate the molecular basis of inherited primary immunological disorders. The focus of this proposal is to identify the genetic defect and the pathogenesis of X-linked Allergic Autoimmune Diabetes (XLAAD), an X-linked recessive immunological disorder characterized by neonatal IDDM and other autoimmune phenomena and associated with severe allergic inflammation. The hypothesis being tested is that this syndrome is a primary immunological disease resulting from a single gene defect that involves a regulator of T helper type 2 (Th2) differentiation. We propose to fine map and identify the gene defect in a cohort of affected pedigrees, and to elucidate the mechanism of skewed T helper subset 2 differentiation that we have noted in patients with this disorder. The proposed studies will provide critical insights into pathogenesis of IDDM and allergic inflammation in this group of patients and, more generally, in diseases of autoimmunity, atopy and immunodeficiency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOPHYSIOLOGY /GENETICS OF DIABETES MELLITUS MODEL Principal Investigator & Institution: Lenzen, Sigurd; Hannover Medical School CarlNeuberg Strasse 1 Hannover, Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Rodent models with spontaneous development of insulin-dependent diabetes mellitus share many features typical for human type 1 diabetes mellitus (T1DM) and have been extremely helpful in identifying etiological and pathophysiological aspects of autoimmune diabetes. The LEW.1AR1/Ztm-iddm rat is a new T1DM animal model. It arose through a spontaneous mutation in a congenic Lewis rat strain with a defined MHC haplotype (RTI.A a B/Du Cu ). This new model is of significant interest because it appears to closely parallel the human disease. In particular this new rat model shows no inherited defects of the immune system. However, detailed knowledge is essential so that this new strain can be well utilized in experimental diabetes research world-wide. In particular information on the pathophysiology, the autoimmunity and the genetics has been requested by the scientific community. We therefore aim at characterizing the new LEW.1AR1/Ztmiddm rat in this project to such an extent that it can be offered as a defined T1DM animal model to the international scientific community complementary to the existing animal models of T1DM. The following three major aims should be addressed: A. Characterization of the autoimmune process to analyze the time course of the autoimmune process during the pre-diabetic phase, both with respect to the initiation of the apoptotic process of beta cell destruction and islet infiltration, ultimately leading to the manifestation of an overt diabetic state. B. Proof of the autoimmune nature of the diabetic syndrome through adoptive transfer to demonstrate the autoimmune nature of the diabetic syndrome in this new animal model through detailed adoptive transfer

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studies with selected T cell subpopulations. C. Analysis of the genetic locus responsible for the insulin-dependent diabetes mellitus to identify the locus which could be associated either with a MHC class II region expressing a mutated rather than a "standard" u-haplotype, or with a mutated immunologically active regulatory locus unrelated to the major histocompatibility complex (MHC). Identification of the key elements of the genetics and pathogenesis of beta cell destruction in this new animal model of autoimmune diabetes will provide the basis for the development of novel therapeutic strategies for the prevention and cure of T1DM in humans. The characterization as proposed in this application will allow the proper use of this new T1 DM rat model for this purpose by the scientific community world-wide. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PERIODONTAL DISEASE IN DIABETIC WOMEN WITH PRETERM BIRTH Principal Investigator & Institution: Offenbacher, Steven; Professor of Periodontology; Periodontology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): This pilot proposal is in response to an RFA to Prevent or Reduce Oral Health Disparities and seeks to establish a collaborative study partnering the periodontal and molecular epidemiology expertise at the University of North Carolina School of Dentistry with the Obstetrics/Gynecology expertise at the University of Hawaii School of Medicine to examine the role of periodontal disease in pre-term deliveries among pregnant diabetic Asian & Pacific Islander (API) women. This is an understudied minority population with a high prevalence of both diabetes and pre-term delivery. Periodontal disease is an oral infection that is more severe among diabetics and also increases insulin resistance among diabetics. Periodontitis also is associated with increased risk for pre-term delivery, pre-term premature rupture of membranes and growth restriction. Diabetes among pregnant women is a risk factor for both pre-term delivery and macrosomia. Thus, we seek to examine whether periodontal infection among diabetic women may provide some contribution to the observed high rate of pre-term delivery among API diabetics. Specifically, this proposal seeks to conduct a pilot case-control study to determine the extent of periodontal disease in API diabetic (Type 1, Type 2 or gestational) and non-diabetic women who have term and pre-term deliveries (<37 weeks gestational age). Approximately 92 diabetic and 92 nondiabetic pre-term delivery API mothers and 184 diabetic and 184 non-diabetic term delivery API mothers will be studied (frequency matched on race 1 case: 2 controls). Full-mouth periodontal examinations will be performed using standardized methods and calibrated examiners. Preliminary data will be generated by analyzing fetal cord blood for markers of fetal exposure to oral pathogens of maternal origin, as indexed by bacterial-specific fetal IgM levels and fetal stress as reflected by slCAM and CRP levels. In addition a subset of fetal membranes will be analyzed for protein expression of IL-lb, TNFa and IL-6 by ELISAs and MMP-8 mRNA by Northerns. Pilot data will be generated to support an R01 application that will originate from the U of H (a minority institution) with Dr. Millar as PI, to test the hypothesis that periodontitis is more extensive among API diabetic women and associated with higher rate of fetal exposure to oral pathogens than among non-diabetics and that the prevalence of periodontal disease and frequency of fetal exposure is higher among pre-term deliveries for both diabetics and nondiabetics, as compared to term deliveries. In this collaboration UNC will also provide the U of H study personnel the periodontal and molecular epidemiology research

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training and experience needed in multi-disciplinary studies of periodontal disease and obstetrics to conduct the planned R01 application. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE I/II TRIAL OF HOKT3(1(ALA-ALA) IN TYPE 1 DIABETES Principal Investigator & Institution: Herold, Kevan C.; Associate Professor; Naomi Berrie Diabetes Center; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 15-JUN-2000; Project End 31-MAR-2005 Summary: (Adapted from the Investigator's abstract): Type I diabetes mellitus (T1DM) is an autoimmune disease thought to be caused by a T cell mediated destruction of the insulin producing beta cells in the islets of Langerhans. Studies in animal models and limited human clinical studies demonstrate that modulation of T cell responses can alter the natural history of diabetes, but none of the currently available immune suppressive treatments induce a permanent remission of the disease. Animal studies, however, suggest that anti-CD3 monoclonal antibody (mAb) can reverse diabetes and induce long term tolerance to recurrent autoimmunity. This application is for a Phase I/II trial of a new anti-CD3 mAb, hOKT3gamma1 (Ala-Ala) for treatment of new onset (T1DM). This mAb is a humanized form of OKT3 that does not bind the FcR receptor and thus, will not cause the cytokine release syndrome or development of neutralizing antibodies that preclude use of OKT3 in otherwise healthy patients with T1DM. These and other studies in mice suggest that the reagent can selectively inhibit previously activated cells that produce Th1 cytokines thought to be involved in diabetes. The aims of this phase I/II trial are to test the safety, tolerability, and immune effects of hOKT3gamma1(Ala-Ala). The investigators have designed their application to have sufficient statistical power to test whether treatment with the drug will alter the natural history of beta-cell destruction in T1DM. They will study the effects of the drug on depletion of peripheral T cells, activation of T cells using cellular approaches, T cell proliferative responses to common antigens, and stimulation of anti-Ig responses. They will also study the effects of the drug on diabetes specific immune responses including the titer and isotype of autoantibodies and cellular responses, including cytokine production, to islet antigens such as IA-2. They will compare the effects of the mAb on these responses, thought to be of a Th/Tc1 phenotype to responses to common allergens, which are of a Th2 phenotype. The hypothesis to be tested in this Project is that non-FcR binding mAb will inhibit islet antigen reactive Th1 cells that mediate the destruction of beta cells, and thereby alter the natural history of T1DM. Their studies will test a new immunologic approach to treatment that is based on the current understanding of the natural history of diabetes. As a result of these studies, future studies will be of broader scope with a focus on clinical efficacy of non-FcR binding anti-CD3 therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHYSICIAN INTERVENTION TO IMPROVE DIABETES CARE Principal Investigator & Institution: O'connor, Patrick J.; Health Partners Research Foundation 8100 34Th Ave S Minneapolis, Mn 55425 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2003 Summary: This is a resubmission of a application reviewed in October 1999. This randomized trial will test the hypothesis that a) an influential physician feedback intervention; b) narrative process trace' feedback intervention, or c) the combined interventions (a+b) are no more effective than (d) usual care in improving the clinical care of adult patients with diabetes mellitus The unit of randomization and the unit of

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analysis will be primary care physicians who have more than 10 adult patients with diabetes mellitus. The 162 physicians eligible for this study provide care to about 6,804 adults with diagnosed diabetes at 24 primary care clinics. The narrative process trace intervention uses AMR-mounted clinical cases to assess physicians' diabetes care decisions, with results provided as feedback to physicians. The influential physician feedback intervention emphasizes individual education of physicians, which will be guided by the narrative process trace in the combined intervention. Usual care includes the use of a diabetes clinical guideline, use of a diabetes patient registry that provides key clinical data for each adult patient with diabetes, and access to clinic-based diabetes education nurses. The applicant has shown in previous controlled studies that the guideline, diabetes registry, and clinic-based education nurses have failed to significantly improve diabetes care on a population basis, thus justifying the additional strong intervention that now will be tested. Dependent variables include glycemic control and cardiovascular risk reduction of all 3360 patients cared for by the 80 study physicians. Secondary analysis will assess rates of screening for microvascular complications. Physicians will be randomized in blocks based on specialty, number of diabetes patients, and years of practice experience. Hierarchical data analysis will be used to accommodate the nested data and propensity scores will be used to correct for selection effects and missing data. Results of this experiment will advance the theoretical understanding of physician behavior change and quantify cost and impact of three specific intervention strategies to improve chronic disease care in the primary care setting. The study will have substantial impact on clinical practice and policy whether the results are positive or negative. If successful, the interventions will be easily disseminated to other primary care practice settings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PI-3-KINASE MEDIATED SIGNALING BY INSULIN AND IGF-1 Principal Investigator & Institution: Field, Seth J.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Type 2 diabetes mellitus seriously impacts on the quality of life and longevity of millions of Americans. Type 2 diabetes mellitus is caused primarily by impaired signaling by insulin. PI-3- kinase plays a crucial role in the insulin signaling pathway. This research project will better define the mechanism by which PI-3-kinase transduces the insulin signal. Preliminary evidence indicates that insulin stimulates the translocation of PI3K to discrete intracellular locations, quite distinct from the response to other growth factors. It is hypothesized that this distinct subcellular localization is partly responsible for the unique signaling effects of insulin. This will be investigated further by defining the subcellular localization of insulinstimulated PI-3-kinase signaling, the mechanism governing this localization, and the function of this localization. It is expected that a better understanding of the signaling pathway utilized by insulin will provide insight into the pathophysiology of diabetes mellitus and identify potential targets for novel therapeutics. This project will also contribute significantly to the career development of Dr. Field. Under the mentorship of Dr. Lewis Cantley and Dr. Anne Klibanski this career development award is expected to foster Dr. Field's development into a successful independent clinician-scientist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PILOT AND FEASIBILITY PROGRAM Principal Investigator & Institution: Bluestone, Jeffrey A.; Professor and Director; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2003; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: (provided by the applicant): The UCSF Diabetes Center Pilot & Feasibility (P&F) Program was established 18 months ago to encourage the pursuit of highly novel research for understanding and treating type 1 and type 2 diabetes. The program has been targeted towards all members of the UCSF community - the existing faculty of the Diabetes Center as well as other investigators from other departments and institutes at UCSF - in order to capitalize on the many and varied opportunities within the institution that have pointed relevance to diabetes. The P&F program implemented at UCSF provides investigators with two years of support at $25,000 per year to support conceptually innovative studies. As importantly, these awards are hoped to provide seed funding that will generate sufficient data to pursue additional research efforts through other funding mechanisms. The DRTC P&F Program will endeavor to: 1. facilitate and allow new investigators and junior faculty to establish research programs in diabetes; 2. facilitate and support established faculty wishing to transfer skills and research developments to the arena of diabetes research; 3. foster highly innovative directions in basic and clinical diabetes research, including clinical studies in minority and other underserved patient groups; and 4. foster new and innovative collaborations amongst DRTC UCSF Faculty. The Pilot & Feasibility Program committee is will be chaired by Dr. Douglas Hanahan and the Committee includes Drs. Gerold Grodsky, Michael German and Ira Goldfine. As a group this committee represents all the aspects of the Center to assist the director in the management of the program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PLAINS INDIANS TRADITIONAL DIETS AND DIABETES CONTROL Principal Investigator & Institution: Kattelmann, Kendra K.; Nutrition, Food Science and Hospitality; South Dakota State University Brookings, Sd 57007 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant): At present, there are no specific dietary guidelines for the Northern Plains Indian with type 2 diabetes. Current medical nutrition therapy practices base the diabetic therapeutic guidelines on the Food Guide Pyramid that encourages a grain-based diet. Anecdotally, Northern Plains Indians have reported a better control of their type 2 diabetes when following a diet higher in protein. Genetic differences may contribute to decreased adaptation to higher carbohydrate loads among Northern Plains Indians compared to Northern European descendents. A diet patterned after the historical hunter-gatherer type diet, or even the early reservation diet (with higher proportion of energy being supplied from protein), may lower the circulating insulin levels and provide better blood glucose control in Northern Plains Indians with type 2 diabetes. The hypothesis of this application is that Northern Plains Indians with non-insulin dependent, type 2 diabetes who receive an educational lesson that promotes a diet patterned according to the traditional consumption of macronutrients (25% calories from protein, 45-50% from carbohydrate, and 25-30% from fat) will have a better control of their diabetes as measured by their HbA1C, blood glucose, and circulating insulin concentrations compared to those educated to consume a grain-based diet that supplies a more typical mix of macronutrients (10-15% calories from protein, 50-55% from carbohydrate, and 30-35% from fat). A 26- week, dietary educational intervention

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given monthly will be conducted in the Northern Plains Indians from the Cheyenne River Reservation (Lakota Sioux). Adult Lakota volunteers with type 2 diabetes will be recruited and randomized to an experimental (Medicine Wheel Model) or control (Usual Care) group. The experimental group will receive dietary training using the Medicine Wheel Model for Native Nutrition, which promotes a diet patterned according to the traditional consumption of macronutrients. The control group will receive the usual care dietary training based on the Food Guide Pyramid. Primary outcome variables of HbA1C, fasting blood glucose, and circulating insulin concentrations and secondary outcome variables of blood lipid concentrations will be measured at the beginning and end of trial. Measurements of potential confounders of weight, height, usual dietary intake, activity levels, medication use, and incidence of infection will be taken at the beginning and end of the study period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES

PLASMINOGEN

ACTIVATORS

IN

PERIODONTITIS

AND

Principal Investigator & Institution: Decarlo, Arthur A.; President and Chief Science Officer; None; Nova Southeastern University College Ave Fort Lauderdale, Fl 33314 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: Periodontal disease in individuals with diabetes mellitus is more frequent and more severe. Both periodontitis and diabetes patients present with extracellular matrix changes associated with the microvasculature. We propose that changes in the microvasculature are a common, fundamental process in the development of tissue pathology in both Adult Periodontitis and diabetes mellitus, and we offer this as an explanation for the increased incidence and severity of periodontitis in diabetics. Because the plasminogen activators (PA) and their inhibitors, plasminogen activator inhibitors (PAIs) are known to have a critical role in angiogenesis and angiopathies, as well as in extracellular remodeling and fibrinolysis, we propose to demonstrate a significant association of the Pas and PAIs with both periodontitis and diabetes severity, and to show that the exacerbation of periodontitis in diabetics is a function of Pas and PAIs. Diabetes-associated pathology will be measured as the level of diabetic retinopathy, previously demonstrated to correlate with periodontitis severity. Gingival microvasculature changes will be measured by morphometric analysis of histologic sections. We will measure Pas and PAIs in three different ways: genotypes, cellular response levels, and in vivo tissue levels. Our hypothesis states that POA/PAI parameters will be similarly associated with measurements of periodontitis and diabetes pathology but significantly different from levels found in healthy control participants. To address pathophysiology mechanisms which would link changes in PAs and PAIs in three different ways: genotypes, cellular response levels, and in vivo tissue levels. Our hypothesis states that PA/PAI parameters will be similarly associated with control participants. To address pathophysiological mechanisms which would link changes in PAs and PAIs with development of microangiopathy we will use an in vitro endothelial cell microvessel assay system, expression and activation of matrix metalloproteinases, and accumulation of matrix proteins such as type IV collagen and laminin. Anticipated results may focus the targeting of therapeutic intervention for pathology associated with periodontal disease and diabetes mellitus towards the Pas and PAIs and may allow earlier intervention for a patient population determined genotypically to be at risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PRESERVATION & REPLACEMENT OF BETA CELLS IN IDDM Principal Investigator & Institution: Fleischer, Norman S.; Professor of Medicine; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2003; Project Start 05-FEB-1998; Project End 31-JUL-2008 Summary: Type 1 diabetes mellitus is caused by the autoimmune destruction of pancreatic beta cells. Thus, efforts in recent years have centered on the development of approaches to slow or prevent the destruction of the endogenous beta cells, provide them from an exogenous source by transplantation, or induce their de novo regeneration. The current proposal focuses on the first two of these directions. The overall long-term goals of this program are 1) to identify key components in the autoimmune response to beta cells and design new therapeutic approaches for the protection and preservation of endogenous beta cells, and 2) to develop genetically engineered human beta-cell lines and human islets to replace damaged or nonfunctional beta cells. These goals are addressed by projects. In Project 1, synthetic and natural peptide ligands will be identified for beta cell-cytotoxic T cells restricted to the human class I MHC molecule HLA-A2. The disease relevance of these ligands will be examined in NOD mice transgenically expressing HLA-A2 using peptide/MHC tetramer and tolerization studies. Findings will be translated to humans by testing the hypothesis that HLA-A2-positive type 1 diabetes patients will exhibit overlapping T cell reactivities to those seen in NOD.HLA-A2.1 mice. In Project 2, the mechanisms by which Adenoviral E3 gene products protect islets from allogeneic rejection and autoimmune destruction will be examined using murine and human islets and beta-cell lines, including conditionally transformed murine cells and the human cells produced in Project 3. In Project 3, human hepatic progenitor cells will be engineered to become surrogate beta-cells having the capacity to store and secrete insulin physiologically, thus serving as an alternative to human islets as a source of transplantable beta-cells. 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.; Associate Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; 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 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,

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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: PSYCHIATRIC DISORDERS IN ADULTS WITH DIABETES MELLITUS Principal Investigator & Institution: Lustman, Patrick J.; Professor of Psychiatry; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 01-JUL-1985; Project End 31-MAR-2004 Summary: Diabetes increases the risks of maternal, fetal, and neonatal complications from pregnancy. Tight glycemic control during pregnancy reduces these risks but is difficult to achieve. Major depression is present in approximately 25 percent of diabetic women and is associated with significant deterioration in glycemic control. There has been no study in diabetic or nondiabetic subjects of depression treatment during pregnancy, and the effects of depression treatment on obstetric outcomes remain unknown. Recently, we showed that cognitive behavior therapy (CBT) was an effective nonpharmacologic treatment for depression in diabetes that produced durable improvements in glycemic control. In this study we plan to treat major depression in pregnant diabetic women with CBT and determine its effects on depression, glycemic control, and maternal and neonatal outcomes. We also plan to assess the relationship of diabetes during pregnancy and postpartum depression to neuropsychological development of the infants. 150 pregnant diabetic women will be recruited for study: 100 with and 50 without major depression. The nondepressed subjects function only as a comparison group in some of the statistical analyses. All subjects will be assessed serially during the 2nd and 3rd trimesters and the 1 year postpartum period while receiving the usual degree of intensive medical care for the diabetic pregnancy. Depressed patients will be assigned randomly to treatment with individual CBT (n =50) or supportive counseling (n =50). The pregnancy care team is informed of the depression status of all subjects and advised to give usual care for depression. The design blinds the pregnancy care team to treatment assignment, controls for nonspecific effects of attention and the influence of enhanced diabetes control on mood, provides a

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comparison group likely to remain depression free during gestation and the postpartum period, and is sensitive to human subject issues. We hypothesize that CBT will be superior to supportive counseling in terms of improving depression and glycemic control, and that the treatment-related improvements in glycemic control will reduce the adverse effects of diabetes in pregnancy, including c-section, macrosomia, neonatal hypoglycemia, and fetal hyperinsulinemia. We also expect that by improving glycemic control during pregnancy and reducing the risk of postpartum depression CBT will improve neuropsychological development in the offspring. The findings should demonstrate the relevance of depression treatment to maternal and neonatal outcomes of diabetic pregnancies and translate directly to the management of patients living with diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: R21 PROJECT: ANTI-DIABETIC EFFECTS OF PANAX GINSENG Principal Investigator & Institution: Yuan, Chun-Su; Anesthesia and Critical Care; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 31-JAN-2004 Summary: Diabetes mellitus or diabetes is a chronic metabolic disease that can cause blindness, kidney failure, nerve damage, and confers an increased risk of ischemic heart disease, stroke and peripheral vascular disease. Diabetes is divided into two major categories: type 1 or insulin- dependent diabetes mellitus (IDDM), and type 2 or noninsulin dependent diabetes mellitus (NIDDM). In this country, the incidence of diabetes is approximately 4.5%, of which 90% is type 2 diabetes. In 1992, diabetes care required roughly 14.6% of the total U.S. health care expenditure ($105 billion). Many of these patients also suffer from diabetic complications. Considering the heterogeneity of this disease, and the limitations of current therapies, such as high secondary failure rates and side effects, there is an urgent need to explore new anti- diabetic agents. This research project is related to the development of useful products in the field of complementary and alternative medicine. This proposal will focus on our studies on anti-diabetic effects of Panax ginseng, and this project is a continuation of our previous ginseng pharmacological studies. Recently, in our preliminary studies, we observed exciting results on anti-diabetic actions in ob/ob mice using Panax ginseng berry (or fruit) extract, other than the commonly used root extract. The ob/ob mice is a genetic model for type 2 diabetes, and these animals are extremely insulin resistant and have fasting blood glucose levels that are significantly higher than that of lean mice. Data from our pilot observation showed that extract of Panax ginseng berry normalized hyperglycemia and increased insulin sensitivity in ob/ob mice. In addition, we analyzed the constituents of the ginseng berry by HPLC analysis and found that, compared to ginseng root, the ginseng berry has a distinctive profile of ginsenosides, the vital constituent of ginseng. In this revised proposal, we will test the hypothesis that Panax ginseng berry extract has significant anti-hyperglycemic activity. The project aims to identify the anti-hyperglycemic constituents of Panax ginseng berry, and synergistic effects between these constituents. We will also investigate mechanisms of action of these active component(s). Our strategy is to use an in vivo-guided chemical fractionation method to isolate the pure, biologically active, anti-hyperglycemic compound(s) from Panax ginseng berry using the ob/ob mouse. Improvements in glucose homeostasis, glucose tolerance, and in vivo insulin sensitivity will be tested. The results of the proposed project will also help fill gaps in our knowledge before therapeutic agents can be developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RACE AND LONG-TERM DIABETES SELF-MANAGEMENT IN AN HMO Principal Investigator & Institution: Ross-Degnan, Dennis; Harvard Pilgrim Health Care, Inc. 93 Worcester St Wellesley, Ma 02481 Timing: Fiscal Year 2002; Project Start 15-JAN-2002; Project End 31-DEC-2004 Summary: (provided by applicant): This project will examine the complex relationships between race, diabetes self-management (including self-monitoring of blood glucose and diabetes drug therapy), glycemic control, and diabetes complications in a managed care setting over a nine-year period. African Americans with diabetes are less likely to be in glycemic control, a major risk factor for development of complications, including nephropathy, retinopathy, and peripheral vascular disease. Randomized controlled trials suggest that diabetes self-management including patient education, drug therapy, changes in diet, and regular exercise can improve glycemic control in the African American population. However, there is little epidemiological evidence regarding the role of race/ethnicity as a determinant of adherence to recommended diabetes selfmanagement practices, or regarding the relationship between self-management, glycemic control, and subsequent clinical outcomes. Further, previous studies of race and diabetes self-management have been limited by short study periods, inadequate sample size, and reliance on self-reported measures of self-monitoring of blood glucose. The clinical setting for this study is Harvard Vanguard Medical Associates (HVMA), a large multi-site, multi-specialty group affiliated with Harvard Pilgrim Health Care. HVMA consists of 14 health centers serving over 300,000 people in the Boston area. We will use an open cohort design to enroll all adult (l8 years) patients between 1991 and 1999 who have 24 months or more of uninterrupted enrollment in HVMA following ascertainment of non-gestational diabetes, defined by (1) hospital discharge diagnosis of diabetes mellitus, (2) outpatient diagnoses of diabetes mellitus, HbAlc lab test result 8.0, or use of a diabetes drug (insulin, sulfonylurea, or metformin). We estimate that the cohort will include approximately 1,800 adults identified as African American and 5,000 identified as Caucasian. Access to HVMA computerized medical records, hospital emergency room and inpatient claims, lab, and pharmacy data will allow us to create reliable, objective measures of self-monitoring (home glucose monitor test strip use), drug therapy. glycemic control (HbAlc lab results), and diabetes complications (as measured in outpatient visits, emergency room visits, and hospitalizations). Stratifying by type of drug therapy (insulin/combined therapy vs. oral therapy), we will use descriptive analyses, generalized linear mixed models, and proportional hazards models to (1) identify racial differences in self-management practices and diabetes-related health outcomes over time; (2) assess whether African American race is an independent predictor of self-monitoring practice or adherence to drug regimen; and (3) whether there are racial/ethnic differences in the association between self-management and specific clinical endpoints, including glycemic control (HbAlc<8.0) and the incidence of diabetes-related complications over the nine-year study period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION COACTIVATORS

OF

INSULIN

GENE

TRANSCRIPTION

BY

Principal Investigator & Institution: Thomas, Melissa K.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2005

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Summary: (Scanned from the applicant's description) Diabetes mellitus affects over 16 million individuals in the United States, resulting in substantial costs in morbidity, mortality, and health care expenditures. Current treatment regimens for diabetes mellitus do not normalize insulin production and/or action efficiently enough to restore normal glucose metabolism and prevent major vascular and neurologic complications of hyperglycemia. One approach to identify novel treatment strategies for diabetes mellitus is to study the regulation of insulin production and the molecular defects that lead to relative or absolute insulin deficiency. An increasing number of transcriptional regulators important for the development of the pancreas and/or the regulation of glucose-responsive insulin gene transcription are targets of mutations in individuals with maturity-onset diabetes of the young (MODY) or type 2 diabetes mellitus. Disrupting the functions of pancreatic beta-cell transcription factors may alter the regulation of islet cell mass, beta-cell function, or insulin gene transcription. Transcription factors essential for pancreatic development or for differentiated beta-cell function, including the regulation of insulin gene transcription, are candidate diabetes genes. We have identified a novel PDZ-domain protein, designated Bridge-1, that interacts with E2A transcription factors as a coactivator of insulin gene transcription. The proposed studies are designed to test the hypothesis that Bridge-1 is an important regulator of transcriptional activation of the insulin gene and a modulator of the function of key transcription factors and coactivators in pancreatic beta cells. To address this hypothesis, we propose the following specific alms: 1) to characterize Bridge-1 regulation of insulin gene transcription via protein-protein interactions in pancreatic beta cells, and 2) to determine whether overexpression of the coactivator Bridge-1 or a Bridge-1 transactivation mutant in pancreatic beta cells of transgenic mice alters insulin gene expression or the normal development of the endocrine pancreas. Because Bridge-1 appears to be an important transcriptional regulator of insulin gene expression we propose that it may be a promising candidate gene contributing to susceptibility for the development of type 2 diabetes mellitus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RENIN ANGIOTENSIN SYSTEM BLOCKAGE-DN (RASS) Principal Investigator & Institution: Mauer, S Michael.; Professor; Pediatrics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 16-MAR-1997; Project End 31-MAY-2008 Summary: (provided by applicant): Diabetes nephropathy (DN) is the most important cause of kidney failure. Patients (pts) with Type 1 diabetes mellitus (DM) who develop DN have a markedly increased death rate from kidney failure, coronary artery disease and stroke. Glycemia only partly explains why some pts develop these DM complications. Further, since tight blood sugar control is extremely difficult to maintain, other efforts need to be made to reduce risks of DM complications. Renin-angiotensin system (RAS) inhibitors slow the progress of established DN. The specific aim of this study is to determine whether treatment at the early stages of DM can slow or stop DN structural changes. The long-term objective is to prevent DN from developing. Two hundred eight five pts ages 16-59 with 2-29 yrs of Type 1 DM and no renal functional abnormalities have been randomized into a parallel, double-blind, placebo-controlled study involving 3 groups (95 pts/group). Each group receives an angiotensinconverting enzyme inhibitor (ACEI) (enalapril), or an angiotensin II receptor blocker (losartan), or placebo. All pts have their usual DM management. Baseline studies included measures of glomerular filtration rate (GFR), urinary albumin excretion rate (UAE), blood pressure (BP), and a percutaneous renal biopsy. Pts are followed by

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quarterly measures of BP, HbA1C, UAE, and drug compliance. There are annual measures of GFR and a repeat renal biopsy after 5 yrs in the study. The main endpoint is kidney structural changes over time, especially mesangial fractional volume [Vv(Mes/glom)]. Secondary endpoints will be other DN structural measures and measures of kidney function (UAE, GFR). These studies will determine whether RAS blockage in the early stages of DN can prevent the early kidney structural changes in this important disorder. Ancillary studies will evaluate the effects of treatment group on the development and progression of diabetic retinopathy and will develop predictors of study participants' compliance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RISK OF TYPE 1 AND TYPE 2 DIABETES AMONG YOUNG FINNS Principal Investigator & Institution: Tuomilehto, Jaakko O.; National Public Health Institute Mannerheimintie 166, Sf-00280 Helsinki, Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): The incidence of type 1 diabetes (DM1) in children (14 years or under) is the highest in the world in Finland. DM1 can, however, develop at any age. Clinical, biological and epidemiological data obtained from children may not be fully applicable to adults with DM1. It will be very important to know about the factors that postpone the disease onset to occur later in life. Such information might be crucial for the development of preventive measures against DM1. Type 2 diabetes (DM2) is increasing rapidly worldwide and its age-of-diagnosis is becoming younger. There are hardly any population-based epidemiological data on DM2 in youth or young adults. This research aims at assessing the incidence of DM1 and DM2 in young adults and we have a unique possibility to compare findings with data from Finnish DM1 children. We will determine the incidence of DM1 and DM2 in young adults (15-39 years) in Finland during 1992 to 2001. This will also permit us to calculate the 10-year trend in incidence, and the cumulative incidence of DM1 in the Finnish population by the age of 40 years. We will assess the familial aggregation and sibling risk of DM1 in young adults and compare it with that in childhood-onset DM1. In addition, we have a possibility to ascertain diabetes in the offspring of these patients with DM1 and DM2 whose age-at-onset of diabetes is in preadolescence or in adulthood. The reasons for the apparent gender differences in the risk of DM1 and the familial aggregation of DM1 will be studied in detail. The effect of intra-uterine growth retardation, fetal programming, and growth and weight development during childhood on the risk of DM1 and DM2 in young adults will be assessed. Cases originally classified as DM2 or gestational diabetes will be followed up five to nine years, and thereby population-based estimates for slowonset DM1 will be obtained. The detailed epidemiological data obtained in this study will also lay a foundation for further research of etiological factors, genetic and environmental, predisposing to DMI and DM2 in this age group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SECRETED ADIPOCYTE PROTEINS, INSULIN RESISTANCE VASCULAR Principal Investigator & Institution: Garvey, W Timothy.; Professor and Chair; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2001; Project Start 30-SEP-1996; Project End 31-AUG-2006 Summary: (provided by applicant) The Insulin Resistance Syndrome (IRS) augments risk for cardiovascular disease in patients both with and without diabetes. The

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development of the IRS is integrally coupled to increased abdominal fat and waist/hip ratio. Our data show that an abnormal NMR lipoprotein subclass profile is associated with high waist/hip and confers increased vascular disease risk in Type 1 diabetes. The dyslipidemic pattern is identical to that observed in normoglycemic IRS and Type 2 Diabetes, and can be reserved by insulin-sensitizing thiazolidinediones. The link between increased abdominal fat and biochemical risk factors in IRS is unknown. Adipocytes secrete a large number of paracrine and endocrine factors that influence adipocyte size and function as well as whole-body physiology. The overall goal of Project 5 is to assess for the first time the effects of secreted adipocyte proteins on the biochemical risk profile and cardiovascular disease events in diabetes and IRS. The studies will involve unique national cohorts of Type 1 (DCCT/EDIC) and 2 (VA Cooperative Trial) diabetic patients, combined with in vitro studies, in order to test specific hypotheses from both epidemiological and mechanistic perspectives. In Specific Aim 1 we will measure circulating levels of novel adipocyte-derived proteins including adiponectin, acylation stimulating protein, CETP, PLTP, PAI-1, angiotensinogen, and leptin, and assess their relationship with cardiovascular risk factors and clinical events in both diabetes cohorts. In Specific Aim 2, we will determine the effects of thiazolidinedione treatment in Type 2 Diabetes on secreted adipocyte proteins, the biochemical risk profile, and cardiovascular events. In Specific Aim 3, we will study cultured adipocytes from insulin sensitive, IRS, and Type 2 diabetics, and assess the secretion rate of adipocyte proteins in vitro to directly assess whether changes in circulating levels are correlated with in vitro secretion rates. We will also study regulation of protein secretion by substrates, autocrine/paracrine factors, and thiazolidinediones. In Specific Aim 4, we will examine whether specific gene polymorphisms influence secretion of adipocyte proteins and cardiovascular disease risk in diabetes. These studies will determine whether secreted adipocyte proteins are responsible for multiple traits in the IRS cluster, and the role of the IRS in mediating increased risk for cardiovascular disease in diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SUSCEPTIBILITY GENES IN TYPE 1 DIABETES Principal Investigator & Institution: Concannon, Patrick J.; Director; Benaroya Research Inst at Virginia Mason 1201 9Th Ave Seattle, Wa 98101 Timing: Fiscal Year 2001; Project Start 01-MAY-1993; Project End 31-MAY-2002 Summary: Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disorder which results from cellular infiltration and destruction of the pancreatic islet cells. The events that initiate this pathogenic process are poorly understood. The tendency of IDDM to cluster in families and the 35-40 percent concordance rate in identical twins suggest that both genetic and environmental factors contribute to IDDM susceptibility. It has been recognized for more than 20 years that a gene or genes in the HLA region plays a significant role in the development of IDDM. However, the segregation of IDDM within families fits no simple pattern and the contribution of other genes to IDDM susceptibility has long been suspected. In an attempt to understand the underlying causes of IDDM, we and others have searched for regions of the human genome that demonstrate genetic linkage to IDDM. Besides HLA, we have identified 1 additional region where there is strongly suggestive evidence of linkage and 6 other regions with at least modest evidence warranting further study. In this current application, we propose to extend these promising results by 4 approaches. (1) There remain gaps in our genome-scan of sufficient size that they could harbor additional, undetected IDDM loci. We will genotype all of our original families using a standard set of markers that will fill

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these gaps and provide a framework for merging our data with other investigators. (2) We have 231 remaining multiplex IDDM families we have not screened for linkage. We will transfer all of these DNAs to an NIH-sponsored genotyping facility where they can be rapidly and efficiently genotyped. We will then merge this data with that from our previously completed genome-scan, and additional datasets provided by investigators in the UK and conduct a joint linkage analysis. (3) Regions with nominal evidence of linkage in this joining analysis will be saturation mapped to confirm the linkage, define the region, and test for allelic association. (4) Finally, for any region yielding compelling evidence of linkage and/or association, we will pursue positional cloning. Identification of such genes should provide important insights into immune pathways that are disrupted in IDDM and may suggest novel preventative or therapeutic approaches. Joint analyses of the single large database this project will generate (greater than 650 affected sibling pairs genotyped at 10 cM resolution) should provide the best picture yet of what inherited factors contribute to the development of IDDM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF LAMININ 5 IN DIABETIC ULCER HEALING Principal Investigator & Institution: Olerud, John E.; Professor; Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: (adapted from the application) One of the stated goals of Healthy People 2000 is to reduce the incidence of lower extremity amputation in diabetic patients from the 1988 baseline rate of 8.2/1000 to a target incidence of 4.9/1000 in the year 2000. Despite efforts directed at prevention, the rate of amputation has continued to rise in patients with DM. A better understanding of the pathogenesis of diabetic ulcers and novel treatment strategies are required to reverse the rising trend in the rate of amputation. The goal of this application is to use new molecular technologies to enhance healing of diabetic ulcers by increasing the migration of cells (keratinocytes) at the ulcer margin. The laminin 5 (Lam 5) cell-signaling pathway is the focus of this investigation. An interdisciplinary team will conduct the proposed experiments in patients and mice with DM. This application will test three general HYPOTHESES: 1. The principle deficit in closure of diabetic ulcers is failure of keratinocyte migration despite marked keratinocyte proliferation at the ulcer margin. 2. Lam 5 mediated signaling, essential for keratinocyte migration, is impaired in diabetes mellitus. 3. Clarification of Lam 5 cellsignaling pathways will lead to novel approaches to stimulate keratinocyte migration and speed healing of diabetic ulcers. In order to test these hypotheses we will carry out the following Specific Aims: Specific Aim 1. Characterize chronic ulcers from patients with diabetes and acute wounds from diabetic and normal human subjects/mice regarding Lam 5 isoforms and Lam 5 mRNA, the Lam 5 associated integrins alpha6-beta4 alpha3-beta1 and the proliferation marker Ki67. Specific Aim 2. Evaluate functions for Lam 5 sub-domains as well as design and produce recombinant isoforms of Lam 5. Specific Aim 3. Evaluate mechanisms by which keratinocytes regulate synthesis and deposition of Lam 5, and evaluate the role of Lam 5 in the migration of normal and diabetic cells. Specific Aim 4. Assess the effects of application of recombinant Lam 5 isoforms to the wounds of db/db diabetic mice and develop bioniaterials that elicit a maximal increase in healing rate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TYPE 1 DIABETES TRIALNET: CLINICAL CENTERS Principal Investigator & Institution: Orban, Tihamer; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 29-SEP-2001; Project End 31-AUG-2008 Summary: (provided by applicant) This is an application from the Joslin Diabetes Center/Children?s Hospital, a current Diabetes Prevention Trial-1 (DPT-1) Clinical Center to become a Clinical Center in the national diabetes trial network for Type 1 diabetes mellitus, the TrialNet. TrialNet, a national network of cooperative clinical research groups will consist of clinical centers and core support facilities. Its common goal will be to perform intervention studies to prevent, treat or ameliorate Type 1 diabetes mellitus in humans. TrialNet will also support natural history and genetic studies in the population screened or enrolled in specific studies aiming to achieve a better understanding of the etiology and pathogenesis of Type 1 diabetes and to develop strategies to prevent the disease. The Joslin Diabetes Center/Children?s Hospital proposed TrialNet Clinical Center includes expanded resources in experienced personnel, in addition to the expanded network of associated institutions to the collaborative effort led by the NIH. Our Clinical Center will have two major objectives: 1.) to complete the ongoing DPT-1 study; 2.) to participate in the design and implementation of existing and future pilot and expanded studies of new agents to prevent, treat or ameliorate Type 1 diabetes mellitus and also to participate and provide resources for genetic and natural history studies. The ongoing Diabetes Prevention Trial for Type 1 Diabetes (DPT-1) is testing, whether early intervention with parenteral or oral insulin in nondiabetic relatives of persons with Type 1 diabetes with increased risk for the disease can delay the clinical onset of Type 1 diabetes. The DPT-1 is currently funded through August 2001 and the TrialNet will be entrusted to carry on and complete the current protocol. Our Joslin/Children?s center is committed to contribute to future clinical studies in Type 1 diabetes mellitus. We also propose a novel interventional protocol, using insulin B-chain in incomplete Freund?s adjuvant in newly diagnosed Type 1 diabetes patients to test its preventive effect in beta cell function decline. The primary outcome measure is mixed meal stimulated C-peptide levels. Phase 1 part of the study is currently underway. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TYPE IMMIGRANTS

2

DIABETES

MELLITUS

IN

KOREAN

AMERICAN

Principal Investigator & Institution: Pistulka, Gina M.; None; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Diabetes is an emerging health problem in many immigrant communities. While considerable progress has been made in many areas of chronic disease management nationwide, Korean American immigrants (KAI) continue to have a high prevalence of Type 2 diabetes mellitus (DM) and complications resulting from an inadequate management of DM. Many existing resources to aid patients with DM in the mainstream community are neither relevant nor effective for the majority of KAI because of language or cultural barriers that Koreans often encounter as a firstgeneration immigrant group. There is an urgent need to understand the experience of the KAI, to adequately assess those aspects that promote good control of glucose in DM, and ultimately to develop strategies that address those components essential for the provision of culturally appropriate care. The specific aim of this research is to

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conceptualize the meaning of wellness and disease in KAI men and women, to establish domains that explain the experience of DM, perceived barriers of self management, and the resources to overcome barriers that influence control of Type 2 diabetes mellitus in KAI. Arthur Kleinman's Health Care Systems Conceptual Explanatory Models will guide the research. A grounded theory qualitative methodology will be employed, using theoretical sampling and appropriate data collection methods, i.e. qualitative interviews. The results will cultivate a strong and accurate understanding of diabetes in the KAI, from which an effective intervention can be developed, thereby decreasing morbidity and mortality related to Type 2 Diabetes Mellitus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: UCSF TRIALNET: A PHASE II TRIAL OF HOKT3GAMMA1 (ALAALA) Principal Investigator & Institution: Gitelman, Stephen E.; Pediatrics; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 29-SEP-2001; Project End 31-AUG-2008 Summary: (provided by applicant) The goal of this application is to establish a Clinical Center of TrialNet at the University of California at San Francisco (UCSF) Diabetes Center, with the ultimate long-term objective to develop therapies to prevent the onset of Type 1 diabetes mellitus (T1DM). UCSF is uniquely positioned to serve as a study site for this multicenter trial, given a strong established diabetes program, a large population base for subject recruitment, and an established track record with clinical research and autoimmune interventions for T1DM. Clinicians at the UCSF Diabetes Center now provide care for approximately 3400 patients, with 100 new patients with Type 1 diabetes each year. In addition, the center has investigators with extensive experience in both clinical and basic science research, and with NIH-funded Pediatric and General Clinical Research Centers. The investigators are well positioned to recruit subjects from within the UCSF system, and widely from a preexisting referral net throughout Northern California. The diversity of the population suggests that subjects will be recruited from a variety of ethnicities. This application will build on UCSF?s past role as an Affiliate in the Diabetes Prevention Trial-1 (DPT-1). Specifically, the study goals are: Specific Aim 1: To implement and continue the DPT-1 protocols. This includes creation of an infrastructure that will enhance follow-up of subjects already entered into the DPT-1, as well as recruitment to screen and stage new subjects, with subsequent enrollment of those at intermediate risk into the oral insulin study arm. Specific Aim 2: To participate in other trials developed through TrialNet. Specific Aim 3: To implement a novel protocol involving treatment of individuals at high risk for Type 1 diabetes with a non-FcR binding anti-CD3 monoclonal antibody (mAb) (hOKT3g1(Ala-Ala)). An ongoing Phase I/II trial of this agent in new onset T1DM has shown that administration of the drug is safe, and has suggested efficacy in preserving insulin secretory capacity over time. Our rationale for this application is that if similar effects are seen in patients in whom the earliest signs of beta cell dysfunction are detected, and then progression to diabetes might be prevented. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: USING GENOMICS TO UNDERSTAND AUTOIMMUNE DIABETES Principal Investigator & Institution: Katz, Jonathan D.; Associate Professor of Pediatrics; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007

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Summary: (provided by applicant): The non-obese diabetic (NOD) mouse provides an excellent model for e type 1 diabetes mellitus (T1DM). Several lines of evidence suggest that T1DM results from a Th1 autoimmune response. For example, studies by our group and others have shown that islet-reactive Th1 (interferon (IFN)-gamma producing) T cells transfer diabetes, while islet-reactive Th2 (interleukin (IL)-4 producing) T cells do not. These and other data support the notion that T1DM development correlates with a Th1 response. However, the pathogenesis of T1DM, like that of other organ-specific autoimmune diseases, clearly involves more than the development of IFN-gamma producing lymphocytes. Indeed, both IFN-gamma- and IFN-gamma receptor-deficient NOD mice develop T1DM. Therefore, it is critical that a deeper, more mechanistic understanding of the immunopathogenesis of T1DM be established. To this end, we have taken advantage of the spectrum of disease exhibited by sub-lines of our isletspecific T cell receptor (TCR) transgenic NOD mice to analyze the molecular evolution of disease in vivo, using the technique of functional genomics. The general hypotheses underlying these studies are: (a) that diabetes in NOD mice is a Th1-associated disease; (b) that disease expression in the NOD mouse is not dependent upon the expression or activity of IFN-gamma, the superficial phenotype marker of a Th1 response; and (c) that global characterization of disease- and tissue-specific gene expression will allow for a more complete understanding of the pathogenesis of diabetes in the NOD mouse. The specific hypothesis being tested in these studies is that a careful, functional genomics approach to molecular pathogenesis will allow for the detailed delineation of those aspects of the Th1-associated inflammatory response that are truly essential for disease pathogenesis in the NOD mouse. To this end, we aim: Aim 1: To establish a limited and verified set of genes whose expression patterns directly stage and predict the course of spontaneous disease progression in NOD mice. Aim 2: To delineate the genetic mechanism by which IFN-gamma- and IFN-gamma receptor-deficient NOD mice develop spontaneous T1DM in the absence of interferon-gamma activity. Aim 3:To establish the differential gene expression pattern associated with disease progression and resistance in NOD recipients of islet-reactive Th1 and Th2 T cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIRUSES AND DIABETES Principal Investigator & Institution: Oldstone, Michael B.; Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 05-APR-2002; Project End 31-MAR-2006 Summary: (Provided by applicant): This is the second revision of a grant requesting funds to continue a highly productive 5 year grant to study how viruses cause autoimmune insulin-dependent diabetes mellitus (IDDM). Utilizing recent information we derived from a transgenic (tg) model created to mimic human IDDM together with reports of other investigators a unifying hypothesis of how viruses cause IDDM and other autoimmune diseases is presented. The testing of this hypothesis comprises this grant proposal. We hypothesize for the initial event to occur the virus must be both tropic for the target organ and via infection of the target organ induce cytokines/chemokines in the local milieu allowing upregulation of MHC and T cell activation molecules, APC and attraction of antiself T cells. When the unresponsive but potential autoimmune antigen-specific T cell population in the periphery is of sufficient numbers and affinity then the virus through stimulation of the innate immune system can cause disease. However, when the antigen-specific antiself T cell pool in the periphery is of low numbers and of low affinity (as often in most instances of autoimmune disease) then the virus must provide a mimic, through the process we

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initially termed molecular mimicry, so that the T cell pool is sufficiently expanded (adoptive immune system) to cause disease. This grant tests the components of this hypothesis with studies of the role of virus tropism, the role of selected components of the innate and adoptive immune response and determines numbers of antigen-specific anti "self" T cells deposited in the target organ in situ in comparison to non-antigenspecific T cells in causing IDDM. To do these experiments we utilize both our established RIP-LCMV and MBP-LCMV tg mice, create new tg models that specifically inhibit viral replication in the target organ, use recombinant viruses tropic or not tropic for pancreas or CNS that carry the "autoimmune self" "viral" antigen, and use MHC tetramers and functional assays to identify and quantitate the antiself antigen-specific T cells deposited in the target organ as well as following their trafficking to that tissue. 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 “diabetes mellitus” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for diabetes mellitus in the PubMed Central database: •

[beta]-Cell Lipotoxicity in the Pathogenesis of Non-Insulin-Dependent Diabetes Mellitus of Obese Rats: Impairment in Adipocyte-[beta]-Cell Relationships. by Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH.; 1994 Nov 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45129

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A Membrane Form of Brain L-Glutamate Decarboxylase: Identification, Isolation, and its Relation to Insulin-Dependent Diabetes Mellitus. by Nathan B, Bao J, Hsu C, Aguilar P, Wu R, Yarom M, Kuo C, Wu J.; 1994 Jan 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42923

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Acceleration of type 1 diabetes mellitus in proinsulin 2 --deficient NOD mice. by Thebault-Baumont K, Dubois-Laforgue D, Krief P, Briand JP, Halbout P, VallonGeoffroy K, Morin J, Laloux V, Lehuen A, Carel JC, Jami J, Muller S, Boitard C.; 2003 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153768

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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Altered Expression of Insulin Receptor Types A and B in the Skeletal Muscle of NonInsulin-Dependent Diabetes Mellitus Patients. by Mosthaf L, Vogt B, Haring HU, Ullrich A.; 1991 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51739

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Analysis of structure and function relationships of an autoantigenic peptide of insulin bound to H-2Kd that stimulates CD8 T cells in insulin-dependent diabetes mellitus. by Wong FS, Moustakas AK, Wen L, Papadopoulos GK, Janeway CA Jr.; 2002 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122807

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Autoantibodies to the GLUT-2 Glucose Transporter of [beta] Cells in InsulinDependent Diabetes Mellitus of Recent Onset. by Inman LR, McAllister CT, Chen L, Hughes S, Newgard CB, Kettman JR, Unger RH, Johnson JH.; 1993 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45856

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Cigarette smoking, health status, socio-economic status and access to health care in diabetes mellitus: a cross-sectional survey. by Gulliford MC, Sedgwick JE, Pearce AJ.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150570

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Cloning, Characterization, and Autoimmune Recognition of Rat Islet Glutamic Acid Decarboxylase in Insulin-Dependent Diabetes Mellitus. by Michelsen BK, Petersen JS, Boel E, Moldrup A, Dyrberg T, Madsen OD.; 1991 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52588

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Cost of managing complications resulting from type 2 diabetes mellitus in Canada. by O'Brien JA, Patrick AR, Caro JJ.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153533

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CTLA4 gene polymorphisms are associated with, and linked to, insulin-dependent diabetes mellitus in a Russian population. by Chistiakov DA, Savost'anov KV, Nosikov VV.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31345

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D-chiro-Inositol Metabolism in Diabetes Mellitus. by Ostlund RE Jr, McGill JB, Herskowitz I, Kipnis DM, Santiago JV, Sherman WR.; 1993 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47698

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Decreased Muscle Glucose Transport/Phosphorylation is an Early Defect in the Pathogenesis of Non-Insulin-Dependent Diabetes Mellitus. by Rothman DL, Magnusson I, Cline G, Gerard D, Kahn CR, Shulman RG, Shulman GI.; 1995 Feb 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42621

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Does screening for gestational diabetes mellitus make a difference? by Sermer M.; 2003 Feb 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=143548

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Gene for Non-Insulin-Dependent Diabetes Mellitus (Maturity-Onset Diabetes of the Young Subtype) is Linked to DNA Polymorphism on Human Chromosome 20q. by

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Bell GI, Xiang K, Newman MV, Wu S, Wright LG, Fajans SS, Spielman RS, Cox NJ.; 1991 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51043 •

Gene Therapy for Diabetes Mellitus in Rats by Hepatic Expression of Insulin. by Kolodka TM, Finegold M, Moss L, Woo SL.; 1995 Apr 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42152

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Glucokinase Mutations Associated with Non-Insulin-Dependent (Type 2) Diabetes Mellitus have Decreased Enzymatic Activity: Implications for Structure/Function Relationships. by Gidh-Jain M, Takeda J, Xu LZ, Lange AJ, Vionnet N, Stoffel M, Froguel P, Velho G, Sun F, Cohen D, Patel P, Lo YD, Hattersley AT, Luthman H, Wedell A, Charles RS, Harrison RW, Weber IT, Bell GI, Pilkis SJ.; 1993 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45994

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Human Glucokinase Gene: Isolation, Characterization, and Identification of Two Missense Mutations Linked to Early-Onset Non-Insulin-Dependent (type 2) Diabetes Mellitus. by Stoffel M, Froguel P, Takeda J, Zouali H, Vionnet N, Nishi S, Weber IT, Harrison RW, Pilkis SJ, Lesage S, Vaxillaire M, Velho G, Sun F, Iris F, Passa P, Cohen D, Bell GI.; 1992 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49778

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Human Monoclonal Islet Cell Antibodies From a Patient with Insulin- Dependent Diabetes Mellitus Reveal Glutamate Decarboxylase as the Target Antigen. by Richter W, Endl J, Eiermann TH, Brandt M, Kientsch-Engel R, Thivolet C, Jungfer H, Scherbaum WA.; 1992 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49941

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Hyperinsulinemia Induces a Reversible Impairment in Insulin Receptor Function Leading to Diabetes in the Sand Rat Model of Non-Insulin-Dependent Diabetes Mellitus. by Kanety H, Moshe S, Shafrir E, Lunenfeld B, Karasik A.; 1994 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43262

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IA-2, a Transmembrane Protein of the Protein Tyrosine Phosphatase Family, is a Major Autoantigen in Insulin-Dependent Diabetes Mellitus. by Lan MS, Wasserfall C, Maclaren NK, Notkins AL.; 1996 Jun 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39028

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Identification of a Second Transmembrane Protein Tyrosine Phosphatase, IA-2[beta], as an Autoantigen in Insulin-Dependent Diabetes Mellitus: Precursor of the 37-kDa Tryptic Fragment. by Lu J, Li Q, Xie H, Chen Z, Borovitskaya AE, Maclaren NK, Notkins AL, Lan MS.; 1996 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39791

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Incomplete gastric metaplasia in children with insulin-dependent diabetes mellitus and celiac disease. An ultrastructural study. by Bertini M, Sbarbati A, Valletta E, Pinelli L, Tato L.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34772

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Influence of diabetes mellitus on heart failure risk and outcome. by Bauters C, Lamblin N, Mc Fadden EP, Van Belle E, Millaire A, de Groote P.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149427

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Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene is Strongly Associated with Coronary Heart Disease in Non-Insulin- Dependent Diabetes Mellitus. by Ruiz J, Blanche H, Cohen N, Velho G, Cambien F, Cohen D, Passa P, Froguel P.; 1994 Apr 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43641

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Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulindependent diabetes mellitus. by Rondinone CM, Wang LM, Lonnroth P, Wesslau C, Pierce JH, Smith U.; 1997 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20591

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Intervening to reduce weight gain in pregnancy and gestational diabetes mellitus in Cree communities: an evaluation. by Gray-Donald K, Robinson E, Collier A, David K, Renaud L, Rodrigues S.; 2000 Nov 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=80308

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Intimal redox stress: Accelerated atherosclerosis in metabolic syndrome and type 2 diabetes mellitus. Atheroscleropathy. by Hayden MR, Tyagi SC.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140143

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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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Laron Dwarfism and Non-Insulin-Dependent Diabetes Mellitus in the Hnf-1[alpha] Knockout Mouse. by Lee YH, Sauer B, Gonzalez FJ.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110684

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Lifestyle changes can prevent the development of diabetes mellitus. by Myers KA.; 2001 Jun 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=81220

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Metabolic syndrome and type 2 diabetes mellitus: focus on peroxisome proliferator activated receptors (PPAR). by Tenenbaum A, Fisman EZ, Motro M.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153546

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Microalbuminuria in diabetes mellitus. by Tobe SW, McFarlane PA, Naimark DM.; 2002 Sep 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=121969

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Newly diagnosed type 2 diabetes mellitus. by Smith SM.; 2003 Jun 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=162128

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NMR Studies of Muscle Glycogen Synthesis in Insulin-Resistant Offspring of Parents with Non-Insulin-Dependent Diabetes Mellitus Immediately after GlycogenDepleting Exercise. by Price TB, Perseghin G, Duleba A, Chen W, Chase J, Rothman DL, Shulman RG, Shulman GI.; 1996 May 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39245

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Paradoxical Structure and Function in a Mutant Human Insulin Associated with Diabetes Mellitus. by Hua QX, Shoelson SE, Inouye K, Weiss MA.; 1993 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45707

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Penetration of Ciprofloxacin into the Interstitial Space of Inflamed Foot Lesions in Non-Insulin-Dependent Diabetes Mellitus Patients. by Muller M, Brunner M, Hollenstein U, Joukhadar C, Schmid R, Minar E, Ehringer H, Eichler HG.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89414

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Randomised controlled trial of structured personal care of type 2 diabetes mellitus. by Olivarius ND, Beck-Nielsen H, Andreasen AH, Horder M, Pedersen PA.; 2001 Oct 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59690

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Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective diabetes study (UKPDS: 23). by Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR.; 1998 Mar 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28484

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Severe anaphylactic reactions to glutamic acid decarboxylase (GAD) self peptides in NOD mice that spontaneously develop autoimmune type 1 diabetes mellitus. by Pedotti R, Sanna M, Tsai M, DeVoss J, Steinman L, McDevitt H, Galli SJ.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153530

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Silent coronary artery disease in type 2 diabetes mellitus: the role of Lipoprotein(a), homocysteine and apo(a) polymorphism. by Gazzaruso C, Garzaniti A, Giordanetti S, Falcone C, Fratino P.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149426

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Smoking during pregnancy and diabetes mellitus in a British longitudinal birth cohort. by Montgomery SM, Ekbom A.; 2002 Jan 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61655

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Spontaneous Diabetes Mellitus in Transgenic Mice Expressing Human Islet Amyloid Polypeptide. by Janson J, Soeller WC, Roche PC, Nelson RT, Torchia AJ, Kreutter DK, Butler PC.; 1996 Jul 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38975

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TAP1 Alleles in Insulin-Dependent Diabetes Mellitus: A Newly Defined Centromeric Boundary of Disease Susceptibility. by Jackson DG, Capra JD.; 1993 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47925

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The 37/40-Kilodalton Autoantigen in Insulin-Dependent Diabetes Mellitus is the Putative Tyrosine Phosphatase IA-2. by Passini N, Larigan JD, Genovese S, Appella E, Sinigaglia F, Rogge L.; 1995 Sep 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40995

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The cardiac phenotype induced by PPAR[alpha] overexpression mimics that caused by diabetes mellitus. by Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP.; 2002 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150824

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The cost of major comorbidity in people with diabetes mellitus. by Simpson SH, Corabian P, Jacobs P, Johnson JA.; 2003 Jun 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161611

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The expression of adipogenic genes is decreased in obesity and diabetes mellitus. by Nadler ST, Stoehr JP, Schueler KL, Tanimoto G, Yandell BS, Attie AD.; 2000 Oct 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17207

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Transgenic Mice Overexpressing Phosphoenolpyruvate Carboxykinase Develop NonInsulin-Dependent Diabetes Mellitus. by Valera A, Pujol A, Pelegrin M, Bosch F.; 1994 Sep 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44765

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Type 2 diabetes mellitus in Canada's First Nations: status of an epidemic in progress. by Young TK, Reading J, Elias B, O'Neil JD.; 2000 Sep 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=80466

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Using fasting plasma glucose concentrations to screen for gestational diabetes mellitus: prospective population based study. by Perucchini D, Fischer U, Spinas GA, Huch R, Huch A, Lehmann R.; 1999 Sep 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28232

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Vasopressin contributes to hyperfiltration, albuminuria, and renal hypertrophy in diabetes mellitus: Study in vasopressin-deficient Brattleboro rats. by Bardoux P, Martin H, Ahloulay M, Schmitt F, Bouby N, Trinh-Trang-Tan MM, Bankir L.; 1999 Aug 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17899

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Vitamin D receptor initiation codon polymorphism influences genetic susceptibility to type 1 diabetes mellitus in the Japanese population. by Ban Y, Taniyama M, Yanagawa T, Yamada S, Maruyama T, Kasuga A, Ban Y.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34514

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Will new diagnostic criteria for diabetes mellitus change phenotype of patients with diabetes? Reanalysis of European epidemiological data. by [No authors listed]; 1998 Aug 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28629

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.

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

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To generate your own bibliography of studies dealing with diabetes mellitus, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “diabetes mellitus” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for diabetes mellitus (hyperlinks lead to article summaries): •

A case of acute renal failure due to rhabdomyolysis, associated with non-autoimmune fulminant type 1B diabetes mellitus. Author(s): Iyoda M, Kuroki A, Kato K, Kato N, Hirano T, Sugisaki T. Source: Clinical Nephrology. 2003 April; 59(4): 301-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708572&dopt=Abstract

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A cohort study of reproductive risk factors, weight and weight change and the development of diabetes mellitus. Author(s): Dawson SI, Smith WC, Watson MS, Wilson BJ, Prescott GJ, Campbell D, Hannaford P. Source: Diabetes, Obesity & Metabolism. 2003 July; 5(4): 244-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12795657&dopt=Abstract

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A genome-wide scan in type 2 diabetes mellitus provides independent replication of a susceptibility locus on 18p11 and suggests the existence of novel Loci on 2q12 and 19q13. Author(s): van Tilburg JH, Sandkuijl LA, Strengman E, van Someren H, Rigters-Aris CA, Pearson PL, van Haeften TW, Wijmenga C. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 May; 88(5): 2223-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727978&dopt=Abstract

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A patient with primary biliary cirrhosis complicated with slowly progressive insulindependent diabetes mellitus. Author(s): Nakasone H, Kinjo K, Yamashiro M, Kamiyama T, Kamiyama S, Miyazato H, Matsushita T, Arakawa Y, Ohshiro T, Toma S, Chinen K, Yamashiro M, Miyagi M, Makishi T, Hokama A, Sakugawa H, Kinjo F, Saito A. Source: Intern Med. 2003 June; 42(6): 496-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857047&dopt=Abstract

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A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus. Author(s): Herz M, Johns D, Reviriego J, Grossman LD, Godin C, Duran S, Hawkins F, Lochnan H, Escobar-Jimenez F, Hardin PA, Konkoy CS, Tan MH. Source: Clinical Therapeutics. 2003 April; 25(4): 1074-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809958&dopt=Abstract

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A study to survey susceptible genetic factors responsible for troglitazone-associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus. Author(s): Watanabe I, Tomita A, Shimizu M, Sugawara M, Yasumo H, Koishi R, Takahashi T, Miyoshi K, Nakamura K, Izumi T, Matsushita Y, Furukawa H, Haruyama H, Koga T. Source: Clinical Pharmacology and Therapeutics. 2003 May; 73(5): 435-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732844&dopt=Abstract

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Aceruloplasminemia with juvenile-onset diabetes mellitus caused by exon skipping in the ceruloplasmin gene. Author(s): Hatanaka Y, Okano T, Oda K, Yamamoto K, Yoshida K. Source: Intern Med. 2003 July; 42(7): 599-604. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879954&dopt=Abstract

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Acute painful neuropathy (insulin neuritis) in a boy following rapid glycemic control for type 1 diabetes mellitus. Author(s): Wilson JL, Sokol DK, Smith LH, Snook RJ, Waguespack SG, Kincaid JC. Source: Journal of Child Neurology. 2003 May; 18(5): 365-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12822825&dopt=Abstract

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Adenosine myocardial perfusion single-photon emission computed tomography in women compared with men. Impact of diabetes mellitus on incremental prognostic value and effect on patient management. Author(s): Berman DS, Kang X, Hayes SW, Friedman JD, Cohen I, Abidov A, Shaw LJ, Amanullah AM, Germano G, Hachamovitch R. Source: Journal of the American College of Cardiology. 2003 April 2; 41(7): 1125-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12679212&dopt=Abstract

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Adrenal insufficiency and diabetes mellitus secondary to the use of topical corticosteroids for cosmetic purpose. Author(s): Sobngwi E, Lubin V, Ury P, Timsit FJ, Gautier JF, Vexiau P. Source: Annales D'endocrinologie. 2003 June; 64(3): 202-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12910062&dopt=Abstract

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Advanced glycation end products in hemodialyzed patients with diabetes mellitus correlate with leptin and leptin/body fat ratio. Author(s): Kalousova M, Sulkova S, Zima T, Deppisch R, Beck W, Bednarova V, Fortova M, Tesar V. Source: Renal Failure. 2003 March; 25(2): 277-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12739834&dopt=Abstract

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Advances and continued controversy in coronary revascularization of patients with diabetes mellitus. Author(s): Petersen JL, McGuire DK, Harrington RA. Source: Curr Diab Rep. 2003 October; 3(5): 351-5. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12975023&dopt=Abstract

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Alcohol drinking patterns and risk of type 2 diabetes mellitus among younger women. Author(s): Wannamethee SG, Camargo CA Jr, Manson JE, Willett WC, Rimm EB. Source: Archives of Internal Medicine. 2003 June 9; 163(11): 1329-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uid s=12796069&dopt=Abstract

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Antipsychotic medications and diabetes mellitus. Author(s): Weinberg AD, Weinberg JD. Source: Director. 2003 Summer; 11(3): 111-3. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13678022&dopt=Abstract

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Are low target blood pressure goals justified in persons with diabetes mellitus? Author(s): Crook ED, Velusamy L. Source: Current Hypertension Reports. 2003 June; 5(3): 231-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724056&dopt=Abstract

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Association of a promoter variant in the inducible cyclooxygenase-2 gene (PTGS2) with type 2 diabetes mellitus in Pima Indians. Author(s): Konheim YL, Wolford JK. Source: Human Genetics. 2003 October; 113(5): 377-81. Epub 2003 August 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12920574&dopt=Abstract

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Association of hepatitis C infection and antiretroviral use with diabetes mellitus in drug users. Author(s): Howard AA, Klein RS, Schoenbaum EE. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 May 15; 36(10): 1318-23. Epub 2003 May 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746779&dopt=Abstract

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Association study of the vitamin D: 1alpha-hydroxylase (CYP1alpha) gene and type 2 diabetes mellitus in a Polish population. Author(s): Malecki MT, Klupa T, Wolkow P, Bochenski J, Wanic K, Sieradzki J. Source: Diabetes & Metabolism. 2003 April; 29(2 Pt 1): 119-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746631&dopt=Abstract

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Associations of blood glucose control with self-efficacy and rated anxiety/depression in type II diabetes mellitus patients. Author(s): Ikeda K, Aoki H, Saito K, Muramatsu Y, Suzuki T. Source: Psychological Reports. 2003 April; 92(2): 540-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12785638&dopt=Abstract

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Associations of diabetes mellitus and ethnicity with mortality in a multiethnic Asian population: data from the 1992 Singapore National Health Survey. Author(s): Ma S, Cutter J, Tan CE, Chew SK, Tai ES. Source: American Journal of Epidemiology. 2003 September 15; 158(6): 543-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12965880&dopt=Abstract

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Bead injection ELISA for the determination of antibodies implicated in type 1 diabetes mellitus. Author(s): Carroll AD, Scampavia L, Luo D, Lernmark A, Ruzicka J. Source: The Analyst. 2003 September; 128(9): 1157-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14529023&dopt=Abstract

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Bedside scoring procedure for the diagnosis of diabetic peripheral neuropathy in young patients with type 1 diabetes mellitus. Author(s): Shalitin S, Josefsberg Z, Lilos P, de-Vries L, Phillip M, Weintrob N. Source: J Pediatr Endocrinol Metab. 2002 May; 15(5): 613-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12014520&dopt=Abstract

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Beneficial effects of a glyburide/metformin combination preparation in type 2 diabetes mellitus. Author(s): Bokhari SU, Gopal UM, Duckworth WC. Source: The American Journal of the Medical Sciences. 2003 February; 325(2): 66-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12589230&dopt=Abstract

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Beneficial effects resulting from thiazolidinediones for treatment of type 2 diabetes mellitus. Author(s): Bell DS. Source: Postgraduate Medicine. 2003 May; Spec No: 35-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12785130&dopt=Abstract

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Beta-blockers after acute myocardial infarction in elderly patients with diabetes mellitus: time to reassess. Author(s): Di Bari M, Marchionni N, Pahor M. Source: Drugs & Aging. 2003; 20(1): 13-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12513113&dopt=Abstract

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Beta-cell apoptosis in the pathogenesis of human type 2 diabetes mellitus. Author(s): Leonardi O, Mints G, Hussain MA. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 August; 149(2): 99-102. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12887285&dopt=Abstract

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Bilateral Carpal tunnel syndrome with type 1 diabetes mellitus in childhood. Author(s): Kayali H, Kahraman S, Sirin S, Beduk A, Timurkaynak E. Source: Pediatric Neurosurgery. 2003 May; 38(5): 262-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12686771&dopt=Abstract

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Biochemical profile of stone-forming patients with diabetes mellitus. Author(s): Pak CY, Sakhaee K, Moe O, Preminger GM, Poindexter JR, Peterson RD, Pietrow P, Ekeruo W. Source: Urology. 2003 March; 61(3): 523-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12639639&dopt=Abstract

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Birth weight as a predictor of type 2 diabetes mellitus: the U-shaped curve. Author(s): Pettitt DJ, Jovanovic L. Source: Curr Diab Rep. 2001 August; 1(1): 78-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762961&dopt=Abstract

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Birth weight influence on the subsequent development of gestational diabetes mellitus. Author(s): Savona-Ventura C, Chircop M. Source: Acta Diabetologica. 2003 June; 40(2): 101-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861409&dopt=Abstract

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Blockade of the renin-angiotensin-aldosterone system and renal protection in diabetes mellitus. Author(s): Parving HH. Source: J Renin Angiotensin Aldosterone Syst. 2000 March; 1(1): 30-1. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11967794&dopt=Abstract

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Blood glucose monitoring in gestational diabetes mellitus: 1- versus 2-h blood glucose determinations. Author(s): Leguizamon G, Krupitzki H, Glujovsky D, Olivera Ravasi M, Reece EA. Source: J Matern Fetal Neonatal Med. 2002 December;12(6):384-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12683648&dopt=Abstract

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Blood sugar control among fasting Muslims with type 2 diabetes mellitus in Ilorin. Author(s): Katibi IA, Akande AA, Bojuwoye BJ, Okesina AB. Source: Niger J Med. 2001 July-September; 10(3): 132-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11806014&dopt=Abstract

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Blood-brain barrier integrity is unaltered in human brain cortex with diabetes mellitus. Author(s): Dai J, Vrensen GF, Schlingemann RO. Source: Brain Research. 2002 November 8; 954(2): 311-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12414115&dopt=Abstract

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Body position and blood pressure measurement in patients with diabetes mellitus. Author(s): Netea RT, Elving LD, Lutterman JA, Thien T. Source: Journal of Internal Medicine. 2002 May; 251(5): 393-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11982738&dopt=Abstract

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Bootstrap confidence intervals for costs-of-illness of type 2 diabetes mellitus in Germany. Author(s): Wagenpfeil S, Neiss A, Goertz A, Reitberger U, Stammer H, Spannheimer A, Liebl A. Source: Value in Health : the Journal of the International Society for Pharmacoeconomics and Outcomes Research. 2002 September-October; 5(5): 397-403. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12201857&dopt=Abstract

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Brain natriuretic peptide increases urinary albumin and alpha-1 microglobulin excretion in Type 1 diabetes mellitus. Author(s): McKenna K, Smith D, Moore K, Glen A, Tormey W, Thompson CJ. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2001 December; 18(12): 973-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11903396&dopt=Abstract

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Brainstem auditory evoked potential in diabetes mellitus. Author(s): Padam A, Puri R, Sharma ML. Source: Indian J Physiol Pharmacol. 2002 July; 46(3): 375-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12613405&dopt=Abstract

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Buccodental pathology in patients with insulin-dependent diabetes mellitus: a clinical study. Author(s): Miralles-Jorda L, Silvestre-Donat FJ, Grau Garcia-Moreno DM, HernandezMijares A. Source: Medicina Oral : Organo Oficial De La Sociedad Espanola De Medicina Oral Y De La Academia Iberoamericana De Patologia Y Medicina Bucal. 2002 July-October; 7(4): 298-302. English, Spanish. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12134131&dopt=Abstract

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Bucco-dental problems in patients with Diabetes Mellitus (I) : Index of plaque and dental caries. Author(s): Arrieta-Blanco JJ, Bartolome-Villar B, Jimenez-Martinez E, Saavedra-Vallejo P, Arrieta-Blanco FJ. Source: Medicina Oral : Organo Oficial De La Sociedad Espanola De Medicina Oral Y De La Academia Iberoamericana De Patologia Y Medicina Bucal. 2003 March-April; 8(2): 97-109. English, Spanish. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12618670&dopt=Abstract

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Causes of renal failure in patients with type 2 diabetes mellitus. Author(s): Onuigbo MA. Source: Jama : the Journal of the American Medical Association. 2003 October 8; 290(14): 1855; Author Reply 1855-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14532312&dopt=Abstract

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Causes of renal failure in patients with type 2 diabetes mellitus. Author(s): Kida Y. Source: Jama : the Journal of the American Medical Association. 2003 October 8; 290(14): 1855; Author Reply 1855-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14532311&dopt=Abstract

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Changes in lymphocyte subsets in children with newly diagnosed type 1 diabetes mellitus. Author(s): Kadziela K, Kowalska H, Rymkiewicz-Kluczynska B, Kowalska M, Miszkurka G, Rybczynska J, Wasik M, Pankowska E. Source: J Pediatr Endocrinol Metab. 2003 February; 16(2): 185-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12713255&dopt=Abstract

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Changes of nailfold microcirculation in patients of type II diabetes mellitus with diabetic retinopathy. Author(s): Yi Y, Baoyu W, Shenyuan Y, Liangxiang Z, Hanqing F, Yuantao L. Source: Chinese Medical Sciences Journal = Chung-Kuo I Hsueh K'o Hsueh Tsa Chih / Chinese Academy of Medical Sciences. 1999 December; 14(4): 233-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894899&dopt=Abstract

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Circulating adhesion molecules and carotid artery structural changes in patients with noninsulin-dependent diabetes mellitus. Author(s): Rizzoni D, Muiesan ML, Porteri E, Castellano M, Salvetti M, Monteduro C, De Ciuceis C, Boari G, Valentini U, Cimino A, Sleiman I, Agabiti-Rosei E. Source: Journal of Human Hypertension. 2003 July; 17(7): 463-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821953&dopt=Abstract

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Clustering of cases of type 1 diabetes mellitus occurring 2-4 years after vaccination is consistent with clustering after infections and progression to type 1 diabetes mellitus in autoantibody positive individuals. Author(s): Classen JB, Classen DC. Source: J Pediatr Endocrinol Metab. 2003 April-May; 16(4): 495-508. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12793601&dopt=Abstract

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Combination therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists in the treatment of patients with type 2 diabetes mellitus. Author(s): Rosner MH, Okusa MD. Source: Archives of Internal Medicine. 2003 May 12; 163(9): 1025-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12742799&dopt=Abstract

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Combination treatment with metformin and glibenclamide versus single-drug therapies in type 2 diabetes mellitus: a randomized, double-blind, comparative study. Author(s): Tosi F, Muggeo M, Brun E, Spiazzi G, Perobelli L, Zanolin E, Gori M, Coppini A, Moghetti P. Source: Metabolism: Clinical and Experimental. 2003 July; 52(7): 862-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870162&dopt=Abstract

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Comparison between repaglinide and glimepiride in patients with type 2 diabetes mellitus: a one-year, randomized, double-blind assessment of metabolic parameters and cardiovascular risk factors. Author(s): Derosa G, Mugellini A, Ciccarelli L, Crescenzi G, Fogari R. Source: Clinical Therapeutics. 2003 February; 25(2): 472-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12749508&dopt=Abstract

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Comparison of 30-day outcome, resource use, and coronary artery disease severity in patients with suspected coronary artery disease with and without diabetes mellitus assigned to chest pain units. Author(s): Sanchez CD, Newby LK, Hasselblad V, McNulty SE, Storrow AB, Gibler WB, Garvey JL, Schreiber DH, Tucker JF, Ohman EM. Source: The American Journal of Cardiology. 2003 May 15; 91(10): 1228-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12745106&dopt=Abstract

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Comparison of the prognostic value of RR-interval variability after acute myocardial infarction in patients with versus those without diabetes mellitus. Author(s): Whang W, Bigger JT Jr. Source: The American Journal of Cardiology. 2003 August 1; 92(3): 247-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12888125&dopt=Abstract

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Complications of pediatric and adolescent type 1 diabetes mellitus. Author(s): Brink SJ. Source: Curr Diab Rep. 2001 August; 1(1): 47-55. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762957&dopt=Abstract

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Continuous glucose monitoring during pregnancy complicated by gestational diabetes mellitus. Author(s): Jovanovic L. Source: Curr Diab Rep. 2001 August; 1(1): 82-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762962&dopt=Abstract

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Continuous subcutaneous insulin infusion in patients with diabetes mellitus. Author(s): Schiel R. Source: Therap Apher Dial. 2003 April; 7(2): 232-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918949&dopt=Abstract

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Coping styles and quality of life in patients with non-insulin-dependent diabetes mellitus. Author(s): Coelho R, Amorim I, Prata J. Source: Psychosomatics. 2003 July-August; 44(4): 312-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12832597&dopt=Abstract

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Correlation between severity of coronary artery athesclerosis and duration and severity of diabetes mellitus in type 2 diabetic patients. Author(s): Uddin SN, Siddiqui NI, Begum F, Malik F, Rahman S. Source: Mymensingh Med J. 2003 July; 12(2): 85-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894038&dopt=Abstract

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Cultural orientation and diabetes self-care in low-income African Americans with type 2 diabetes mellitus. Author(s): de Groot M, Welch G, Buckland GT 3rd, Fergus M, Ruggiero L, Chipkin SR. Source: Ethn Dis. 2003 Winter; 13(1): 6-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723006&dopt=Abstract

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Current concepts of cardiovascular diseases in diabetes mellitus. Author(s): Ali Raza J, Movahed A. Source: International Journal of Cardiology. 2003 June; 89(2-3): 123-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767534&dopt=Abstract

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Current management of diabetes mellitus in adults. Risk factor reduction is key. Author(s): Coyle CG. Source: Adv Nurse Pract. 2003 May; 11(5): 32-7; Quiz 38. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12754980&dopt=Abstract

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Current management strategies for coexisting diabetes mellitus and obesity. Author(s): Scheen AJ. Source: Drugs. 2003; 63(12): 1165-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790691&dopt=Abstract

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Dental implants in patients with type 2 diabetes mellitus: a clinical study. Author(s): Peled M, Ardekian L, Tagger-Green N, Gutmacher Z, Machtei EE. Source: Implant Dentistry. 2003; 12(2): 116-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861878&dopt=Abstract

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Diabetes mellitus adversely affects the outcomes of thrombolytic therapy in patients with acute myocardial infarction. Author(s): Tikiz H, Tezcan U, Ileri M, Balbay Y, Atak R, Kutuk E. Source: Angiology. 2003 July-August; 54(4): 449-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12934765&dopt=Abstract

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Diabetes mellitus and acute myocardial infarction: more data supporting a poorer microvasculature reperfusion. Author(s): Moreno R, Hernandez-Antolin R, Alfonso F, Macaya C. Source: American Heart Journal. 2003 August; 146(2): E6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891213&dopt=Abstract

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Diabetes mellitus and heart failure. Author(s): Jagasia D, McNulty PH. Source: Congestive Heart Failure (Greenwich, Conn.). 2003 May-June; 9(3): 133-9; Quiz 140-1. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826771&dopt=Abstract

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Diabetes mellitus and impaired glucose tolerance in patients with schizophrenia. Author(s): Subramaniam M, Chong SA, Pek E. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2003 June; 48(5): 345-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866342&dopt=Abstract

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Diabetes mellitus and the dental pulp. Author(s): Bender IB, Bender AB. Source: Journal of Endodontics. 2003 June; 29(6): 383-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814220&dopt=Abstract

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Diabetes mellitus and viral hepatitis: the unsolved mystery. Author(s): Akbar DH. Source: Acta Diabetologica. 2003 June; 40(2): 77-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861404&dopt=Abstract

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Diabetes mellitus as a modulating factor of endodontic infections. Author(s): Fouad AF. Source: J Dent Educ. 2003 April; 67(4): 459-67. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12749575&dopt=Abstract

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Diabetes mellitus in HIV-infected women. Author(s): Nagy GS. Source: Aids Clin Care. 2003 May; 15(5): 44-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12793350&dopt=Abstract

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Diabetes mellitus is associated with insufficient microvascular reperfusion following revascularization for anterior acute myocardial infarction. Author(s): Kurisu S, Inoue I, Kawagoe T, Ishihara M, Shimatani Y, Nishioka K, Umemura T, Nakamura S, Yoshida M. Source: Intern Med. 2003 July; 42(7): 554-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879945&dopt=Abstract

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Diabetes mellitus may increase risk for idiopathic pulmonary fibrosis. Author(s): Enomoto T, Usuki J, Azuma A, Nakagawa T, Kudoh S. Source: Chest. 2003 June; 123(6): 2007-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796182&dopt=Abstract

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Diabetes mellitus: a 2003 perspective. Author(s): Smith RJ. Source: Medicine and Health, Rhode Island. 2003 April; 86(4): 92-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12751361&dopt=Abstract

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Diagnosis and treatment of heart failure in primary health care among elderly patients with non-insulin-dependent diabetes mellitus, with special reference to use of echocardiography. Author(s): Halling A, Berglund J. Source: Scandinavian Journal of Primary Health Care. 2003 June; 21(2): 96-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12877372&dopt=Abstract

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Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. Author(s): Diamant M, Lamb HJ, Groeneveld Y, Endert EL, Smit JW, Bax JJ, Romijn JA, de Roos A, Radder JK. Source: Journal of the American College of Cardiology. 2003 July 16; 42(2): 328-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875772&dopt=Abstract

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Differences between males and females in the seasonality of birth and month of clinical onset of disease in children with type 1 diabetes mellitus in Ireland. Author(s): Roche EF, Lewy H, Hoey HM, Laron Z. Source: J Pediatr Endocrinol Metab. 2003 June; 16(5): 779-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12880128&dopt=Abstract

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Differential effects of antipsychotic agents on the risk of development of type 2 diabetes mellitus in patients with mood disorders. Author(s): Gianfrancesco F, Grogg A, Mahmoud R, Wang RH, Meletiche D. Source: Clinical Therapeutics. 2003 April; 25(4): 1150-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809963&dopt=Abstract

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Disparities in use of lipid-lowering medications among people with type 2 diabetes mellitus. Author(s): Safford M, Eaton L, Hawley G, Brimacombe M, Rajan M, Li H, Pogach L. Source: Archives of Internal Medicine. 2003 April 28; 163(8): 922-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12719201&dopt=Abstract

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DNA damage and antioxidant defense in peripheral leukocytes of patients with Type I diabetes mellitus. Author(s): Dincer Y, Akcay T, Ilkova H, Alademir Z, Ozbay G. Source: Mutation Research. 2003 June 19; 527(1-2): 49-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12787913&dopt=Abstract

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Drug resistant tuberculosis in diabetes mellitus: a retrospective study from south India. Author(s): Subhash HS, Ashwin I, Mukundan U, Danda D, John G, Cherian AM, Thomas K. Source: Trop Doct. 2003 July; 33(3): 154-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870601&dopt=Abstract

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Dual blockade with candesartan cilexetil and lisinopril in hypertensive patients with diabetes mellitus: rationale and design. Author(s): Andersen NH, Knudsen ST, Poulsen PL, Poulsen SH, Helleberg K, Eiskjaer H, Hansen KW, Bek T, Mogensen CE. Source: J Renin Angiotensin Aldosterone Syst. 2003 June; 4(2): 96-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12806591&dopt=Abstract

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Early diagnosis of gestational diabetes mellitus and prevention of diabetes-related complications. Author(s): Bartha JL, Martinez-Del-Fresno P, Comino-Delgado R. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2003 July 1; 109(1): 41-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818441&dopt=Abstract

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Eating disorders and type 1 diabetes mellitus in adolescence. Author(s): Grylli V, Karwautz A, Hafferl-Gattermayer A, Schober E. Source: Eat Weight Disord. 2003 June; 8(2): 88-94. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12880184&dopt=Abstract

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Economic model of first-line drug strategies to achieve recommended glycaemic control in newly diagnosed type 2 diabetes mellitus. Author(s): Ramsdell JW, Braunstein SN, Stephens JM, Bell CF, Botteman MF, Devine ST. Source: Pharmacoeconomics. 2003; 21(11): 819-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12859222&dopt=Abstract

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Effect of diabetes mellitus on myocardial 18F-FDG SPECT using acipimox for the assessment of myocardial viability. Author(s): Schinkel AF, Bax JJ, Valkema R, Elhendy A, van Domburg RT, Vourvouri EC, Bountioukos MA, Krenning EP, Roelandt JR, Poldermans D. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2003 June; 44(6): 877-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12791813&dopt=Abstract

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Effect of fasting glucose levels on mortality rate in patients with and without diabetes mellitus and coronary artery disease undergoing percutaneous coronary intervention. Author(s): Muhlestein JB, Anderson JL, Horne BD, Lavasani F, Allen Maycock CA, Bair TL, Pearson RR, Carlquist JF; Intermountain Heart Collaborative Study Group. Source: American Heart Journal. 2003 August; 146(2): 351-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891207&dopt=Abstract

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Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Author(s): Schauer PR, Burguera B, Ikramuddin S, Cottam D, Gourash W, Hamad G, Eid GM, Mattar S, Ramanathan R, Barinas-Mitchel E, Rao RH, Kuller L, Kelley D. Source: Annals of Surgery. 2003 October; 238(4): 467-84; Discussion 84-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14530719&dopt=Abstract

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Effect of lipase inhibition on gastric emptying of, and the glycemic and incretin responses to, an oil/aqueous drink in type 2 diabetes mellitus. Author(s): Pilichiewicz A, O'Donovan D, Feinle C, Lei Y, Wishart JM, Bryant L, Meyer JH, Horowitz M, Jones KL. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3829-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915676&dopt=Abstract

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Effect of losartan on microalbuminuria in normotensive patients with type 2 diabetes mellitus. A randomized clinical trial. Author(s): Zandbergen AA, Baggen MG, Lamberts SW, Bootsma AH, de Zeeuw D, Ouwendijk RJ. Source: Annals of Internal Medicine. 2003 July 15; 139(2): 90-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12859158&dopt=Abstract

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Effect of modem transmission of blood glucose data on telephone consultation time, clinic work flow, and patient satisfaction for patients with gestational diabetes mellitus. Author(s): Kruger DF, White K, Galpern A, Mann K, Massirio A, McLellan M, Stevenson J. Source: Journal of the American Academy of Nurse Practitioners. 2003 August; 15(8): 371-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14509102&dopt=Abstract

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Effect of pravastatin on intermediate-density and low-density lipoproteins containing apolipoprotein CIII in patients with diabetes mellitus. Author(s): Lee SJ, Sacks FM. Source: The American Journal of Cardiology. 2003 July 15; 92(2): 121-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860210&dopt=Abstract

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Effect of the microsomal triglyceride transfer protein -493 G/T polymorphism and type 2 diabetes mellitus on LDL subfractions. Author(s): Chen SP, Tan KC, Lam KS. Source: Atherosclerosis. 2003 April; 167(2): 287-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818411&dopt=Abstract

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Effectiveness of diabetes mellitus screening recommendations. Author(s): Dallo FJ, Weller SC. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 September 2; 100(18): 10574-9. Epub 2003 August 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925739&dopt=Abstract

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Effects of glucagon-like peptide-1 and feeding on gastric volumes in diabetes mellitus with cardio-vagal dysfunction. Author(s): Delgado-Aros S, Vella A, Camilleri M, Low PA, Burton DD, Thomforde GM, Stephens D. Source: Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society. 2003 August; 15(4): 435-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846732&dopt=Abstract

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Effects of policosanol and lovastatin on lipid profile and lipid peroxidation in patients with dyslipidemia associated with type 2 diabetes mellitus. Author(s): Castano G, Menendez R, Mas R, Amor A, Fernandez JL, Gonzalez RL, Lezcay M, Alvarez E. Source: Int J Clin Pharmacol Res. 2002; 22(3-4): 89-99. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12837046&dopt=Abstract

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Efficacy and safety of a combination of metformin and rosiglitaone in patients with type 2 diabetes mellitus--a postmarketing study. Author(s): Ballary C, Desai A. Source: J Indian Med Assoc. 2003 February; 101(2): 113-4, 123. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841496&dopt=Abstract

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Elevated concentrations of C-reactive protein in subjects with type 2 diabetes mellitus are moderately influenced by glycemic control. Author(s): Rodriguez-Moran M, Guerrero-Romero F. Source: J Endocrinol Invest. 2003 March; 26(3): 216-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809171&dopt=Abstract

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Enhanced lipid peroxidation and platelet activation in the early phase of type 1 diabetes mellitus: role of interleukin-6 and disease duration. Author(s): Davi G, Chiarelli F, Santilli F, Pomilio M, Vigneri S, Falco A, Basili S, Ciabattoni G, Patrono C. Source: Circulation. 2003 July 1; 107(25): 3199-203. Epub 2003 June 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810609&dopt=Abstract

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Essential diabetes mellitus care principles. Arkansas Wellness Coalition. Author(s): Arkansas Wellness Coalition. Source: J Ark Med Soc. 2003 August; 100(2): 63. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12971083&dopt=Abstract

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Estimates of direct medical costs for microvascular and macrovascular complications resulting from type 2 diabetes mellitus in the United States in 2000. Author(s): O'Brien JA, Patrick AR, Caro J. Source: Clinical Therapeutics. 2003 March; 25(3): 1017-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12852716&dopt=Abstract

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Experiences and guidelines for footcare practices of patients with diabetes mellitus. Author(s): Matwa P, Chabeli MM, Muller M, Levitt NS; Working Group of the National Diabetes Advisory Board; European IDDM Policy Group. Source: Curationis. 2003 May; 26(1): 11-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14509114&dopt=Abstract

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Factors affecting perinatal morbidity and mortality in pregnancies complicated by diabetes mellitus in Sudan. Author(s): Abdelgadir M, Elbagir M, Eltom A, Eltom M, Berne C. Source: Diabetes Research and Clinical Practice. 2003 April; 60(1): 41-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12639764&dopt=Abstract

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Factors associated with the development of diabetes mellitus in HIV-infected patients on antiretroviral therapy: a case-control study. Author(s): Palacios R, Santos J, Ruiz J, Gonzalez M, Marquez M. Source: Aids (London, England). 2003 April 11; 17(6): 933-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12660547&dopt=Abstract

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Factors influencing remission phase in children with type 1 diabetes mellitus. Author(s): Buyukgebiz A, Cemeroglu AP, Bober E, Mohn A, Chiarelli F. Source: J Pediatr Endocrinol Metab. 2001 November-December; 14(9): 1585-96. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11795651&dopt=Abstract

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Family history and risk of type 1 diabetes mellitus. Author(s): Sipetic S, Vlajinac H, Kocev N, Marinkovic J, Radmanovic S, Denic L. Source: Acta Diabetologica. 2002 September; 39(3): 111-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12357294&dopt=Abstract

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Fatal malignant hyperthermia-like syndrome with rhabdomyolysis complicating the presentation of diabetes mellitus in adolescent males. Author(s): Hollander AS, Olney RC, Blackett PR, Marshall BA. Source: Pediatrics. 2003 June; 111(6 Pt 1): 1447-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777570&dopt=Abstract

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Fatty acid abnormalities in chronic pancreatitis: effect of concomitant diabetes mellitus. Author(s): Quilliot D, Walters E, Bohme P, Lacroix B, Bonte JP, Fruchart JC, Drouin P, Duriez P, Ziegler O. Source: European Journal of Clinical Nutrition. 2003 March; 57(3): 496-503. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627189&dopt=Abstract

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Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Author(s): Kelley DE, McKolanis TM, Hegazi RA, Kuller LH, Kalhan SC. Source: American Journal of Physiology. Endocrinology and Metabolism. 2003 October; 285(4): E906-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959938&dopt=Abstract

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Fetal surveillance in pregnancy complicated by diabetes mellitus: is it necessary? Author(s): Landon MB, Vickers S. Source: J Matern Fetal Neonatal Med. 2002 December;12(6):413-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12683653&dopt=Abstract

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Fibrinolysis defect in long-term hemodialysis patients with type 2 diabetes mellitus and its relation to metabolic disorders. Author(s): Opatrny K Jr, Zemanova P, Mares J, Vit L, Opatrna S, Sefrna F, Hejda V, Tomsu M, Eiselt J, Massry SG. Source: American Journal of Nephrology. 2002 September-December; 22(5-6): 429-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12381940&dopt=Abstract

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First-trimester sex hormone binding globulin and subsequent gestational diabetes mellitus. Author(s): Thadhani R, Wolf M, Hsu-Blatman K, Sandler L, Nathan D, Ecker JL. Source: American Journal of Obstetrics and Gynecology. 2003 July; 189(1): 171-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861158&dopt=Abstract

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Fluvastatin prevents development of arterial stiffness in haemodialysis patients with type 2 diabetes mellitus. Author(s): Ichihara A, Hayashi M, Ryuzaki M, Handa M, Furukawa T, Saruta T. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2002 August; 17(8): 1513-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12147804&dopt=Abstract

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Follow up of 318 cases of diabetes mellitus. Author(s): Patel JC, Lingan V, Deshpande PS. Source: Indian Journal of Medical Sciences. 2003 June; 57(6): 259-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14510344&dopt=Abstract

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Food selection and eating patterns: themes found among people with type 2 diabetes mellitus. Author(s): Savoca M, Miller C. Source: Journal of Nutrition Education. 2001 July-August; 33(4): 224-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11953244&dopt=Abstract

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Foot dimensions of elderly people with and without diabetes mellitus - a data basis for shoe design. Author(s): Chantelau E, Gede A. Source: Gerontology. 2002 July-August; 48(4): 241-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12053114&dopt=Abstract

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For the patient. Customs and beliefs can affect your health. Cultural orientation and diabetes self-care in low-income African-Americans with type 2 diabetes mellitus. Author(s): de Groot M. Source: Ethn Dis. 2003 Winter; 13(1): 145. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723022&dopt=Abstract

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Frequency distribution of apoprotein(a) isoforms in patients with diabetes mellitus and healthy subjects. Author(s): Labudovic DD, Toseska KN, Alabakovska SB, Dimitrovski C, Jurhar M, Isjanovska R, Spiroski M, Todorova BB. Source: Croatian Medical Journal. 2003 August; 44(4): 435-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12950147&dopt=Abstract

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Frequency of coeliac disease in Hungarian children with type 1 diabetes mellitus. Author(s): Arato A, Korner A, Veres G, Dezsofi A, Ujpal I, Madacsy L. Source: European Journal of Pediatrics. 2003 January; 162(1): 1-5. Epub 2002 November 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12486500&dopt=Abstract

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Fulminant diabetes mellitus associated with pregnancy: case reports and literature review. Author(s): Inagaki T, Nishii Y, Suzuki N, Suzuki S, Koizumi Y, Aizawa T, Hashizume K. Source: Endocrine Journal. 2002 June; 49(3): 319-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12201215&dopt=Abstract

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Functional status and health outcomes in older americans with diabetes mellitus. Author(s): Blaum CS, Ofstedal MB, Langa KM, Wray LA. Source: Journal of the American Geriatrics Society. 2003 June; 51(6): 745-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757559&dopt=Abstract

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Further reports on diabetes mellitus after the exstirpation of the pancreas. Author(s): Minkowski O, Bretzel RG. Source: Journal of Molecular Medicine (Berlin, Germany). 2002 January; 80(1): 3; Discussion 3-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11862318&dopt=Abstract

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Gene- and cell-based therapeutics for type I diabetes mellitus. Author(s): Bottino R, Lemarchand P, Trucco M, Giannoukakis N. Source: Gene Therapy. 2003 May; 10(10): 875-89. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732873&dopt=Abstract

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Gene and cell-based therapy for diabetes mellitus: endocrine gene therapeutics. Author(s): Sasaki T, Fujimoto K, Sakai K, Nemoto M, Nakai N, Tajima N. Source: Endocrine Pathology. 2003 Summer; 14(2): 141-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858004&dopt=Abstract

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Genes with linkage or association with type 2 diabetes mellitus. Author(s): Bastian W. Source: J Pediatr Endocrinol Metab. 2002 April; 15 Suppl 1: 471-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12017219&dopt=Abstract

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Gestational diabetes mellitus and glucose intolerance among Mexican pregnant adolescents. Author(s): Ramirez-Torres MA, Rodriguez-Pezino J, Zambrana-Castaneda M, LiraPlascencia J, Parra A. Source: J Pediatr Endocrinol Metab. 2003 March; 16(3): 401-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12705365&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14551018&dopt=Abstract

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Gestational diabetes mellitus. Author(s): American Diabetes Association. Source: Diabetes Care. 2000 January; 23 Suppl 1: S77-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12017686&dopt=Abstract

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Gestational diabetes mellitus: accuracy of Midwives Data Collection. Author(s): Moses RG, Webb AJ, Comber CD. Source: The Medical Journal of Australia. 2003 August 18; 179(4): 218-9; Discussion 219. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12914515&dopt=Abstract

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Gestational diabetes mellitus: is a diagnosis associated with an increase in maternal anxiety and stress in the short and intermediate term? Author(s): Daniells S, Grenyer BF, Davis WS, Coleman KJ, Burgess JA, Moses RG. Source: Diabetes Care. 2003 February; 26(2): 385-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547867&dopt=Abstract

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Glibenclamide vs gliclazide in reducing oxidative stress in patients of noninsulin dependent diabetes mellitus--a double blind randomized study. Author(s): Chugh SN, Dhawan R, Kishore K, Sharma A, Chugh K. Source: J Assoc Physicians India. 2001 August; 49: 803-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11837468&dopt=Abstract

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Glimepiride in type 2 diabetes mellitus Thai patients. Author(s): Deerochanawong C, Chandraprasert S, Suthijumroon A, Vichayanrat A, Himathongkam T, Nitiyanant W, Benjasuratawong Y, Suwanwalaikorn S, Sarinnapakorn V, Vongterapak S. Source: J Med Assoc Thai. 2001 September; 84(9): 1221-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11800292&dopt=Abstract

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Glimepiride in type 2 diabetes mellitus: a review of the worldwide therapeutic experience. Author(s): Massi-Benedetti M. Source: Clinical Therapeutics. 2003 March; 25(3): 799-816. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12852703&dopt=Abstract

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Glucose homoeostasis in young adults without diagnosis of diabetes mellitus. Author(s): von Eyben FE, Mouridsen E, Holm J, Montvilas P, Dimcevski G. Source: Lancet. 2002 December 14; 360(9349): 1978-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12493296&dopt=Abstract

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Glucose homoeostatis in young adults without diagnosis of diabetes mellitus. Author(s): Kowalska I, Kinalska I, Telejko B. Source: Lancet. 2002 December 14; 360(9349): 1979. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12493297&dopt=Abstract

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Glucose screening and the risk of complications in Type 2 diabetes mellitus. Author(s): Schellhase KG, Koepsell TD, Weiss NS, Wagner EH, Reiber GE. Source: Journal of Clinical Epidemiology. 2003 January; 56(1): 75-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12589873&dopt=Abstract

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Glucotoxicity and beta-cell failure in type 2 diabetes mellitus. Author(s): Kaiser N, Leibowitz G, Nesher R. Source: J Pediatr Endocrinol Metab. 2003 January; 16(1): 5-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12585335&dopt=Abstract

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Gluten sensitivity in a subset of children with insulin dependent diabetes mellitus. Author(s): Troncone R, Franzese A, Mazzarella G, Paparo F, Auricchio R, Coto I, Mayer M, Greco L. Source: The American Journal of Gastroenterology. 2003 March; 98(3): 590-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12650792&dopt=Abstract

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Glycemic control in patients with type 2 diabetes mellitus switched from twice-daily immediate-release metformin to a once-daily extended-release formulation. Author(s): Fujioka K, Pans M, Joyal S. Source: Clinical Therapeutics. 2003 February; 25(2): 515-29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12749511&dopt=Abstract

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Glycemic control with different premixed insulin in Taiwanese people with type two diabetes mellitus. Author(s): Su CC, Chen HS, Lin HD. Source: J Chin Med Assoc. 2003 March; 66(3): 155-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12779035&dopt=Abstract

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Guidelines for improving the care of the older person with diabetes mellitus. Author(s): Brown AF, Mangione CM, Saliba D, Sarkisian CA; California Healthcare Foundation/American Geriatrics Society Panel on Improving Care for Elders with Diabetes. Source: Journal of the American Geriatrics Society. 2003 May; 51(5 Suppl Guidelines): S265-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694461&dopt=Abstract

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Gut peptides and type 2 diabetes mellitus treatment. Author(s): Ahren B. Source: Curr Diab Rep. 2003 October; 3(5): 365-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12975025&dopt=Abstract

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Healthcare use by veterans treated for diabetes mellitus in the Veterans Affairs medical care system. Author(s): Ashton CM, Septimus J, Petersen NJ, Souchek J, Menke TJ, Collins TC, Wray NP. Source: Am J Manag Care. 2003 February; 9(2): 145-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12597602&dopt=Abstract

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Helicobacter pylori, gastrointestinal symptoms, and metabolic control in young type 1 diabetes mellitus patients. Author(s): Candelli M, Rigante D, Marietti G, Nista EC, Crea F, Bartolozzi F, Schiavino A, Pignataro G, Silveri NG, Gasbarrini G, Gasbarrini A. Source: Pediatrics. 2003 April; 111(4 Pt 1): 800-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12671115&dopt=Abstract

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Hepatic steatosis and type 2 diabetes mellitus. Author(s): Clark JM, Diehl AM. Source: Curr Diab Rep. 2002 June; 2(3): 210-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12643175&dopt=Abstract

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Hidden diabetes in the UK: use of capture-recapture methods to estimate total prevalence of diabetes mellitus in an urban population. Author(s): Gill GV, Ismail AA, Beeching NJ, Macfarlane SB, Bellis MA. Source: Journal of the Royal Society of Medicine. 2003 July; 96(7): 328-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12835444&dopt=Abstract

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High incidence of Type 2 diabetes mellitus in South African Indians: a 10-year follow-up study. Author(s): Motala AA, Pirie FJ, Gouws E, Amod A, Omar MA. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 January; 20(1): 23-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12519316&dopt=Abstract

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Higher drive for thinness in adolescent males with insulin-dependent diabetes mellitus compared with healthy controls. Author(s): Svensson M, Engstrom I, Aman J. Source: Acta Paediatrica (Oslo, Norway : 1992). 2003; 92(1): 114-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12650311&dopt=Abstract

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Higher frequency of paronychia (nail bed infections) in pediatric and adolescent patients with type 1 diabetes mellitus than in non-diabetic peers. Author(s): Kapellen TM, Galler A, Kiess W. Source: J Pediatr Endocrinol Metab. 2003 June; 16(5): 751-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12880125&dopt=Abstract

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HLA-DRB1, DQB1, and DQA1 allele profile in Brazilian patients with type 1 diabetes mellitus. Author(s): Fernandes AP, Louzada-Junior P, Foss MC, Donadi EA. Source: Annals of the New York Academy of Sciences. 2002 April; 958: 305-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12021129&dopt=Abstract

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HLA-DRw3 in juvenile onset diabetes mellitus in Chinese. Author(s): Maeda H, Takeuchi F, Juji T, Akanuma Y, Kasuga M, Lee YS, Kosaka K, Tsai SH. Source: Tissue Antigens. 1980 February; 15(2): 173-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12735317&dopt=Abstract

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Hormonal influences: effects of diabetes mellitus and endogenous female sex steroid hormones on the periodontium. Author(s): Mealey BL, Moritz AJ. Source: Periodontology 2000. 2003; 32: 59-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12756034&dopt=Abstract

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Hormone replacement therapy and risk of acute myocardial infarction in postmenopausal women with diabetes mellitus. Author(s): Gami AS, Wright RS, Ballman KV, Kopecky SL, Hayes SN. Source: The American Journal of Cardiology. 2003 May 15; 91(10): 1275-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12745121&dopt=Abstract

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Hospital admission guidelines for diabetes mellitus. Author(s): American Diabetes Association. Source: Diabetes Care. 2000 January; 23 Suppl 1: S83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12017688&dopt=Abstract

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Host and environmental factors defining the epidemiology of type 1 diabetes mellitus in a group of Lebanese children and young adults. Author(s): Zalloua PA, Terwedow H, Shbaklo H, Halaby G, Xu X, Azar ST. Source: J Pediatr Endocrinol Metab. 2003 June; 16(5): 759-69. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12880126&dopt=Abstract

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How beneficial are thiazolidinediones for diabetes mellitus? Author(s): Culhane NS, Graves R. Source: The Journal of Family Practice. 2002 May; 51(5): 424. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12019048&dopt=Abstract

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Humalog Mix25 improves 24-hour plasma glucose profiles compared with the human insulin mixture 30/70 in patients with type 2 diabetes mellitus. Author(s): Herz M, Arora V, Campaigne BN, Scholtz HE, Potgieter MA, Mollentze W. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 2003 March; 93(3): 219-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12768948&dopt=Abstract

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Hyperhomocysteinemia and impaired vasomotor function in type 2 diabetes mellitus. Author(s): Tan KC, O K, Chow WS, Ai VH, Siow YL, Lam KS. Source: European Journal of Clinical Investigation. 2002 May; 32(5): 328-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12027872&dopt=Abstract

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Hyperhomocysteinemia and its relationship to cardiovascular disease in ESRD: influence of hypoalbuminemia, malnutrition, inflammation, and diabetes mellitus. Author(s): Suliman ME, Stenvinkel P, Barany P, Heimburger O, Anderstam B, Lindholm B. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2003 March; 41(3 Suppl 1): S89-95. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12612961&dopt=Abstract

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Hyperlipidemia in children with type 2 diabetes mellitus. Author(s): Taha D. Source: J Pediatr Endocrinol Metab. 2002 April; 15 Suppl 1: 505-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12017224&dopt=Abstract

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Hypertension and diabetes mellitus. Author(s): Jayakumar RV. Source: J Indian Med Assoc. 2003 April; 101(4): 254-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12964645&dopt=Abstract

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Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus. Author(s): Yatagai T, Nagasaka S, Taniguchi A, Fukushima M, Nakamura T, Kuroe A, Nakai Y, Ishibashi S. Source: Metabolism: Clinical and Experimental. 2003 October; 52(10): 1274-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14564678&dopt=Abstract

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Impact of antidiabetic medications on physical and cognitive functioning of older Mexican Americans with diabetes mellitus: a population-based cohort study. Author(s): Wu JH, Haan MN, Liang J, Ghosh D, Gonzalez HM, Herman WH. Source: Annals of Epidemiology. 2003 May; 13(5): 369-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821276&dopt=Abstract

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Impaired acute collateral recruitment as a possible mechanism for increased cardiac adverse events in patients with diabetes mellitus. Author(s): Werner GS, Richartz BM, Heinke S, Ferrari M, Figulla HR. Source: European Heart Journal. 2003 June; 24(12): 1134-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804928&dopt=Abstract

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Impaired cardiovagal and vasomotor responses to baroreceptor stimulation in type II diabetes mellitus. Author(s): Sanya EO, Brown CM, Dutsch M, Zikeli U, Neundorfer B, Hilz MJ. Source: European Journal of Clinical Investigation. 2003 July; 33(7): 582-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814395&dopt=Abstract

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Impaired gastric emptying and altered intragastric meal distribution in diabetes mellitus related to autonomic neuropathy? Author(s): Stacher G, Lenglinger J, Bergmann H, Schneider C, Brannath W, Festa A, Meghdadi S, Stacher-Janotta G. Source: Digestive Diseases and Sciences. 2003 June; 48(6): 1027-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12822859&dopt=Abstract

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Impaired taste acuity in patients with diabetes mellitus on maintenance hemodialysis. Author(s): Matsuo S, Nakamoto M, Nishihara G, Yasunaga C, Yanagida T, Matsuo K, Sakemi T. Source: Nephron. Clinical Practice [electronic Resource]. 2003; 94(2): C46-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845237&dopt=Abstract

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Improved patient survival in recipients of simultaneous pancreas-kidney transplant compared with kidney transplant alone in patients with type 1 diabetes mellitus and end-stage renal disease. Author(s): Mohan P, Safi K, Little DM, Donohoe J, Conlon P, Walshe JJ, O'Kelly P, Thompson CJ, Hickey DP. Source: The British Journal of Surgery. 2003 September; 90(9): 1137-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12945083&dopt=Abstract

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Improved survival in patients with type 1 diabetes mellitus after renal transplantation compared with hemodialysis: a case-control study. Author(s): Brunkhorst R, Lufft V, Dannenberg B, Kliem V, Tusch G, Pichlmayr R. Source: Transplantation. 2003 July 15; 76(1): 115-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865796&dopt=Abstract

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Improving glycaemic control in patients with Type 2 diabetes mellitus without insulin therapy. Author(s): Goudswaard AN, Stolk RP, de Valk HW, Rutten GE. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 July; 20(7): 540-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823234&dopt=Abstract

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Inaccurate glycosylated hemoglobin A1C measurements in human immunodeficiency virus-positive patients with diabetes mellitus. Author(s): Polgreen PM, Putz D, Stapleton JT. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 August 15; 37(4): E53-6. Epub 2003 July 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12905153&dopt=Abstract

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Income-related differences in the use of evidence-based therapies in older persons with diabetes mellitus in for-profit managed care. Author(s): Brown AF, Gross AG, Gutierrez PR, Jiang L, Shapiro MF, Mangione CM. Source: Journal of the American Geriatrics Society. 2003 May; 51(5): 665-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12752842&dopt=Abstract

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Increased incidence of cytomegalovirus but not Chlamydia pneumoniae in atherosclerotic lesions of arteries of lower extremities from patients with diabetes mellitus undergoing amputation. Author(s): Lin TM, Chen WJ, Chen HY, Wang PW, Eng HL. Source: Journal of Clinical Pathology. 2003 June; 56(6): 429-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783969&dopt=Abstract

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Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. Author(s): Vilsboll T, Krarup T, Sonne J, Madsbad S, Volund A, Juul AG, Holst JJ. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 June; 88(6): 2706-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788877&dopt=Abstract

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Inflammation and emerging risk factors in diabetes mellitus and atherosclerosis. Author(s): Theuma P, Fonseca VA. Source: Curr Diab Rep. 2003 June; 3(3): 248-54. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762974&dopt=Abstract

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Influence of glucose control, lipoproteins, and haemostasis function on brachial endothelial reactivity and carotid intima-media area, stiffness and diameter in Type 1 diabetes mellitus patients. Author(s): Johansson J, Reichard P, Jensen-Urstad K, Rosfors S, Jensen-Urstad M. Source: European Journal of Clinical Investigation. 2003 June; 33(6): 472-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12795643&dopt=Abstract

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Inhaled insulin in diabetes mellitus. Author(s): Royle P, Waugh N, McAuley L, McIntyre L, Thomas S. Source: Cochrane Database Syst Rev. 2003; (3): Cd003890. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917994&dopt=Abstract

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Insulin glargine: a new once-daily basal insulin for the management of type 1 and type 2 diabetes mellitus. Author(s): Lam S. Source: Heart Disease. 2003 May-June; 5(3): 231-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783637&dopt=Abstract

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Insulin lispro: a potential role in preventing nocturnal hypoglycaemia in young children with diabetes mellitus. Author(s): Ford-Adams ME, Murphy NP, Moore EJ, Edge JA, Ong KL, Watts AP, Acerini CL, Dunger DB. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 August; 20(8): 656-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873294&dopt=Abstract

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Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. Author(s): Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, Backlund JY, O'Leary DH, Genuth S; Diabetes Control and Complications Trial; Epidemiology of Diabetes Interventions and Complications Research Group. Source: The New England Journal of Medicine. 2003 June 5; 348(23): 2294-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788993&dopt=Abstract

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Introduction: New insight into understanding the relation of type 2 diabetes mellitus, insulin resistance, and cardiovascular disease. Author(s): Hsueh WA. Source: The American Journal of Cardiology. 2003 August 18; 92(4A): 1J-2J. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957320&dopt=Abstract

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Ischaemia-reperfusion studies and diabetes mellitus. Author(s): Canbaz S, Duran E. Source: British Journal of Anaesthesia. 2003 July; 91(1): 158; Author Reply 158-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821579&dopt=Abstract

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Ketosis and the generation of oxygen radicals in diabetes mellitus. Author(s): Jain SK, Kannan K. Source: Advances in Experimental Medicine and Biology. 2001; 498: 221-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11900372&dopt=Abstract

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Kidney function and glomerulopathy over 8 years in young patients with Type I (insulin-dependent) diabetes mellitus and microalbuminuria. Author(s): Bangstad HJ, Osterby R, Rudberg S, Hartmann A, Brabrand K, Hanssen KF. Source: Diabetologia. 2002 February; 45(2): 253-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11935157&dopt=Abstract

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Lack of association between serum paraoxonase 1 activities and increased oxidized low-density lipoprotein levels in impaired glucose tolerance and newly diagnosed diabetes mellitus. Author(s): Kopprasch S, Pietzsch J, Kuhlisch E, Graessler J. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 April; 88(4): 1711-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12679462&dopt=Abstract

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Lack of gender difference in acetazolamide-induced cerebral vasomotor reactivity in patients suffering from type-1 diabetes mellitus. Author(s): Fulesdi B, Limburg M, Olah L, Bereczki D, Csiba L, Kollar J. Source: Acta Diabetologica. 2001; 38(3): 107-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11827430&dopt=Abstract

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Laser correlation spectroscopy as an effective method of detection of DNA-containing and other macromolecular complexes in blood serum of patients with diabetes mellitus. Author(s): Kovalev IE, Karganov MY, Rumyantseva EI, Kovaleva OI. Source: Doklady. Biochemistry and Biophysics. 2002 September-October; 386: 281-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474767&dopt=Abstract

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Lessons learned from landmark trials of type 2 diabetes mellitus and potential applications to clinical practice. Author(s): Drexler AJ. Source: Postgraduate Medicine. 2003 May; Spec No: 15-26. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12785128&dopt=Abstract

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Lessons learned from urban Latinas with type 2 diabetes mellitus. Author(s): Adams CR. Source: Journal of Transcultural Nursing : Official Journal of the Transcultural Nursing Society / Transcultural Nursing Society. 2003 July; 14(3): 255-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861928&dopt=Abstract

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Lifetime risk for diabetes mellitus in the United States. Author(s): Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Source: Jama : the Journal of the American Medical Association. 2003 October 8; 290(14): 1884-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14532317&dopt=Abstract

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Lipid and protein oxidation contribute to a prothrombotic state in patients with type 2 diabetes mellitus. Author(s): De Cristofaro R, Rocca B, Vitacolonna E, Falco A, Marchesani P, Ciabattoni G, Landolfi R, Patrono C, Davi G. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 February; 1(2): 250-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871497&dopt=Abstract

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Lipodystrophy, insulin resistance, diabetes mellitus, dyslipidemia, and cardiovascular disease in human immunodeficiency virus infection. Author(s): Tanwani LK, Mokshagundam SL. Source: Southern Medical Journal. 2003 February; 96(2): 180-8; Quiz 189. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12630645&dopt=Abstract

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Lipoprotein (a) and glycaemic control in Pakistani subjects with diabetes mellitus. Author(s): Habib SS, Aslam M, Naveed AK, Sattar A. Source: J Pak Med Assoc. 2003 February; 53(2): 54-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12705484&dopt=Abstract

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Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia. Author(s): Ayyobi AF, Brunzell JD. Source: The American Journal of Cardiology. 2003 August 18; 92(4A): 27J-33J. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957324&dopt=Abstract

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Lispro insulin and metformin versus other combination in the diabetes mellitus type 2 management after secondary oral antidiabetic drug failure. Author(s): Kokic S, Bukovic D, Radman M, Capkun V, Gabric N, Lesko V, Karelovic D, Stanceric T. Source: Coll Antropol. 2003 June; 27(1): 181-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974145&dopt=Abstract

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Localization, cDNA sequence and genomic organization of the rat seipin gene (Bscl2) and sequence analysis in inbred rat models of Type 2 diabetes mellitus. Author(s): Kaisaki PJ, Sebag-Montefiore LM, Brown JH, Magre J, Lathrop M, Capeau J, Gauguier D. Source: Cytogenetic and Genome Research. 2002; 98(1): 71-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12584444&dopt=Abstract

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Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure. Author(s): Reddy KS, Stablein D, Taranto S, Stratta RJ, Johnston TD, Waid TH, McKeown JW, Lucas BA, Ranjan D. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2003 February; 41(2): 464-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12552511&dopt=Abstract

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Loss of temporal lobe beta power in young adults with type 1 diabetes mellitus. Author(s): Brismar T, Hyllienmark L, Ekberg K, Johansson BL. Source: Neuroreport. 2002 December 20; 13(18): 2469-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499851&dopt=Abstract

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Low plasma aldosterone despite normal plasma renin activity in uncomplicated type 1 diabetes mellitus: effects of RAAS stimulation. Author(s): Luik PT, Kerstens MN, Hoogenberg K, Navis GJ, Dullaart RP. Source: European Journal of Clinical Investigation. 2003 September; 33(9): 787-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925038&dopt=Abstract

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Malignant glucagonoma of the pancreas diagnoses through anemia and diabetes mellitus. Author(s): Koike N, Hatori T, Imaizumi T, Harada N, Fukuda A, Takasaki K, Iwamoto Y. Source: Journal of Hepato-Biliary-Pancreatic Surgery. 2003; 10(1): 101-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918465&dopt=Abstract

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Management of diabetes mellitus and insulin resistance in patients with cardiovascular disease. Author(s): Fonseca VA. Source: The American Journal of Cardiology. 2003 August 18; 92(4A): 50J-60J. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957327&dopt=Abstract

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Management of diabetes mellitus complicating pregnancy. Author(s): Gabbe SG, Graves CR. Source: Obstetrics and Gynecology. 2003 October; 102(4): 857-68. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14551019&dopt=Abstract

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Medical pearl: Scleroderma-like skin changes in patients with diabetes mellitus. Author(s): Yosipovitch G, Loh KC, Hock OB. Source: Journal of the American Academy of Dermatology. 2003 July; 49(1): 109-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12833019&dopt=Abstract

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Microalbuminuria in controlled type 2 diabetes mellitus patients. Author(s): Adedapo KS, Abbiyesuku FM, Adedapo AD, Osotimehin BO. Source: Afr J Med Med Sci. 2001 December; 30(4): 323-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14510112&dopt=Abstract

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Micro-albuminuria in diabetes mellitus--significance and screening. Author(s): Motala AA. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 1998 March; 88(3 Endocrinology): 365-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12886698&dopt=Abstract

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Microvascular basement membranes in diabetes mellitus. Author(s): Tsilibary EC. Source: The Journal of Pathology. 2003 July; 200(4): 537-46. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845621&dopt=Abstract

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Mitochondrial genome and susceptibility to diabetes mellitus. Author(s): Sudoyo H, Suryadi H, Sitorus N, Soegondo S, Pranoto A, Marzuki S. Source: Advances in Experimental Medicine and Biology. 2003; 531: 19-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916778&dopt=Abstract

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Mononeuritis multiplex in diabetes mellitus: evidence for underlying immune pathogenesis. Author(s): Kelkar P, Parry GJ. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 June; 74(6): 803-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12754358&dopt=Abstract

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Multicenter, randomized, double-masked, parallel-group assessment of simultaneous glipizide/metformin as second-line pharmacologic treatment for patients with type 2 diabetes mellitus that is inadequately controlled by a sulfonylurea. Author(s): Goldstein BJ, Pans M, Rubin CJ. Source: Clinical Therapeutics. 2003 March; 25(3): 890-903. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12852706&dopt=Abstract

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National surveillance for type 2 diabetes mellitus in Taiwanese children. Author(s): Wei JN, Sung FC, Lin CC, Lin RS, Chiang CC, Chuang LM. Source: Jama : the Journal of the American Medical Association. 2003 September 10; 290(10): 1345-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12966126&dopt=Abstract

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Naturally occurring antioxidant vitamin levels in patients with type-II diabetes mellitus. Author(s): Ahmad M, Khan MA, Khan AS. Source: J Ayub Med Coll Abbottabad. 2003 January-March; 15(1): 54-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870320&dopt=Abstract

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Negative effects of chronic inflammatory periodontal disease on diabetes mellitus. Author(s): Nishimura F, Kono T, Fujimoto C, Iwamoto Y, Murayama Y. Source: J Int Acad Periodontol. 2000 April; 2(2): 49-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12666961&dopt=Abstract

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Nephropathy in patients with recently diagnosed type 2 diabetes mellitus in black Africans. Author(s): Wanjohi FW, Otieno FC, Ogola EN, Amayo EO. Source: East Afr Med J. 2002 August; 79(8): 399-404. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12638839&dopt=Abstract

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Neuroadrenergic denervation of the lung in type I diabetes mellitus complicated by autonomic neuropathy. Author(s): Antonelli Incalzi R, Fuso L, Giordano A, Pitocco D, Maiolo C, Calcagni ML, Ghirlanda G. Source: Chest. 2002 February; 121(2): 443-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11834655&dopt=Abstract

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NEUROD polymorphism Ala45Thr is associated with Type 1 diabetes mellitus in Czech children. Author(s): Cinek O, Drevinek P, Sumnik Z, Bendlova B, Sedlakova P, Kolouskova S, Snajderova M, Vavrinec J. Source: Diabetes Research and Clinical Practice. 2003 April; 60(1): 49-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12639765&dopt=Abstract

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New solutions for type 2 diabetes mellitus: the role of pioglitazone. Author(s): Grossman LD. Source: Pharmacoeconomics. 2002; 20 Suppl 1: 1-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12036379&dopt=Abstract

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Newborn screening for high-risk human leukocyte antigen markers associated with insulin-dependent diabetes mellitus: the ABIS study. Author(s): Berzina L, Shtauvere-Brameus A, Ludvigsson J, Sanjeevi CB. Source: Annals of the New York Academy of Sciences. 2002 April; 958: 312-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12021131&dopt=Abstract

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Newly diagnosed type 2 diabetes mellitus. Author(s): Smith SM. Source: Bmj (Clinical Research Ed.). 2003 June 21; 326(7403): 1371. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816825&dopt=Abstract

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Nutrition recommendations and principles for people with diabetes mellitus. Author(s): American Diabetes Association. Source: Diabetes Care. 2000 January; 23 Suppl 1: S43-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12017676&dopt=Abstract

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Occurrence of gestational diabetes mellitus and the value of different screening indicators for the oral glucose tolerance test. Author(s): Ostlund I, Hanson U. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 February; 82(2): 103-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12648169&dopt=Abstract

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Ocular factors relevant to keratoepitheliopathy in glaucoma patients with and without diabetes mellitus. Author(s): Inoue K, Okugawa K, Kato S, Inoue Y, Oshika T, Amano S. Source: Japanese Journal of Ophthalmology. 2003 May-June; 47(3): 287-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12782166&dopt=Abstract

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Open ankle fractures in patients with diabetes mellitus. Author(s): White CB, Turner NS, Lee GC, Haidukewych GJ. Source: Clinical Orthopaedics and Related Research. 2003 September; (414): 37-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12966274&dopt=Abstract

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Optimizing target-organ protection in patients with diabetes mellitus: angiotensinconverting enzyme inhibitors or angiotensin receptor blockers? Author(s): Lu WX, Lakkis J, Weir MR. Source: Current Hypertension Reports. 2003 June; 5(3): 192-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724050&dopt=Abstract

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Optimizing treatment for diabetes mellitus induced erectile dysfunction. Author(s): Costabile RA. Source: The Journal of Urology. 2003 August; 170(2 Pt 2): S35-8; Discussion S39. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853771&dopt=Abstract

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Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients failing on sildenafil citrate therapy alone. Author(s): Kalinchenko SY, Kozlov GI, Gontcharov NP, Katsiya GV. Source: The Aging Male : the Official Journal of the International Society for the Study of the Aging Male. 2003 June; 6(2): 94-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898793&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12735552&dopt=Abstract

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Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. Author(s): DeWitt DE, Hirsch IB. Source: Jama : the Journal of the American Medical Association. 2003 May 7; 289(17): 2254-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12734137&dopt=Abstract

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Oxidative DNA damage in peripheral blood cells in type 2 diabetes mellitus: higher vulnerability of polymorphonuclear leukocytes. Author(s): Pitozzi V, Giovannelli L, Bardini G, Rotella CM, Dolara P. Source: Mutation Research. 2003 August 28; 529(1-2): 129-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943926&dopt=Abstract

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Oxidative stress parameters in type I, type II and insulin-treated type 2 diabetes mellitus; insulin treatment efficiency. Author(s): Seghrouchni I, Drai J, Bannier E, Riviere J, Calmard P, Garcia I, Orgiazzi J, Revol A. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2002 July; 321(1-2): 89-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12031597&dopt=Abstract

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Pediatricians' perceptions and practices regarding prevention and treatment of type 2 diabetes mellitus in children and adolescents. Author(s): Ditmyer MM, Price JH, Telljohann SK, Rogalski F. Source: Archives of Pediatrics & Adolescent Medicine. 2003 September; 157(9): 913-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12963598&dopt=Abstract

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Percutaneous transhepatic pancreatic islet cell transplantation in type 1 diabetes mellitus: radiologic aspects. Author(s): Owen RJ, Ryan EA, O'Kelly K, Lakey JR, McCarthy MC, Paty BW, Bigam DL, Kneteman NM, Korbutt GS, Rajotte RV, Shapiro AM. Source: Radiology. 2003 October; 229(1): 165-70. Epub 2003 August 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12944593&dopt=Abstract

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Pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus: an intravascular ultrasound scanning study. Author(s): Takagi T, Yamamuro A, Tamita K, Yamabe K, Katayama M, Mizoguchi S, Ibuki M, Tani T, Tanabe K, Nagai K, Shiratori K, Morioka S, Yoshikawa J. Source: American Heart Journal. 2003 August; 146(2): E5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891212&dopt=Abstract

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Plasma antioxidants and type 2 diabetes mellitus. Author(s): Palanduz S, Ademoglu E, Gokkusu C, Tamer S. Source: Res Commun Mol Pathol Pharmacol. 2001; 109(5-6): 309-18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12889514&dopt=Abstract

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Poor prognosis of patients with acute myocardial infarction complicated by diabetes mellitus; possible role of impaired microvascular function. Author(s): Ishikawa K. Source: Intern Med. 2003 July; 42(7): 543-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879939&dopt=Abstract

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Preproghrelin Leu72Met polymorphism in patients with type 2 diabetes mellitus. Author(s): Ukkola O, Kesaniemi YA. Source: Journal of Internal Medicine. 2003 October; 254(4): 391-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974878&dopt=Abstract

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Prevalence and predictors of diabetic foot syndrome in type 2 diabetes mellitus in Jordan. Author(s): Jbour AS, Jarrah NS, Radaideh AM, Shegem NS, Bader IM, Batieha AM, Ajlouni KM. Source: Saudi Med J. 2003 July; 24(7): 761-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883610&dopt=Abstract

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Prevalence, incidence and mortality of type 2 diabetes mellitus revisited: a prospective population-based study in The Netherlands (ZODIAC-1). Author(s): Ubink-Veltmaat LJ, Bilo HJ, Groenier KH, Houweling ST, Rischen RO, Meyboom-de Jong B. Source: European Journal of Epidemiology. 2003; 18(8): 793-800. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974556&dopt=Abstract

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Prevention and treatment of type 2 diabetes mellitus in children, with special emphasis on American Indian and Alaska Native children. American Academy of Pediatrics Committee on Native American Child Health. Author(s): Gahagan S, Silverstein J; American Academy of Pediatrics Committee on Native American Child Health; American Academy of Pediatrics Section on Endocrinology. Source: Pediatrics. 2003 October; 112(4): E328. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14523221&dopt=Abstract

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Psychological aspects of diabetes mellitus. Author(s): Szydlo D, van Wattum PJ, Woolston J. Source: Child Adolesc Psychiatr Clin N Am. 2003 July; 12(3): 439-58, Vi. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12910817&dopt=Abstract

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QT interval dispersion in patients with insulin-dependent diabetes mellitus after acute myocardial infarction. Author(s): Perepelytsa M, Fainyk A, Pavluk S, Cherkavska M, Cherkavskiy V, Sorokivskiy M, Koval O. Source: Acta Cardiol. 2002 February; 57(1): 65-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11918158&dopt=Abstract

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QTc interval prolongation is a predictor of future strokes in patients with type 2 diabetes mellitus. Author(s): Cardoso CR, Salles GF, Deccache W. Source: Stroke; a Journal of Cerebral Circulation. 2003 September; 34(9): 2187-94. Epub 2003 July 31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12893949&dopt=Abstract

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Quantification of the Risk of Corticosteroid-induced Diabetes Mellitus Among the Elderly. Author(s): Blackburn D, Hux J, Mamdani M. Source: Journal of General Internal Medicine : Official Journal of the Society for Research and Education in Primary Care Internal Medicine. 2002 September; 17(9): 717-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12220369&dopt=Abstract

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QUICKI is useful for following improvements in insulin sensitivity after therapy in patients with type 2 diabetes mellitus. Author(s): Katsuki A, Sumida Y, Gabazza EC, Murashima S, Urakawa H, Morioka K, Kitagawa N, Tanaka T, Araki-Sasaki R, Hori Y, Nakatani K, Yano Y, Adachi Y. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 June; 87(6): 2906-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12050271&dopt=Abstract

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Recent advances in the treatment of erectile dysfunction in patients with diabetes mellitus. Author(s): Koppiker N, Boolell M, Price D. Source: Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2003 January-February; 9(1): 52-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917094&dopt=Abstract

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Registered nurses' actual and perceived knowledge of diabetes mellitus. Author(s): el-Deirawi KM, Zuraikat N. Source: Journal for Nurses in Staff Development : Jnsd : Official Journal of the National Nursing Staff Development Organization. 2001 January-February; 17(1): 5-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12759934&dopt=Abstract

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Relation of hemoglobin A1c to left ventricular relaxation in patients with type 1 diabetes mellitus and without overt heart disease. Author(s): Shishehbor MH, Hoogwerf BJ, Schoenhagen P, Marso SP, Sun JP, Li J, Klein AL, Thomas JD, Garcia MJ. Source: The American Journal of Cardiology. 2003 June 15; 91(12): 1514-7, A9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804750&dopt=Abstract

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Relationship between human leukocyte antigen status and proliferative diabetic retinopathy in patients with younger-onset type 1 diabetes mellitus. Author(s): Mimura T, Funatsu H, Uchigata Y, Kitano S, Noma H, Shimizu E, Konno Y, Amano S, Araie M, Yoshino O, Iwamoto Y, Hori S. Source: American Journal of Ophthalmology. 2003 June; 135(6): 844-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788125&dopt=Abstract

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Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. Author(s): Kramer HJ, Nguyen QD, Curhan G, Hsu CY. Source: Jama : the Journal of the American Medical Association. 2003 June 25; 289(24): 3273-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824208&dopt=Abstract

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Research into policy. Hypertension and diabetes mellitus in the Caribbean. Author(s): Forrester TE. Source: The West Indian Medical Journal. 2003 June; 52(2): 164-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974071&dopt=Abstract

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Rheumatologic manifestations of diabetes mellitus. Author(s): Crispin JC, Alcocer-Varela J. Source: The American Journal of Medicine. 2003 June 15; 114(9): 753-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829202&dopt=Abstract

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Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Author(s): Salpeter S, Greyber E, Pasternak G, Salpeter E. Source: Cochrane Database Syst Rev. 2003; (2): Cd002967. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804446&dopt=Abstract

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Risperidone-associated diabetes mellitus: a pharmacovigilance study. Author(s): Koller EA, Cross JT, Doraiswamy PM, Schneider BS. Source: Pharmacotherapy. 2003 June; 23(6): 735-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820816&dopt=Abstract

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Routine hospital admission versus out-patient or home care in children at diagnosis of type 1 diabetes mellitus. Author(s): Clar C, Waugh N, Thomas S. Source: Cochrane Database Syst Rev. 2003; (3): Cd004099. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918002&dopt=Abstract

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Screening for gestational diabetes mellitus: recommendation and rationale. Author(s): U.S. Preventive Services Task Force (USPSTF). Source: American Family Physician. 2003 July 15; 68(2): 331-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12892353&dopt=Abstract

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Self-reported social class, self-management behaviors, and the effect of diabetes mellitus in urban, minority young people and their families. Author(s): Lipton R, Drum M, Burnet D, Mencarini M, Cooper A, Rich B. Source: Archives of Pediatrics & Adolescent Medicine. 2003 September; 157(9): 919-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12963599&dopt=Abstract

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Severe hypoglycemia and long-term spatial memory in children with type 1 diabetes mellitus: a retrospective study. Author(s): Hershey T, Lillie R, Sadler M, White NH. Source: Journal of the International Neuropsychological Society : Jins. 2003 July; 9(5): 740-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901780&dopt=Abstract

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Simultaneous occurrence of diabetes mellitus and juvenile dermatomyositis: report of two cases. Author(s): Singh R, Cuchacovich R, Gomez R, Vargas A, Espinoza LR, Gedalia A. Source: Clinical Pediatrics. 2003 June; 42(5): 459-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12862353&dopt=Abstract

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Simultaneous occurrence of type I diabetes mellitus and juvenile rheumatoid arthritis. Author(s): Agrawal S, Desai MP. Source: Indian Pediatrics. 2003 June; 40(6): 568-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824669&dopt=Abstract

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Specialist nurses in diabetes mellitus. Author(s): Loveman E, Royle P, Waugh N. Source: Cochrane Database Syst Rev. 2003; (2): Cd003286. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804458&dopt=Abstract

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Stavudine or indinavir-containing regimens are associated with an increased risk of diabetes mellitus in HIV-infected individuals. Author(s): Brambilla AM, Novati R, Calori G, Meneghini E, Vacchini D, Luzi L, Castagna A, Lazzarin A. Source: Aids (London, England). 2003 September 5; 17(13): 1993-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12960836&dopt=Abstract

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Subclinical diabetes mellitus: is it really “sub-clinical”? Author(s): Keebler ME, McGuire DK. Source: American Heart Journal. 2003 August; 146(2): 210-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891185&dopt=Abstract

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Sugars and starch in the nutritional management of diabetes mellitus. Author(s): Kelley DE. Source: The American Journal of Clinical Nutrition. 2003 October; 78(4): 858S-864S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14522750&dopt=Abstract

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Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Author(s): Writing Team For The Diabetes Control And Complications Trial/Epidemiology Of Diabetes Interventions And Complications Research Group. Source: Jama : the Journal of the American Medical Association. 2003 October 22; 290(16): 2159-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14570951&dopt=Abstract

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Testing for micro-albuminuria in diabetes mellitus. Author(s): Bonnici F. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 1998 March; 88(3 Endocrinology): 347-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12886693&dopt=Abstract

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The emerging role of electronic diaries in the management of diabetes mellitus. Author(s): Kerkenbush NL, Lasome CE. Source: Aacn Clinical Issues. 2003 August; 14(3): 371-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12909805&dopt=Abstract

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The impact of an insulin sensitizer, troglitazone, on glucose metabolism in African Americans at risk for type 2 diabetes mellitus: a placebo-controlled, 24-month randomized study. Author(s): Schuster D, Gaillard T, Rhinesmith S, Habash D, Osei K. Source: Metabolism: Clinical and Experimental. 2003 September; 52(9): 1211-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506629&dopt=Abstract

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The potential role of peroxisome proliferator-activated receptors on inflammation in type 2 diabetes mellitus and atherosclerosis. Author(s): Plutzky J. Source: The American Journal of Cardiology. 2003 August 18; 92(4A): 34J-41J. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957325&dopt=Abstract

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The transition from knowing to doing: teaching junior doctors how to use insulin in the management of diabetes mellitus. Author(s): Conn JJ, Dodds AE, Colman PG. Source: Medical Education. 2003 August; 37(8): 689-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12895248&dopt=Abstract

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Thyroid function in children with newly diagnosed type 1 diabetes mellitus. Author(s): Lin CH, Lee YJ, Huang CY, Kao HA, Shih BF, Wang AM, Lo FS. Source: Acta Paediatr Taiwan. 2003 May-June; 44(3): 145-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14521019&dopt=Abstract

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Transplantation for diabetes mellitus. Author(s): Mamode N, Sutherland DE. Source: The British Journal of Surgery. 2003 September; 90(9): 1031-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12945068&dopt=Abstract

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Type 1 diabetes mellitus in patients with chronic hepatitis C before and after interferon therapy. Author(s): Fabris P, Floreani A, Tositti G, Vergani D, De Lalla F, Betterle C. Source: Alimentary Pharmacology & Therapeutics. 2003 September 15; 18(6): 549-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12969081&dopt=Abstract

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Type 1 diabetes mellitus. Author(s): Kaufman FR. Source: Pediatrics in Review / American Academy of Pediatrics. 2003 September; 24(9): 291-300. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12949265&dopt=Abstract

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Type 2 diabetes mellitus in youth. Author(s): Quarry-Horn JL, Evans BJ, Kerrigan JR. Source: J Sch Nurs. 2003 August; 19(4): 195-203. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882602&dopt=Abstract

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Ulnar neuropathy in the forearm: A possible complication of diabetes mellitus. Author(s): Acosta JA, Hoffman SN, Raynor EM, Nardin RA, Rutkove SB. Source: Muscle & Nerve. 2003 July; 28(1): 40-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811771&dopt=Abstract

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Ultrasonographic evaluation of pes anserinus tendino-bursitis in patients with type 2 diabetes mellitus. Author(s): Unlu Z, Ozmen B, Tarhan S, Boyvoda S, Goktan C. Source: The Journal of Rheumatology. 2003 February; 30(2): 352-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12563695&dopt=Abstract

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Umbilical arterial Doppler sonography for fetal surveillance in pregnancies complicated by pregestational diabetes mellitus. Author(s): Maulik D, Lysikiewicz A, Sicuranza G. Source: J Matern Fetal Neonatal Med. 2002 December;12(6):417-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12683654&dopt=Abstract

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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:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725703&dopt=Abstract

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Urinary N-acetyl-beta-D-glucosaminidase activity in type I diabetes mellitus. Author(s): Mungan N, Yuksel B, Bakman M, Topaloglu AK, Ozer G. Source: Indian Pediatrics. 2003 May; 40(5): 410-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12768043&dopt=Abstract

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Urinary stone disease in diabetes mellitus. Author(s): Meydan N, Barutca S, Caliskan S, Camsari T. Source: Scandinavian Journal of Urology and Nephrology. 2003; 37(1): 64-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12745748&dopt=Abstract

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Use of angiotensin-converting enzyme inhibitors after coronary artery bypass grafting in patients with diabetes mellitus. Author(s): Bistritz L, Amad H, Tandon P, Man J, Mullen JC, McAlister FA. Source: The American Journal of Cardiology. 2003 July 1; 92(1): 77-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842254&dopt=Abstract

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Use of clinical laboratory parameters to evaluate wound healing potential in diabetes mellitus. Author(s): Abu-Rumman PL, Armstrong DG, Nixon BP. Source: Journal of the American Podiatric Medical Association. 2002 January; 92(1): 3847. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11796798&dopt=Abstract

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Use of scanning laser ophthalmoscope microperimetry in clinically significant macular edema in type 2 diabetes mellitus. Author(s): Mori F, Ishiko S, Kitaya N, Hikichi T, Sato E, Takamiya A, Yoshida A. Source: Japanese Journal of Ophthalmology. 2002 November-December; 46(6): 650-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543192&dopt=Abstract

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Utilization of lipid-lowering drugs in elderly persons with increased serum lowdensity lipoprotein cholesterol associated with coronary artery disease, symptomatic peripheral arterial disease, prior stroke, or diabetes mellitus before and after an educational program on dyslipidemia treatment. Author(s): Ghosh S, Aronow WS. Source: The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2003 May; 58(5): M432-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12730252&dopt=Abstract

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Variant screening of PRKAB2, a type 2 diabetes mellitus susceptibility candidate gene on 1q in Pima Indians. Author(s): Prochazka M, Farook VS, Ossowski V, Wolford JK, Bogardus C. Source: Molecular and Cellular Probes. 2002 December; 16(6): 421-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490143&dopt=Abstract

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Vascular function and carotid intimal-medial thickness in children with insulindependent diabetes mellitus. Author(s): Singh TP, Groehn H, Kazmers A. Source: Journal of the American College of Cardiology. 2003 February 19; 41(4): 661-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598080&dopt=Abstract

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Vascular function in women with previous gestational diabetes mellitus. Author(s): Hannemann MM, Liddell WG, Shore AC, Clark PM, Tooke JE. Source: Journal of Vascular Research. 2002 July-August; 39(4): 311-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12187121&dopt=Abstract

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Vascular reactivity in diabetes mellitus. Author(s): Chaudhuri A. Source: Curr Diab Rep. 2002 August; 2(4): 305-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12643189&dopt=Abstract

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Vascular structural and functional changes in type 2 diabetes mellitus: evidence for the roles of abnormal myogenic responsiveness and dyslipidemia. Author(s): Schofield I, Malik R, Izzard A, Austin C, Heagerty A. Source: Circulation. 2002 December 10; 106(24): 3037-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12473548&dopt=Abstract

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Vascular targets of redox signalling in diabetes mellitus. Author(s): Tomazic M. Diabetologia. 2002 Dec;45(12):1744 Source: Diabetologia. 2002 April; 45(4): 476-94. Review. /entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12555745

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Vasoconstricting effect of angiotensin II in human hand veins: influence of aging, diabetes mellitus and hypertension. Author(s): Harada K, Ohmori M, Fujimura A. Source: Hypertens Res. 2002 September; 25(5): 683-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12452319&dopt=Abstract

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Ventricular repolarization in diabetes mellitus: still much to learn. Author(s): Cardoso C, Salles G. Source: Clinical Autonomic Research : Official Journal of the Clinical Autonomic Research Society. 2002 October; 12(5): 346-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12481749&dopt=Abstract

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Vitamin D 1alpha-hydroxylase (CYP1alpha) polymorphism in Graves' disease, Hashimoto's thyroiditis and type 1 diabetes mellitus. Author(s): Pani MA, Regulla K, Segni M, Krause M, Hofmann S, Hufner M, Herwig J, Pasquino AM, Usadel KH, Badenhoop K. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2002 June; 146(6): 777-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12039697&dopt=Abstract

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Vitamin D binding protein gene and genetic susceptibility to type 2 diabetes mellitus in a Polish population. Author(s): Malecki MT, Klupa T, Wanic K, Cyganek K, Frey J, Sieradzki J. Source: Diabetes Research and Clinical Practice. 2002 August; 57(2): 99-104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12062854&dopt=Abstract

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Weight in adolescents with type 1 diabetes mellitus during continuous subcutaneous insulin infusion (CSII) therapy. Author(s): Raile K, Noelle V, Landgraf R, Schwarz HP. Source: J Pediatr Endocrinol Metab. 2002 May; 15(5): 607-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12014519&dopt=Abstract

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WFS1 mutations in Spanish patients with diabetes mellitus and deafness. Author(s): Domenech E, Gomez-Zaera M, Nunes V. Source: European Journal of Human Genetics : Ejhg. 2002 July; 10(7): 421-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12107816&dopt=Abstract

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What employees with rheumatoid arthritis, diabetes mellitus and hearing loss need to cope at work. Author(s): Detaille SI, Haafkens JA, van Dijk FJ. Source: Scand J Work Environ Health. 2003 April; 29(2): 134-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12718499&dopt=Abstract

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When diet fails: insulin and oral hypoglycemic agents as alternatives for the management of gestational diabetes mellitus. Author(s): Langer O. Source: J Matern Fetal Neonatal Med. 2002 April;11(4):218-25. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12375674&dopt=Abstract

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Which contraceptive methods are recommended for young women with type 1 diabetes mellitus? A survey among gynaecologists in Greece. Author(s): Manolopoulos K, Kiess W, Braems GA, Deligeoroglou E, Creatsas G, Michalas S, Lang U. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2001 December 1; 99(2): 232-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11788178&dopt=Abstract

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WHO and ADA criteria for the diagnosis of diabetes mellitus in relation to body mass index. Insulin sensitivity and secretion in resulting subcategories of glucose tolerance. Author(s): Melchionda N, Forlani G, Marchesini G, Baraldi L, Natale S. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2002 January; 26(1): 90-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11791152&dopt=Abstract

•

Why is the ADA classification of diabetes mellitus not always applied? Author(s): Prisco F, Iafusco D. Source: Diabetologia. 2002 May; 45(5): 747. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12120622&dopt=Abstract

•

Women diagnosed with gestational diabetes mellitus do not carry antibodies against minor islet cell antigens. Author(s): Balaji M, Shtauvere-Brameus A, Balaji V, Seshiah V, Sanjeevi CB. Source: Annals of the New York Academy of Sciences. 2002 April; 958: 281-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12021124&dopt=Abstract

•

Women's experiences of being screened for gestational diabetes mellitus. Author(s): Rumbold AR, Crowther CA. Source: The Australian & New Zealand Journal of Obstetrics & Gynaecology. 2002 May; 42(2): 131-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12069138&dopt=Abstract

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CHAPTER 2. NUTRITION AND DIABETES MELLITUS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and diabetes mellitus.

Finding Nutrition Studies on Diabetes Mellitus 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 “diabetes mellitus” (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 diabetes mellitus: •

Genetic errors that result in diabetes mellitus. Author(s): University of Georgia, Athens. Source: Berdanier, C.D. Nutrition-today (USA). (February 1994). volume 29(1) page 1724.

•

Nutrition considerations in the control of diabetes mellitus. Author(s): Stanford University Medical Center. Source: Coulston, A.M. Nutrition-today (USA). (February 1994). volume 29(1) page 6-11.

•

Nutrition recommendations for people with diabetes mellitus: a break with tradition. Source: Coulston, A.M. Nutrition-today (USA). (June 1994). volume 29(3) page 10-11.

Additional consumer oriented references include: •

A planned randomized clinical trial of treatment for mild gestational diabetes mellitus. Author(s): The Maternal Fetal Medicine Units Network, The National Institute of Child Health and Human Development, Bethesda, Maryland, USA. Source: Landon, M B Thom, E Spong, C Y Gabbe, S G Leindecker, S Johnson, F Lain, K Miodovnik, M Carpenter, M J-Matern-Fetal-Neonatal-Med. 2002 April; 11(4): 226-31 1476-7058

•

Can diabetes mellitus be induced by medication? Author(s): Division of Child and Adolescent Psychiatry, Schneider Children's Hospital, North Shore Long Island Jewish Health System, New Hyde Park, New York 11040, USA. [email protected] Source: Saito, E Kafantaris, V J-Child-Adolesc-Psychopharmacol. 2002 Fall; 12(3): 231-6 1044-5463

•

Diabetes mellitus and obesity. Author(s): Department of Family Practice, Mount Sinai School of Medicine, Jamaica Hospital Medical Center, 8900 Van Wyck Expressway, Jamaica, NY 11418, USA. [email protected] Source: Roth, A Prim-Care. 2002 June; 29(2): 279-95 0095-4543

•

Education and multidisciplinary team care concepts for pediatric and adolescent diabetes mellitus. Author(s): New England Diabetes and Endocrinology Center, Waltham, MA 02451-1136, USA. [email protected] Source: Brink, S J Miller, M Moltz, K C J-Pediatr-Endocrinol-Metab. 2002 Sep-October; 15(8): 1113-30

•

Effects of Aronia melanocarpa juice as part of the dietary regimen in patients with diabetes mellitus. Author(s): Clinic of Endocrinology, Medical University, Plovdiv, Bulgaria. Source: SimeoNovember, S B Botushanov, N P Karahanian, E B Pavlova, M B Husianitis, H K Troev, D M Folia-Med-(Plovdiv). 2002; 44(3): 20-3 0204-8043

•

Hypoglycemic effect of aqueous extract of Enicostemma littorale Blume (chhota chirayata) on alloxan induced diabetes mellitus in rats. Author(s): Department of Biochemistry, Faculty of Science, M.S. University of Baroda, Baroda 390 002, India. [email protected]

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Source: Vijayvargia, R KuMarch, M Gupta, S Indian-J-Exp-Biol. 2000 August; 38(8): 7814 0019-5189 •

Hypoglycemic effect of methanol extract of Phyllanthus amarus Schum & Thonn on alloxan induced diabetes mellitus in rats and its relation with antioxidant potential. Author(s): Amala Cancer Research Center, Amalanagar, Thrissur 680 553, India. Source: Raphael, K R Sabu, M C Kuttan, R Indian-J-Exp-Biol. 2002 August; 40(8): 905-9 0019-5189

•

Impaired NO-dependent vasodilation in patients with Type II (non-insulindependent) diabetes mellitus is restored by acute administration of folate. Author(s): Department of Vascular Medicine and Diabetes, University Medical Center, Utrecht, The Netherlands. Source: van Etten, R W de Koning, E J Verhaar, M C Gaillard, C A Rabelink, T J Diabetologia. 2002 July; 45(7): 1004-10 0012-186X

•

Influence of beta-resorcylidene aminoguanidine on selected metabolic parameters and antioxidant status of rats with diabetes mellitus. Author(s): Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University, Bratislava, Slovak republic. [email protected] Source: Liptakova, A Carsky, J Ulicna, O Vancova, O Bozek, P Durackova, Z PhysiolRes. 2002; 51(3): 277-84 0862-8408

•

Insulin effect on leucine kinetics in type 2 diabetes mellitus. Author(s): Division of Endocrinology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. Source: Halvatsiotis, P G Turk, D Alzaid, A Dinneen, S Rizza, R A Nair, K S DiabetesNutr-Metab. 2002 June; 15(3): 136-42 0394-3402

•

Optic disc swelling in an adolescent with insulin dependent diabetes mellitus. Author(s): Department of Ophthalmology, Prince of Wales Hospital, Sydney, New South Wales, Australia. Source: Fraser Bell, S Capon, M Clin-Experiment-Ophthalmol. 2002 December; 30(6): 434-6 1442-6404

•

Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent. Author(s): Department of Medical and Surgical Sciences, University of Padova, Italy. [email protected] Source: Lirussi, F Beccarello, A Zanette, G De Monte, A Donadon, V Velussi, M Crepaldi, G Diabetes-Nutr-Metab. 2002 August; 15(4): 222-31 0394-3402

•

The role of coping with disease in adherence to treatment regimen and disease control in type 1 and insulin treated type 2 diabetes mellitus. Author(s): Davranis Bilimleri Enstitusu (Institute for Behavioral Studies), Istanbul. [email protected] Source: Turan, B Osar, Z Molzan Turan, J Damci, T Ilkova, H Diabetes-Metab. 2002 June; 28(3): 186-93 1262-3636

•

When diet fails: insulin and oral hypoglycemic agents as alternatives for the management of gestational diabetes mellitus. Author(s): Department of Obstetrics and Gynecology, St Luke's-Roosevelt Hospital Center, New York, New York 10019, USA. Source: Langer, O J-Matern-Fetal-Neonatal-Med. 2002 April; 11(4): 218-25 1476-7058

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

A planned randomized clinical trial of treatment for mild gestational diabetes mellitus. Author(s): The Maternal Fetal Medicine Units Network, The National Institute of Child Health and Human Development, Bethesda, Maryland, USA. Source: Landon, M B Thom, E Spong, C Y Gabbe, S G Leindecker, S Johnson, F Lain, K Miodovnik, M Carpenter, M J-Matern-Fetal-Neonatal-Med. 2002 April; 11(4): 226-31 1476-7058

•

Can diabetes mellitus be induced by medication? Author(s): Division of Child and Adolescent Psychiatry, Schneider Children's Hospital, North Shore Long Island Jewish Health System, New Hyde Park, New York 11040, USA. [email protected] Source: Saito, E Kafantaris, V J-Child-Adolesc-Psychopharmacol. 2002 Fall; 12(3): 231-6 1044-5463

•

Diabetes mellitus and obesity. Author(s): Department of Family Practice, Mount Sinai School of Medicine, Jamaica Hospital Medical Center, 8900 Van Wyck Expressway, Jamaica, NY 11418, USA. [email protected] Source: Roth, A Prim-Care. 2002 June; 29(2): 279-95 0095-4543

•

Education and multidisciplinary team care concepts for pediatric and adolescent diabetes mellitus. Author(s): New England Diabetes and Endocrinology Center, Waltham, MA 02451-1136, USA. [email protected] Source: Brink, S J Miller, M Moltz, K C J-Pediatr-Endocrinol-Metab. 2002 Sep-October; 15(8): 1113-30

•

Effects of Aronia melanocarpa juice as part of the dietary regimen in patients with diabetes mellitus. Author(s): Clinic of Endocrinology, Medical University, Plovdiv, Bulgaria. Source: SimeoNovember, S B Botushanov, N P Karahanian, E B Pavlova, M B Husianitis, H K Troev, D M Folia-Med-(Plovdiv). 2002; 44(3): 20-3 0204-8043

•

Hypoglycemic effect of aqueous extract of Enicostemma littorale Blume (chhota chirayata) on alloxan induced diabetes mellitus in rats. Author(s): Department of Biochemistry, Faculty of Science, M.S. University of Baroda, Baroda 390 002, India. [email protected] Source: Vijayvargia, R KuMarch, M Gupta, S Indian-J-Exp-Biol. 2000 August; 38(8): 7814 0019-5189

•

Impaired NO-dependent vasodilation in patients with Type II (non-insulindependent) diabetes mellitus is restored by acute administration of folate. Author(s): Department of Vascular Medicine and Diabetes, University Medical Center, Utrecht, The Netherlands. Source: van Etten, R W de Koning, E J Verhaar, M C Gaillard, C A Rabelink, T J Diabetologia. 2002 July; 45(7): 1004-10 0012-186X

•

Influence of beta-resorcylidene aminoguanidine on selected metabolic parameters and antioxidant status of rats with diabetes mellitus. Author(s): Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University, Bratislava, Slovak republic. [email protected]

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Source: Liptakova, A Carsky, J Ulicna, O Vancova, O Bozek, P Durackova, Z PhysiolRes. 2002; 51(3): 277-84 0862-8408 •

Insulin effect on leucine kinetics in type 2 diabetes mellitus. Author(s): Division of Endocrinology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. Source: Halvatsiotis, P G Turk, D Alzaid, A Dinneen, S Rizza, R A Nair, K S DiabetesNutr-Metab. 2002 June; 15(3): 136-42 0394-3402

•

Optic disc swelling in an adolescent with insulin dependent diabetes mellitus. Author(s): Department of Ophthalmology, Prince of Wales Hospital, Sydney, New South Wales, Australia. Source: Fraser Bell, S Capon, M Clin-Experiment-Ophthalmol. 2002 December; 30(6): 434-6 1442-6404

•

Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent. Author(s): Department of Medical and Surgical Sciences, University of Padova, Italy. [email protected] Source: Lirussi, F Beccarello, A Zanette, G De Monte, A Donadon, V Velussi, M Crepaldi, G Diabetes-Nutr-Metab. 2002 August; 15(4): 222-31 0394-3402

•

The role of coping with disease in adherence to treatment regimen and disease control in type 1 and insulin treated type 2 diabetes mellitus. Author(s): Davranis Bilimleri Enstitusu (Institute for Behavioral Studies), Istanbul. [email protected] Source: Turan, B Osar, Z Molzan Turan, J Damci, T Ilkova, H Diabetes-Metab. 2002 June; 28(3): 186-93 1262-3636

•

When diet fails: insulin and oral hypoglycemic agents as alternatives for the management of gestational diabetes mellitus. Author(s): Department of Obstetrics and Gynecology, St Luke's-Roosevelt Hospital Center, New York, New York 10019, USA. Source: Langer, O J-Matern-Fetal-Neonatal-Med. 2002 April; 11(4): 218-25 1476-7058

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

•

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/

•

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

•

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

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

Vitamins Niacin Source: Integrative Medicine Communications; www.drkoop.com Pantothenic Acid and Pantethine Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin A Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B3 (niacin) Source: Integrative Medicine Communications; www.drkoop.com Vitamin B6 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin C Source: Prima Communications, Inc.www.personalhealthzone.com

Nutrition

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

Minerals Biotin Source: Prima Communications, Inc.www.personalhealthzone.com Chromium Source: Integrative Medicine Communications; www.drkoop.com Chromium Source: Prima Communications, Inc.www.personalhealthzone.com L-carnitine Source: Healthnotes, Inc.; www.healthnotes.com Magnesium Source: Integrative Medicine Communications; www.drkoop.com Magnesium Source: Prima Communications, Inc.www.personalhealthzone.com Manganese Source: Integrative Medicine Communications; www.drkoop.com Selenium Source: Prima Communications, Inc.www.personalhealthzone.com Vanadium Source: Healthnotes, Inc.; www.healthnotes.com Vanadium Alternative names: Vanadate, Vanadyl Source: Integrative Medicine Communications; www.drkoop.com Vanadium Source: Prima Communications, Inc.www.personalhealthzone.com Zinc Source: Prima Communications, Inc.www.personalhealthzone.com

•

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

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CHAPTER 3. ALTERNATIVE MEDICINE AND DIABETES MELLITUS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to diabetes mellitus. At the conclusion of this chapter, we will provide additional sources.

The Combined Health Information Database The Combined Health Information Database (CHID) is a bibliographic database produced by health-related agencies of the U.S. federal government (mostly from the National Institutes of Health) that can offer concise information for a targeted search. The CHID database is updated four times a year at the end of January, April, July, and October. Check the titles, summaries, and availability of CAM-related information by using the “Simple Search” option at the following Web site: http://chid.nih.gov/simple/simple.html. In the drop box at the top, select “Complementary and Alternative Medicine.” Then type “diabetes mellitus” (or synonyms) in the second search box. We recommend that you select 100 “documents per page” and to check the “whole records” options. The following was extracted using this technique: •

Alternative Medicine Update Source: Alternative Health Practitioner. 3(3): 157-160. Fall/Winter 1997. Summary: This journal article reports the results of 12 studies funded by the Office of Alternative Medicine in 1993 and 1994. The studies were classified as either mind/body interventions or as pharmacological or biological treatments. The 10 mind/body intervention studies include the following therapies: biofeedback, dance movement therapy, guided imagery, hypnotic imagery, music therapy, prayer, and yoga. Conditions studied include pain, diabetes mellitus, cystic fibrosis, asthma, immunity, cancer, AIDS, brain injury, and drug abuse. The two pharmacological and biological studies were 'Enzyme Therapy and Experimental Memory Metastasis' and 'Pharmacological Treatment of Cancer by Antioxidants.'.

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

A phytosterol-enriched spread improves the lipid profile of subjects with type 2 diabetes mellitus A randomized controlled trial under free-living conditions. Author(s): Lee YM, Haastert B, Scherbaum W, Hauner H. Source: European Journal of Nutrition. 2003 April; 42(2): 111-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12638032&dopt=Abstract

•

An integrative approach to the management of type 2 diabetes mellitus. Author(s): Kligler B, Lynch D. Source: Alternative Therapies in Health and Medicine. 2003 November-December; 9(6): 24-32; Quiz 33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14618854&dopt=Abstract

•

Antioxidant activity in medicinal plants associated with the symptoms of diabetes mellitus used by the indigenous peoples of the North American boreal forest. Author(s): McCune LM, Johns T. Source: Journal of Ethnopharmacology. 2002 October; 82(2-3): 197-205. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12241996&dopt=Abstract

•

Antioxidant effects of Gongronema latifolium in hepatocytes of rat models of noninsulin dependent diabetes mellitus. Author(s): Ugochukwu NH, Babady NE. Source: Fitoterapia. 2002 December; 73(7-8): 612-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490219&dopt=Abstract

•

Antioxidant effects of zinc supplementation in tunisians with type 2 diabetes mellitus. Author(s): Roussel AM, Kerkeni A, Zouari N, Mahjoub S, Matheau JM, Anderson RA. Source: Journal of the American College of Nutrition. 2003 August; 22(4): 316-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12897047&dopt=Abstract

•

Approaches to the treatement of diabetes mellitus: an overview. Author(s): Suji G, Sivakami S.

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Source: Cell Mol Biol (Noisy-Le-Grand). 2003 June; 49(4): 635-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899455&dopt=Abstract •

Can perinatal supplementation of long-chain polyunsaturated fatty acids prevent diabetes mellitus? Author(s): Das UN. Source: European Journal of Clinical Nutrition. 2003 February; 57(2): 218-26. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571652&dopt=Abstract

•

Cultural orientation and diabetes self-care in low-income African Americans with type 2 diabetes mellitus. Author(s): de Groot M, Welch G, Buckland GT 3rd, Fergus M, Ruggiero L, Chipkin SR. Source: Ethn Dis. 2003 Winter; 13(1): 6-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723006&dopt=Abstract

•

Diabetes mellitus and obesity. Author(s): Roth A. Source: Primary Care. 2002 June; 29(2): 279-95. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12391712&dopt=Abstract

•

Dietary fats and diabetes mellitus: is there a good fat? Author(s): Segal-Isaacson CJ, Carello E, Wylie-Rosett J. Source: Curr Diab Rep. 2001 October; 1(2): 161-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12643112&dopt=Abstract

•

Effect of glucose/insulin infusion and magnesium supplementation on serum and muscle sodium and potassium and muscle [3H]ouabain binding capacity in Type 1 diabetes mellitus. Author(s): Djurhuus MS, Klitgaard NA, Pedersen KK. Source: Scandinavian Journal of Clinical and Laboratory Investigation. 2003; 63(2): 93102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12751690&dopt=Abstract

•

Effect of lipase inhibition on gastric emptying of, and the glycemic and incretin responses to, an oil/aqueous drink in type 2 diabetes mellitus. Author(s): Pilichiewicz A, O'Donovan D, Feinle C, Lei Y, Wishart JM, Bryant L, Meyer JH, Horowitz M, Jones KL. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3829-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915676&dopt=Abstract

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•

Effect of oral magnesium supplementation on the lipid profile and blood glucose of patients with type 2 diabetes mellitus. Author(s): Lal J, Vasudev K, Kela AK, Jain SK. Source: J Assoc Physicians India. 2003 January; 51: 37-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12693452&dopt=Abstract

•

Effects of Aronia melanocarpa juice as part of the dietary regimen in patients with diabetes mellitus. Author(s): Simeonov SB, Botushanov NP, Karahanian EB, Pavlova MB, Husianitis HK, Troev DM. Source: Folia Med (Plovdiv). 2002; 44(3): 20-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12580526&dopt=Abstract

•

Effects of goshajinkigan on corneal sensitivity, superficial punctate keratopathy and tear secretion in patients with insulin-dependent diabetes mellitus. Author(s): Nagaki Y, Hayasaka S, Hayasaka Y, Kadoi C, Sekiya N, Terasawa K, Sakakibara I. Source: The American Journal of Chinese Medicine. 2003; 31(1): 103-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723759&dopt=Abstract

•

Effects of Inula racemosa root and Gymnema sylvestre leaf extracts in the regulation of corticosteroid induced diabetes mellitus: involvement of thyroid hormones. Author(s): Gholap S, Kar A. Source: Pharmazie. 2003 June; 58(6): 413-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857006&dopt=Abstract

•

Effects of low-dose omega-3 fatty acid substitution in type-2 diabetes mellitus with special reference to oxidative stress--a prospective preliminary study. Author(s): Jain S, Gaiha M, Bhattacharjee J, Anuradha S. Source: J Assoc Physicians India. 2002 August; 50: 1028-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12421024&dopt=Abstract

•

Ethnopharmacological survey of medicinal plants used for the treatment of diabetes mellitus, hypertension and cardiac diseases in the south-east region of Morocco (Tafilalet). Author(s): Eddouks M, Maghrani M, Lemhadri A, Ouahidi ML, Jouad H. Source: Journal of Ethnopharmacology. 2002 October; 82(2-3): 97-103. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12241983&dopt=Abstract

•

Gene and cell therapies for diabetes mellitus: strategies and clinical potential. Author(s): Giannoukakis N, Robbins PD.

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Source: Biodrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy. 2002; 16(3): 149-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12102644&dopt=Abstract •

Gene and cell-based therapy for diabetes mellitus: endocrine gene therapeutics. Author(s): Sasaki T, Fujimoto K, Sakai K, Nemoto M, Nakai N, Tajima N. Source: Endocrine Pathology. 2003 Summer; 14(2): 141-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858004&dopt=Abstract

•

Genes and engineered cells as drugs for type I and type II diabetes mellitus therapy and prevention. Author(s): Giannoukakis N, Pietropaolo M, Trucco M. Source: Curr Opin Investig Drugs. 2002 May; 3(5): 735-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12090547&dopt=Abstract

•

Herbal medicine in the treatment of diabetes mellitus. Author(s): Al-Rowais NA. Source: Saudi Med J. 2002 November; 23(11): 1327-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12506289&dopt=Abstract

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Histomorphometric evaluation of the effect of doxycycline on the healing of bone defects in experimental diabetes mellitus: a pilot study. Author(s): Alkan A, Erdem E, Gunhan O, Karasu C. Source: Journal of Oral and Maxillofacial Surgery : Official Journal of the American Association of Oral and Maxillofacial Surgeons. 2002 August; 60(8): 898-904. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12149735&dopt=Abstract

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Hypoglycemic effect of methanol extract of Phyllanthus amarus Schum & Thonn on alloxan induced diabetes mellitus in rats and its relation with antioxidant potential. Author(s): Raphael KR, Sabu MC, Kuttan R. Source: Indian J Exp Biol. 2002 August; 40(8): 905-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12597020&dopt=Abstract

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Intake of refined carbohydrates and whole grain foods in relation to risk of type 2 diabetes mellitus and coronary heart disease. Author(s): Liu S. Source: Journal of the American College of Nutrition. 2002 August; 21(4): 298-306. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12166526&dopt=Abstract

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Lessons learned from urban Latinas with type 2 diabetes mellitus. Author(s): Adams CR.

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Source: Journal of Transcultural Nursing : Official Journal of the Transcultural Nursing Society / Transcultural Nursing Society. 2003 July; 14(3): 255-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861928&dopt=Abstract •

Lifestyle modification in management of diabetes mellitus. Author(s): Sahay BK, Sahay RK. Source: J Indian Med Assoc. 2002 March; 100(3): 178-80. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12408279&dopt=Abstract

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Long-chain polyunsaturated fatty acids and chemically induced diabetes mellitus. Effect of omega-3 fatty acids. Author(s): Suresh Y, Das UN. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2003 March; 19(3): 213-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12620523&dopt=Abstract

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Oligofructose does not affect the development of type 1 diabetes mellitus induced by dietary proteins in the diabetes-prone BB rat model. Author(s): Perrin IV, Marchesini M, Rochat FC, Schiffrin EJ, Schilter B. Source: Diabetes Nutr Metab. 2003 April; 16(2): 94-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846448&dopt=Abstract

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Preparing nurses to face the pandemic of diabetes mellitus: a literature review. Author(s): Hjelm K, Mufunda E, Nambozi G, Kemp J. Source: Journal of Advanced Nursing. 2003 March; 41(5): 424-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603567&dopt=Abstract

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Prevalence and prognostic value of perfusion defects detected by stress technetium99m sestamibi myocardial perfusion single-photon emission computed tomography in asymptomatic patients with diabetes mellitus and no known coronary artery disease. Author(s): De Lorenzo A, Lima RS, Siqueira-Filho AG, Pantoja MR. Source: The American Journal of Cardiology. 2002 October 15; 90(8): 827-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372568&dopt=Abstract

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Religious and cultural distance in beliefs about health and illness in women with diabetes mellitus of different origin living in Sweden. Author(s): Hjelm K, Bard K, Nyberg P, Apelqvist J. Source: International Journal of Nursing Studies. 2003 August; 40(6): 627-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12834928&dopt=Abstract

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Role of chromium supplementation in Indians with type 2 diabetes mellitus. Author(s): Ghosh D, Bhattacharya B, Mukherjee B, Manna B, Sinha M, Chowdhury J, Chowdhury S.

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Source: The Journal of Nutritional Biochemistry. 2002 November; 13(11): 690-697. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12550067&dopt=Abstract •

Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent. Author(s): Lirussi F, Beccarello A, Zanette G, De Monte A, Donadon V, Velussi M, Crepaldi G. Source: Diabetes Nutr Metab. 2002 August; 15(4): 222-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12416659&dopt=Abstract

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Sugars and starch in the nutritional management of diabetes mellitus. Author(s): Kelley DE. Source: The American Journal of Clinical Nutrition. 2003 October; 78(4): 858S-864S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14522750&dopt=Abstract

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The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Author(s): Scroggie DA, Albright A, Harris MD. Source: Archives of Internal Medicine. 2003 July 14; 163(13): 1587-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860582&dopt=Abstract

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The effect of taurine supplementation on patients with type 2 diabetes mellitus. Author(s): Chauncey KB, Tenner TE Jr, Lombardini JB, Jones BG, Brooks ML, Warner RD, Davis RL, Ragain RM. Source: Advances in Experimental Medicine and Biology. 2003; 526: 91-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12908588&dopt=Abstract

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Therapeutic strategies for Type 1 and Type 2 diabetes mellitus. Author(s): Giannoukakis N, Pietropaolo M, Trucco M. Source: Diabetes Nutr Metab. 2002 June; 15(3): 173-203. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12173733&dopt=Abstract

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Use of complementary and alternative medicine among persons with diabetes mellitus: results of a national survey. Author(s): Yeh GY, Eisenberg DM, Davis RB, Phillips RS. Source: American Journal of Public Health. 2002 October; 92(10): 1648-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12356615&dopt=Abstract

136 Diabetes Mellitus

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

General Overview Amenorrhea Source: Integrative Medicine Communications; www.drkoop.com Bell's Palsy Source: Healthnotes, Inc.; www.healthnotes.com Capillary Fragility Source: Healthnotes, Inc.; www.healthnotes.com Cardiomyopathy Source: Healthnotes, Inc.; www.healthnotes.com Cirrhosis Source: Integrative Medicine Communications; www.drkoop.com Diabetes Source: Healthnotes, Inc.; www.healthnotes.com

Alternative Medicine 137

Diabetes Source: Prima Communications, Inc.www.personalhealthzone.com Gout Source: Integrative Medicine Communications; www.drkoop.com High Cholesterol Source: Integrative Medicine Communications; www.drkoop.com Hypercholesterolemia Source: Integrative Medicine Communications; www.drkoop.com Immune Function Source: Healthnotes, Inc.; www.healthnotes.com Liver Disease Source: Integrative Medicine Communications; www.drkoop.com Obesity Source: Integrative Medicine Communications; www.drkoop.com Osteoarthritis Source: Prima Communications, Inc.www.personalhealthzone.com Preeclampsia Source: Healthnotes, Inc.; www.healthnotes.com Pyloric Stenosis Source: Integrative Medicine Communications; www.drkoop.com Rubella Source: Integrative Medicine Communications; www.drkoop.com Tendinitis Source: Integrative Medicine Communications; www.drkoop.com Vertigo Source: Healthnotes, Inc.; www.healthnotes.com Vitiligo Source: Healthnotes, Inc.; www.healthnotes.com •

Alternative Therapy Massage Source: Integrative Medicine Communications; www.drkoop.com Nutrition Source: Integrative Medicine Communications; www.drkoop.com

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Chinese Medicine Hongqi Alternative names: Manyinflorescenced Sweetvetch Root; Radix Hedysari Source: Chinese Materia Medica Huangqi Alternative names: Milkvetch; Radix Astragali Source: Chinese Materia Medica

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Herbs and Supplements Aloe Alternative names: Aloe vera, Aloe barbadensis Source: Healthnotes, Inc.; www.healthnotes.com Aloe Alternative names: Aloe vera, Aloe barbadensis, Aloe ferox , Aloe Vera Source: Integrative Medicine Communications; www.drkoop.com Aloe Vera Source: Integrative Medicine Communications; www.drkoop.com American Ginseng Alternative names: Panax quinquefolius Source: Healthnotes, Inc.; www.healthnotes.com Bitter Melon Alternative names: Momordica charantia Source: Healthnotes, Inc.; www.healthnotes.com Coenzyme Q10 Source: Healthnotes, Inc.; www.healthnotes.com Coenzyme Q10 Source: Integrative Medicine Communications; www.drkoop.com Coenzyme Q10 (CoQ10) Source: Prima Communications, Inc.www.personalhealthzone.com Coq10 Source: Integrative Medicine Communications; www.drkoop.com Dehydroepiandrosterone (DHEA) Source: Healthnotes, Inc.; www.healthnotes.com Docosahexaenoic Acid Source: Healthnotes, Inc.; www.healthnotes.com Eicosapentaenoic Acid (EPA) Source: Integrative Medicine Communications; www.drkoop.com

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EPA Source: Integrative Medicine Communications; www.drkoop.com Fenugreek Source: Prima Communications, Inc.www.personalhealthzone.com Fiber Source: Healthnotes, Inc.; www.healthnotes.com GLA (Gamma-Linolenic Acid) Source: Prima Communications, Inc.www.personalhealthzone.com Glipizide Source: Healthnotes, Inc.; www.healthnotes.com Glucomannan Source: Healthnotes, Inc.; www.healthnotes.com Glucosamine Source: Integrative Medicine Communications; www.drkoop.com Glucosamine Source: Prima Communications, Inc.www.personalhealthzone.com Glyburide Source: Healthnotes, Inc.; www.healthnotes.com Glycyrrhiza1 Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Gymnema Alternative names: Gurmar; Gymnema sylvestre Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Gymnema Alternative names: Gymnema sylvestre Source: Healthnotes, Inc.; www.healthnotes.com Gymnema Source: Prima Communications, Inc.www.personalhealthzone.com Hibiscus Alternative names: Hibiscus, Roselle; Hibiscus sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Insulin Source: Healthnotes, Inc.; www.healthnotes.com Insulin Alternative names: Humalog, Humulin, Iletin, Novolin, Velosulin Source: Prima Communications, Inc.www.personalhealthzone.com

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Lipoic Acid Source: Prima Communications, Inc.www.personalhealthzone.com Medium Chain Triglycerides Source: Healthnotes, Inc.; www.healthnotes.com Momordica Alternative names: Bitter Gourd, Karela; Momordica charantia Linn. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Musa Banana Alternative names: Plantain, Banana; Musa sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Oral Corticosteroids Source: Healthnotes, Inc.; www.healthnotes.com Oral Hypoglycemics Source: Prima Communications, Inc.www.personalhealthzone.com Reishi Alternative names: Ganoderma lucidum Source: Healthnotes, Inc.; www.healthnotes.com Repaglinide Source: Healthnotes, Inc.; www.healthnotes.com Stevia Alternative names: Sweetleaf; Stevia rebaudiana Bertoni Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Sulfonylureas Source: Integrative Medicine Communications; www.drkoop.com Taurine Source: Healthnotes, Inc.; www.healthnotes.com Taurine Source: Prima Communications, Inc.www.personalhealthzone.com Thymus Extracts Source: Healthnotes, Inc.; www.healthnotes.com Trigonella Alternative names: Fenugreek; Trigonella foenum graecum L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Vanadate Source: Integrative Medicine Communications; www.drkoop.com

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Vanadyl Source: Integrative Medicine Communications; www.drkoop.com

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

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CHAPTER 4. DISSERTATIONS ON DIABETES MELLITUS Overview In this chapter, we will give you a bibliography on recent dissertations relating to diabetes mellitus. 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 “diabetes mellitus” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on diabetes mellitus, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Diabetes Mellitus 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 diabetes mellitus. 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: •

A Comparison of Intensity of Educational Intervention on Knowledge, Attitude, Weight and Metabolic Control in Obese Individuals with Type Ii Non-insulin Dependent Diabetes Mellitus by D'eramo, Gail Ann, Edd from Columbia University Teachers College, 1987, 157 pages http://wwwlib.umi.com/dissertations/fullcit/8804209

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A Diabetic Camp: Its Implications for Coping with Juvenile Diabetes Mellitus by Sperlich, Sonja B., Ph.D from The Catholic University of America, 1982, 196 pages http://wwwlib.umi.com/dissertations/fullcit/8221445

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A Genetic Dissection of Obesity and Type 2 Diabetes Mellitus in the Mouse by Stoehr, Jonathan Paul; Ph.D from The University of Wisconsin - Madison, 2002, 235 pages http://wwwlib.umi.com/dissertations/fullcit/3060449

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A History of Diabetes Mellitus in the United States, 1880-1990 by Presley, James Wright, Ph.D from The University of Texas at Austin, 1991, 1118 pages http://wwwlib.umi.com/dissertations/fullcit/9200706

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A Program Design for Hispanic Caregivers of Children with Newly Diagnosed Type 1 Diabetes Mellitus by Deris-atassi, Sandra; Psyd from Carlos Albizu University, 2002, 80 pages http://wwwlib.umi.com/dissertations/fullcit/3077971

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A Quantitative Investigation of Policies and Their Associated Costs for the Clinical Management of Diabetes Mellitus by Armstrong, Charles Paul, Ph.D from The University of Arizona, 1973, 230 pages http://wwwlib.umi.com/dissertations/fullcit/7328791

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A Self-control Behavior Techniques Course to Increase Adherence to the Goal for Frequency of Self-monitoring of Blood Glucose (diabetes Mellitus) by Jones, Phyllis Marie, Ph.D from University of Pittsburgh, 1989, 387 pages http://wwwlib.umi.com/dissertations/fullcit/8921397

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A Study of Knowledge, Beliefs, and Behavior Regarding Cardiovascular Health in a Sample of Adults with Diabetes Mellitus by Crici, Richard J.; Edd from Columbia University Teachers College, 2001, 107 pages http://wwwlib.umi.com/dissertations/fullcit/3014757

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Academic Achievement, Intellectual Functioning and Psychosocial Adjustment in Adolescents with a Chronic Illness (diabetes Mellitus, Seizure Disorder) by Segal, Stuart S., Ph.D from The University of Michigan, 1992, 316 pages http://wwwlib.umi.com/dissertations/fullcit/9308442

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Acute Effects of a Single Bout of Resistance Exercise on Insulin Sensitivity in Persons with Type-1 Diabetes Mellitus by Jimenez, Carolyn C.; Ph.D from Temple University, 2002, 181 pages http://wwwlib.umi.com/dissertations/fullcit/3040324

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Altered Renal Organic Cation Transport in Streptozotocin-induced Diabetes Mellitus by Grover, Brett Loring; Ph.D from University of Cincinnati, 2002, 177 pages http://wwwlib.umi.com/dissertations/fullcit/3041140

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An Exploratory Study of the Organization of Family Roles and Responsibilities around the Presence of Insulin-dependent Diabetes in a Child (diabetes Mellitus, Childhood Diabetes) by Diulio, Rosemary J., Edd from Columbia University Teachers College, 1990, 159 pages http://wwwlib.umi.com/dissertations/fullcit/9113464

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An Exploratory Study of Women and Their Families Managing Type 2 Diabetes Mellitus by Gerstle, Jinny Franze, Edd from Columbia University Teachers College, 1998, 152 pages http://wwwlib.umi.com/dissertations/fullcit/9839068

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An Investigation of a Predictive Model of Self-management and Quality of Life in Adults with Non-insulin-dependent Diabetes Mellitus by Sabik, Sharon Frances; Ph.D from University of Arkansas, 2002, 135 pages http://wwwlib.umi.com/dissertations/fullcit/3067058

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B Cells in Autoimmune Diabetes Mellitus: a Role for Maternal Humoral Immunity by Greeley, Siri Atma White; Ph.D from University of Pennsylvania, 2002, 156 pages http://wwwlib.umi.com/dissertations/fullcit/3043879

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Bittersweet: the Transformation of Diabetes into a Chronic Illness in Twentiethcentury America (diabetes Mellitus) by Feudtner, Chris, Ph.D from University of Pennsylvania, 1995, 614 pages http://wwwlib.umi.com/dissertations/fullcit/9532174

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Changes in Stature and Health Status As Related to the Emergence of Diabetes among Eastern Cherokee Indians in North Carolina (diabetes Mellitus, Eastern Cherokees) by Stivers, Deann Lee, Ph.D from The University of Tennessee, 1990, 144 pages http://wwwlib.umi.com/dissertations/fullcit/9112884

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Characterisation of Pathological Changes in the Pancreas and Kidneys in Type 2 Diabetes Mellitus by Zhao, Hailu; Ph.D from Chinese University of Hong Kong (people's Republic of China), 2002, 210 pages http://wwwlib.umi.com/dissertations/fullcit/3066614

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Characterization of Non-insulin-dependent Diabetes Mellitus in an Amerindian Population: the New World Syndrome among the Mvskoke (non Insulin Dependent) by Valdez, Rodolfo Antonio, Ph.D from The Pennsylvania State University, 1991, 215 pages http://wwwlib.umi.com/dissertations/fullcit/9127439

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Cigarette Smoking, Alcohol Use, and Type 2 Diabetes Mellitus among United States Adults: Findings from the Nhanes Iii, 1988--1994 by Fu, Qiang; , Ph.D from The University of Alabama, 1998, 122 pages http://wwwlib.umi.com/dissertations/fullcit/9958550

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Cognitive Functioning in the Elderly with Type Ii Adult Onset Diabetes Mellitus by Belfor, Nataliya V.; Ph.D from Pacific Graduate School of Psychology, 2002, 165 pages http://wwwlib.umi.com/dissertations/fullcit/3038055

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Correlates of Neurocognitive Abilities in Adolescents with Insulin-dependent Diabetes Mellitus (iddm) by Pollard, Naomi Lampert; Ph.D from The George Washington University, 2002, 119 pages http://wwwlib.umi.com/dissertations/fullcit/3045183

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Ct99: a Novel Nutraceutical Therapy for the Treatment of Diabetes Mellitus by Clark, Tod Andrew; Msc from The University of Manitoba (canada), 2002, 170 pages http://wwwlib.umi.com/dissertations/fullcit/MQ76917

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Cultural Construction of Diabetes Mellitus among Oklahoma Choctaw Elders and Choctaw Nation Health Care Providers: an Examination of Concordance between Models and Implications for Care-seeking and Compliance by Henderson, Linda Carson; Ph.D from University of South Florida, 2002, 154 pages http://wwwlib.umi.com/dissertations/fullcit/3078440

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Determinants of Differential Behavioral Responses to Diabetes Mellitus among an Urban Puerto Rican Population by Bernal, Henrietta, Ph.D from The University of Connecticut, 1984, 361 pages http://wwwlib.umi.com/dissertations/fullcit/8429755

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Diabetes Mellitus and Oklahoma Native Americans: a Case Study of Culture Change in Oklahoma Cherokee. by Wiedman, Dennis William, Ph.D from The University of Oklahoma, 1979, 246 pages http://wwwlib.umi.com/dissertations/fullcit/7918742

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Disease Related Knowledge and Disease Control of the Patient with Type Ii Diabetes Mellitus (tennessee) by Miller, Barbara Cratty, Ph.D from The University of Tennessee, 1986, 222 pages http://wwwlib.umi.com/dissertations/fullcit/8701808

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Disease Susceptibility in Human Insulin-dependent Diabetes Mellitus by Walsh, Linda Jane; Ph.D from Queen's University at Kingston (canada), 1980 http://wwwlib.umi.com/dissertations/fullcit/NK46411

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Disordered Eating in Female Adolescents with Insulin Dependent Diabetes Mellitus by Schwartz, Stefanie Anrea; Ph.D from The Herman M. Finch U. of Health Sciences the Chicago Medical Sch., 2002, 224 pages http://wwwlib.umi.com/dissertations/fullcit/3061543

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Effect of Acute Isocaloric Exercise at Different Intensities on Glucose and Insulin Metabolism in Obese Individuals and Obese Patients with Non-insulin-dependent Diabetes Mellitus by Kang, Jie, Ph.D from University of Pittsburgh, 1994, 86 pages http://wwwlib.umi.com/dissertations/fullcit/9508282

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Effectiveness of a Nurse Coordinated System of Telemedicine Care for Patients with Type 2 Diabetes Mellitus by Yip, Mei Po; Ph.D from Chinese University of Hong Kong (people's Republic of China), 2002, 237 pages http://wwwlib.umi.com/dissertations/fullcit/3052122

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Effectiveness of a Program Development Model for Training Health Care Professionals in the Management of Diabetes Mellitus by Villeneuve, Mary Elizabeth, Edd from Columbia University Teachers College, 1987, 137 pages http://wwwlib.umi.com/dissertations/fullcit/8804249

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Endothelial Activation in Young Adults with Type 1a Diabetes Mellitus: an Evaluation of Soluble Cellular Adhesion Molecules by Young, Laura Anne; Ph.D from University of Cincinnati, 2002, 82 pages http://wwwlib.umi.com/dissertations/fullcit/3062628

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Enzyme Adaptation and Diabetes Mellitus in Pima Indians. by Mandarino, Lawrence John, Ph.D from Arizona State University, 1978, 130 pages http://wwwlib.umi.com/dissertations/fullcit/7810564

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Evaluation of an Andragogical Intervention on the Self-care Behaviors of Adults with Non-insulin Dependent Diabetes Mellitus by Robertson, Judith Lee; Ph.D from University of Arkansas, 2002, 113 pages http://wwwlib.umi.com/dissertations/fullcit/3055343

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Evaluation of the Acute Effects of Alpha-lipoic Acid and Fish Oil, Alone and in Combination, on the Postprandial Lipemic Response in Non-insulin-dependent Diabetes Mellitus by Kaye, Suzanne Avril; MSC from University of Guelph (canada), 2002, 84 pages http://wwwlib.umi.com/dissertations/fullcit/MQ71198

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Evaluation of the Effectiveness of an Educational Program Designed to Train Undereducated Diabetes Mellitus Patients to Follow the Diabetic Diet by Barnes, Clara Jean Houghtaling, Ph.D from Virginia Polytechnic Institute and State University, 1981, 99 pages http://wwwlib.umi.com/dissertations/fullcit/8206726

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Evaluation of the Effectiveness of Home Health Care Services for Inpatients Discharged with a Diagnosis of Cerebrovascular Disease or Diabetes Mellitus (taiwan) by Lin, Cheng-chieh; Ph.D from University of South Carolina, 2002, 189 pages http://wwwlib.umi.com/dissertations/fullcit/3059455

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Facilitating Small Group Education for Adults Living with Type Ii Diabetes Mellitus by Loveys, W. Joy; Maded from St. Francis Xavier University (canada), 2002, 131 pages http://wwwlib.umi.com/dissertations/fullcit/MQ73382

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Factors That Predict Self-care Behaviors of Non-insulin-dependent African Americans (diabetes Mellitus) by Campbell, Hal Lloyd, Edd from Northern Illinois University, 1993, 217 pages http://wwwlib.umi.com/dissertations/fullcit/9414226

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Family Factors: a Study of Diabetic and Non-diabetic Families (diabetes Mellitus) by Claes, Jacalyn Anne, Ph.D from The University of Iowa, 1990, 135 pages http://wwwlib.umi.com/dissertations/fullcit/9112407

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Fatigue in Diabetes Mellitus: Testing a Middle Range Theory of Well-being Derived from Neuman's Theory of Optimal Client System Stability and the Neuman Systems Model by Casalenuovo, Gregory Allen; Ph.D from The University of Tennessee, 2002, 117 pages http://wwwlib.umi.com/dissertations/fullcit/3054100

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General and Health Specific Locus of Control: Factors Associated with Adjustment in Children with Diabetes Mellitus by Berger, Merrill, Ph.D from University of Southern California, 1983 http://wwwlib.umi.com/dissertations/fullcit/f2688565

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Glycosylated Hemoglobin and the Oxygen Kinetics in Individuals with Type Ii Diabetes (diabetes Mellitus, Ventilatory Threshold) by Dwyer, Gregory Byron, Ph.D from Indiana University, 1992, 152 pages http://wwwlib.umi.com/dissertations/fullcit/9310326

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Health and Social Support in Families with Children with Diabetes Mellitus by Frey, Maureen Ann, Ph.D from Wayne State University, 1987, 252 pages http://wwwlib.umi.com/dissertations/fullcit/8714539

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Health Beliefs, Social Support, and Self-care Behaviors of Older Thai Persons with Non-insulin-dependent Diabetes Mellitus (niddm) by Surit, Pattama; Dnsc from The Catholic University of America, 2002, 171 pages http://wwwlib.umi.com/dissertations/fullcit/3047162

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High Incidence of Diabetes in the O'odham: Community Approach in Prevention and Control for a Native American Tribe (diabetes Mellitus, Arizona) by Cudel, Evelyne, Ph.D from University of California, Riverside, 1994, 182 pages http://wwwlib.umi.com/dissertations/fullcit/9522251

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Identification of Genetic Factors Contributing to the Development of Type 1 (insulindependent) Diabetes Mellitus in the Northern Ireland Population by Mccormack, Rose Margaret; Ph.D from Queen's University of Belfast (northern Ireland), 2002 http://wwwlib.umi.com/dissertations/fullcit/f327697

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Impact of Social Support, Self-efficacy, and Outcome Expectations on Self-care Behaviors and Glycemic Control in Caucasian and African-american Adults with Type 2 Diabetes Mellitus by Chlebowy, Diane Orr; Ph.D from The Ohio State University, 2002, 195 pages http://wwwlib.umi.com/dissertations/fullcit/3059218

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Insulin Injection Site Selection and Cognitive Factors Associated with Diabetes Mellitus in Children by Rickabaugh, Timothy Elwood, Ph.D from Syracuse University, 1997, 156 pages http://wwwlib.umi.com/dissertations/fullcit/9842222

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Insulin-dependent Diabetes Mellitus and Cognitive Dysfunction by Nash, Stacey S.; Ma from Florida Atlantic University, 2002, 55 pages http://wwwlib.umi.com/dissertations/fullcit/1410397

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Intrinsic Motivation, Health Status, and Health Behavior in Adults with Diabetes Mellitus: Implications for Patient Education by Heady, Susan A., Ph.D from Saint Louis University, 1992, 109 pages http://wwwlib.umi.com/dissertations/fullcit/9233798

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Introducing a Clinically Applicable Ultrasound Method for the Study of Gastric Emptying in Health and Disease: a Study in Healthy Subjects and Patients with Diabetes Mellitus by Darwiche, Gassan; Ph.D from Lunds Universitet (sweden), 2003, 140 pages http://wwwlib.umi.com/dissertations/fullcit/f148401

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Investigation of Biochemical Mechanisms Associated with Insulin Resistance in the Non-insulin-dependent Diabetes Mellitus by Huang, To-yu; Ph.D from The University of Tennessee, 2002, 141 pages http://wwwlib.umi.com/dissertations/fullcit/3062309

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Liver Transplantation in Cirrhotic Patients with Diabetes Mellitus: Midterm Results, Survival, and Adverse Events by Blanco Gonzalez, Jose Javier; Dr from Universidad De Navarra (spain), 2002, 158 pages http://wwwlib.umi.com/dissertations/fullcit/f722465

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Living with Diabetes Mellitus: the Experience of Native American Indians by Parker, Judy Goforth, Ph.D from Texas Woman's University, 1992, 220 pages http://wwwlib.umi.com/dissertations/fullcit/9227096

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Loss of Protective Foot Sensation and Shoe Wearing Habits in Persons with Diabetes Mellitus by Broussard, Craig L.; Ph.D from Texas Woman's University, 2002, 127 pages http://wwwlib.umi.com/dissertations/fullcit/3046299

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Maternal Weight Relationships and Infant Outcomes in Women with Gestational Diabetes Mellitus As Compared to the Weight Gain Recommendations for Pregnancy of the Institutes of Medicine by Jonaitis, Mary Ann; Edd from Columbia University Teachers College, 2002, 136 pages http://wwwlib.umi.com/dissertations/fullcit/3052886

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Morphometric, Histochemical, and Hormonal Studies of the Testis in Experimental Diabetes Mellitus in the Rat by Anderson, Judith Esther; Ph.D from The University of Manitoba (canada), 1985 http://wwwlib.umi.com/dissertations/fullcit/NL33535

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Mortality from Ischemic Heart Disease and Diabetes Mellitus in Bexar County: a Comparison of the Mexican Origin and Anglo Populations by Tan, Joo Ean, Ph.D from The University of Texas at Austin, 1991, 190 pages http://wwwlib.umi.com/dissertations/fullcit/9212651

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Mothers' Perceptions of Their Families' Needs When One of Their Children Has Diabetes Mellitus: a Developmental Perspective (chronic Illness) by Vanfleet, Rise Jayne, Ph.D from The Pennsylvania State University, 1985, 221 pages http://wwwlib.umi.com/dissertations/fullcit/8606395

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Non-insulin Dependent (type Ii) Diabetes Mellitus in the Eastern Cherokee of Western North Carolina (native American) by Quiggins, Patricia Ann, Ph.D from The University of Tennessee, 1990, 113 pages http://wwwlib.umi.com/dissertations/fullcit/9112876

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Oxygen Free Radical Scavenging Systems in Clinical and Experimental (chemical and Spontaneous) Diabetes Mellitus by Wohaieb, Saleh A; Ph.D from The University of British Columbia (canada), 1987 http://wwwlib.umi.com/dissertations/fullcit/NL41877

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Perceptions and Coping Strategies of Parents of Preschool Children with Insulindependent Diabetes Mellitus by Feldman, Hilary Lee, Ph.D from University of Pittsburgh, 1993, 147 pages http://wwwlib.umi.com/dissertations/fullcit/9421463

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Perceptions of Pediatricians Regarding the Treatment and Prevention of Type 2 Diabetes Mellitus in Children and Adolescents by Ditmyer, Marcia Mastracci; Ph.D from The University of Toledo, 2002, 250 pages http://wwwlib.umi.com/dissertations/fullcit/3046006

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Prevention of Non-insulin-dependent Diabetes Mellitus (niddm) among the Southern Cheyenne: an Analysis of Its Prevalence, Risk Factors and Initial Treatment among Full-blood Indians by Lohn, Christina, Ph.D from University of Kansas, 1995, 199 pages http://wwwlib.umi.com/dissertations/fullcit/9627489

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Proinsulin and Insulin Sensitivity As Predictors for Type 2 Diabetes Mellitus and Coronary Heart Disease: Clinical Epidemiological Studies with Up to 27 Years of Follow-up by Zethelius, Bjorn; Md from Uppsala Universitet (sweden), 2003, 67 pages http://wwwlib.umi.com/dissertations/fullcit/f158145

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Psychological Stress, Hardiness, and Glycemic Control in Adults with Type Ii Diabetes (diabetes Mellitus) by Hanks, Robert Bush, Edd from Auburn University, 1993, 89 pages http://wwwlib.umi.com/dissertations/fullcit/9411413

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Psychosocial Determinants of Self-care Practices and Glycemic Control in Black Women with Type Ii - Diabetes Mellitus by Skelly, Anne Herrstrom, Ph.D from State University of New York at Buffalo, 1992, 277 pages http://wwwlib.umi.com/dissertations/fullcit/9228094

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Quality of Life and Family Dynamics among People with Type 1 Diabetes (diabetes Mellitus) by Rajaram, Shireen Sheela, Ph.D from University of Kentucky, 1993, 188 pages http://wwwlib.umi.com/dissertations/fullcit/9402848

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Relationship of Metabolic Control of Diabetes Mellitus to Cognitive Development, Social Support, and Diabetes-related Knowledge by Saathoff, Jeanne K., Ph.D from University of Missouri - Columbia, 1989, 72 pages http://wwwlib.umi.com/dissertations/fullcit/9010596

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Relationships between Health Beliefs and Self Foot Care Practices among Persons with Type 2 Diabetes Mellitus by Crowder, Katherine Pennigar; Msn from Clarkson College, 2002, 121 pages http://wwwlib.umi.com/dissertations/fullcit/1410656

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Self-efficacy and Stage of Change As Predictors of Self-care Behaviors in Children with Insulin-dependent Diabetes Mellitus by Cant, M. E. Catherine; Ph.D from The George Washington University, 2003, 116 pages http://wwwlib.umi.com/dissertations/fullcit/3075179

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Semicarbazide-sensitive Amine Oxidase and Vascular Complications in Diabetes Mellitus: Biochemical and Molecular Aspects by Nordquist, Jenny; Ph.D from Uppsala Universitet (sweden), 2002, 51 pages http://wwwlib.umi.com/dissertations/fullcit/f744945

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Sociocultural Risk Factors of Non-insulin Dependent Diabetes Mellitus among Middle-class African Americans in Central Ohio by Robinson, Jacquelyn Patricia Price; Ph.D from The Ohio State University, 2003, 233 pages http://wwwlib.umi.com/dissertations/fullcit/3088884

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The Association between Hepatitis C Virus Infection and Type 2 Diabetes Mellitus by Mehta, Shruti Hemendra; Ph.D from The Johns Hopkins University, 2002, 166 pages http://wwwlib.umi.com/dissertations/fullcit/3046513

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The Biocultural Profile of a Population at Risk in the U.s.-mexico Border (united States Mexico Border, Mexico, Arizona, Diabetes Mellitus, Farmworkers) by Cabreramereb, Claudine, Ph.D from The University of Arizona, 1992, 417 pages http://wwwlib.umi.com/dissertations/fullcit/9309019

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The Development of a Board Game on Self Management of Diabetes Mellitus for Children with Type I Diabetes (health, Chronic Disease) by Mason, David Lawrence, Edd from Temple University, 1986, 225 pages http://wwwlib.umi.com/dissertations/fullcit/8611896

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The Diagnosis and Inheritance of Diabetes Mellitus in Kk Mice by Harris, Muriel Joyce; Advdeg from University of Toronto (canada), 1969 http://wwwlib.umi.com/dissertations/fullcit/NK06312

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The Effect of a Psychosocial Support Group on Adaptations and Coping Strategies of Women with Insulin-dependent Diabetes Mellitus by Holvey, Erin Lyn, Ph.D from University of Southern California, 1989 http://wwwlib.umi.com/dissertations/fullcit/f3124324

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The Effect of Anxiety Management Training on the Course and Control of Juvenile Diabetes Mellitus by Rose, Malcolm I; Ph.D from University of Ottawa (canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK53282

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The Effect of Family Responsibility Patterns on Diabetes Control in Children and Adolescents with Insulin-dependent Diabetes Mellitus by Vella, Anne Maxwell Mostellar, Edd from Auburn University, 1996, 104 pages http://wwwlib.umi.com/dissertations/fullcit/9619214

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The Effect of Menstrual Cycle on Fasting Blood Glucose Patterns of Insulin Dependent Women with Diabetes Mellitus by Kandt, Denise Charmane, Edd from University of Arkansas, 1992, 159 pages http://wwwlib.umi.com/dissertations/fullcit/9334094

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The Effect of Stress Inoculation Training Procedures on the Control of Blood Glucose and Stress Levels in Individuals with Diabetes Mellitus by Amory, Kevin Vincent, Ph.D from The University of Iowa, 1987, 103 pages http://wwwlib.umi.com/dissertations/fullcit/8729432

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The Effects of a Physical Activity Program on Children Ages 5 to 11 Years with Insulin-dependent Diabetes Mellitus by Campaigne, Barbara Naomi, Ph.D from The University of Michigan, 1982, 165 pages http://wwwlib.umi.com/dissertations/fullcit/8304458

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The Effects of an Aerobic Circuit Training Program on Cardiorespiratory Endurance, Metabolic Control and Muscular Strength in Adolescent Males with Type I Diabetes Mellitus by Mosher, Patricia Elizabeth, Edd from University of Miami, 1989, 137 pages http://wwwlib.umi.com/dissertations/fullcit/9007221

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The Efficacy of Intensive Individual Play Therapy for Children Diagnosed with Insulin-dependent Diabetes Mellitus by Jones, Elizabeth Murphy; Ph.D from University of North Texas, 2000, 117 pages http://wwwlib.umi.com/dissertations/fullcit/9990800

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The Functioning of Families Relative to the Visibility of a Disabling Condition: a Study of Cerebral Palsy and Diabetes (visible Disabilities, Diabetes Mellitus) by Saddler, Anne Leigh, Ph.D from Wayne State University, 1989, 189 pages http://wwwlib.umi.com/dissertations/fullcit/9022444

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The Interaction of Family Characteristics and Metabolic Control in Type Ii Noninsulin-requiring Diabetes Mellitus (systems Theory) by Smith, Nancy M., Ph.D from The Florida State University, 1986, 208 pages http://wwwlib.umi.com/dissertations/fullcit/8616907

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The Long-term Effectiveness of Dialysis, Kidney Transplantation and Pancreas Transplantation for Patients with Diabetes Mellitus and Renal Failure: a Decision Analysis by Knoll, Gregory Allan; Msc from University of Ottawa (canada), 2002, 122 pages http://wwwlib.umi.com/dissertations/fullcit/MQ72774

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The Personal Meaning of Chronic Illness Within the Context of Everday Life: a Case Study of the Experiences of People with Insulin-dependent Diabetes (diabetes Mellitus) by Oram, Barbara Jean, Ph.D from University of Toronto (canada), 1992, 225 pages http://wwwlib.umi.com/dissertations/fullcit/NN73787

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The Relationship between Diabetes Self-management and Executive Functions in Non-insulin-dependent Diabetes Mellitus by Merrick, Euriel Elsworth; Ph.D from Pacific Graduate School of Psychology, 2002, 113 pages http://wwwlib.umi.com/dissertations/fullcit/3071917

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The Relationship between Perceived Self-efficacy, Regimen Adherence, and Glycemic Control in Adolescents with Type 1 Diabetes Mellitus: a Pilot Study by Alteza, Antonieta Pelias; Msn from The University of Texas - Pan American, 2002, 83 pages http://wwwlib.umi.com/dissertations/fullcit/1410270

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The Relationship of Cognitive Development on Assuming Self-management in Juvenile Diabetes Mellitus: an Application of Piagetian Theory in Assessing Readiness for Self-care in a Chronic Illness (glycohemoglobin, Locus of Control, Information) by Diamond, Kenneth, Ph.D from State University of New York at Buffalo, 1984, 104 pages http://wwwlib.umi.com/dissertations/fullcit/8410540

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The Relationship of Metabolic Control to Hardiness, Self-efficacy, and Perceived Medication Adherence in Adults with Diabetes Mellitus by Allison, Ok Chon Pyon; Ph.D from Virginia Commonwealth University, 2003, 142 pages http://wwwlib.umi.com/dissertations/fullcit/3091822

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The Relationship of Obesity and Body Fat Distribution to Non-insulin Dependent Diabetes Mellitus in a Navajo Community by Hall, Teri-christine Ruan, Ph.D from The University of Wisconsin - Madison, 1990, 92 pages http://wwwlib.umi.com/dissertations/fullcit/9027499

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The Relationship of Self-efficacy and Health Value to Type 2 Diabetes Mellitus Outcomes by Matheis-huene, Melanie Marie; Ph.D from Indiana State University, 2002, 51 pages http://wwwlib.umi.com/dissertations/fullcit/3061557

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The Relationships among Knowledge of Diabetes, Attitude toward Diabetes, Family and Friends' Support, Benefits of and Barriers to Treatment and Compliance with Health Regimens of Jordanian Adolescents with Insulin Dependent Diabetes Mellitus by Al-akour, Nemeh Ahmad; Dnsc from Widener University School of Nursing, 2003, 214 pages http://wwwlib.umi.com/dissertations/fullcit/3082998

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The Short-term Efficacy of Bay G 5421 (acarbose) in Patients with Non-insulin Dependent Diabetes Mellitus by Silver, Dorothy Claire, Edd from Boston University, 1983, 112 pages http://wwwlib.umi.com/dissertations/fullcit/8401844

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The Social Implications of Diabetes Mellitus on the Adolescent and the Family by Schoeman, Johanna Petronella, Dphil from University of Pretoria (south Africa), 1989 http://wwwlib.umi.com/dissertations/fullcit/f3584020

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Treatment Acceptability for the Prevention of Obesity and Type 2 Diabetes Mellitus: the Effects of Ethnicity, Weight, and Genetic Predisposition by Thaw, Jean Marie; Ph.D from Louisiana State University and Agricultural & Mechanical College, 2002, 97 pages http://wwwlib.umi.com/dissertations/fullcit/3069735

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Wellness Stories of Native American Patients of the Winnebago/omaha Project: an Ethnographic Perspective (diabetes Mellitus) by Hovland, Marcia Lee Kaiser, Edd from University of South Dakota, 1995, 453 pages http://wwwlib.umi.com/dissertations/fullcit/9535508

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

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

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

A Study To Evaluate The Safety And Efficacy Of An Investigational Diabetes Drug In Poorly Controlled Type II Diabetics Condition(s): Non-Insulin-Dependent Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): (Sponsor Name Pending) Purpose - Excerpt: The purpose of this research study is to determine if a new investigational diabetes drug is safe and effective in treating people who have Type II diabetes mellitus with very high HbA1c or FPG (fasting plasma glucose) levels. The HbA1c test, also called the hemoglobin A1c test or glycated hemoglobin test, is a measurement of the average amount of sugar in the blood over the last 2 to 3 months. FPG (fasting plasma glucose) is a test that measures the amount of sugar in the blood after an 8 hour fast. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00067951

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These are listed at www.ClinicalTrials.gov.

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Action to Control Cardiovascular Risk in Diabetes (ACCORD) Condition(s): Atherosclerosis; Cardiovascular Diseases; Hypercholesterolemia; Hypertension; Diabetes Mellitus, non-insulin dependent; Diabetes Mellitus; Coronary Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To prevent major cardiovascular events (heart attack, stroke or cardiovascular death) in adults with Type 2 diabetes mellitus using intensive glycemic control, intensive blood pressure control, and intensive lipid management. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000620

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Bypass Angioplasty Revascularization Investigation in Type 2 Diabetics (BARI 2D) Condition(s): Coronary Disease; Cardiovascular Diseases; Heart Diseases; Insulin Resistance; Diabetes Mellitus; Diabetes Mellitus, non-insulin dependent Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The BARI 2D trial is a multicenter study that uses a 2x2 factorial design, with 2800 patients being assigned at random to initial elective revascularization with aggressive medical therapy or aggressive medical therapy alone with equal probability, and simultaneously being assigned at random to an insulin providing or insulin sensitizing strategy of glycemic control (with a target value for HbA1c of <7.0% for all patients). SPECIFIC AIMS A. Primary Aim The primary aim of the BARI 2D trial is to test the following two hypotheses of treatment efficacy in 2800 patients with Type 2 diabetes mellitus and documented stable CAD, in the setting of uniform glycemic control and intensive management of all other risk factors including dyslipidemia, hypertension, smoking, and obesity: 1. Coronary Revascularization Hypothesis: a strategy of initial elective revascularization of choice (surgical or catheter-based) combined with aggressive medical therapy results in lower 5-year mortality compared to a strategy of aggressive medical therapy alone; 2. Method of Glycemic Control Hypothesis: with a target HbA1c level of <7.0%, a strategy of hyperglycemia management directed at insulin sensitization results in lower 5-year mortality compared to a strategy of insulin provision. B. Secondary Aims The secondary aims of the BARI 2D trial include: a) comparing the death, myocardial infarction or stroke combined endpoint event rate between the revascularization versus medical therapy groups and between the insulin sensitization versus insulin provision groups; b) comparing rates of myocardial infarction, other ischemic events, angina and quality of life associated with each revascularization and hyperglycemia management strategy; c) evaluating the relative economic costs associated with the trial treatment strategies, d) exploring the effect of glycemic control strategy on the progression and mechanism of vasculopathy including changes in PAI-1 gene expression. Phase(s): Phase III Study Type: Interventional

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006305 •

Compare blood sugar level between Lantus in the morning and other insulins in Type 1 diabetes adolescents Condition(s): Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): Aventis Pharmaceuticals Purpose - Excerpt: The purpose of the study is to compare the effect in blood sugar control between Lantus and twice daily intermediate acting insulins (NPH or Lente) when used as the basal insulin in a multiple daily injection setting with fast acting insulin (Lispro) Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00046501

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Continuous Glucose Monitoring in Children With Type 1 Diabetes Mellitus Condition(s): Diabetes Mellitus, Insulin-Dependent Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Child Health and Human Development (NICHD); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: This study will evaluate the safety and effectiveness of a continuous glucose monitor in children with Type 1 diabetes mellitus (T1DM). Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069628

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Effect of AC2993 with or without Immunosuppression on Beta Cell Function in Patients with Type I Diabetes Condition(s): Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: This study will determine 1) the safety of AC2993 in patients with type I diabetes; 2) the ability of AC2993 to improve beta cell function; and 3) the effects of immunosuppression on beta cell function. Type I diabetes is an autoimmune disease, in which the immune system attacks the beta cells of the pancreas. These cells produce insulin, which regulates blood sugar. AC2993 may improve the pancreas's ability to produce insulin and help control blood sugar, but it may also activate the original immune response that caused the diabetes. Thus, this study will examine the effects of AC2993 alone as well as in combination with immunosuppressive drugs. Patients between 18 and 60 years of age who have type I diabetes mellitus may be eligible for

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this 20-month study. They must have had diabetes for at least 5 years and require insulin treatment. Candidates will be screened with a questionnaire, followed by medical history and physical examination, blood and urine tests, a chest x-ray and skin test for tuberculosis, electrocardiogram (EKG), and arginine stimulated C-peptide test (see description below). Participants will undergo the following tests and procedures: Advanced screening phase: Participants undergo a diabetes education program, including instruction on frequent blood glucose monitoring, dietary education on counting carbohydrates, intensive insulin therapy, review of signs and symptoms of low blood sugar (hypoglycemia), and potential treatment with glucagon shots. Patients must administer insulin via an insulin pump or take at least four injections per day including glargine (Lantus) insulin. 4-month run-in phase - Arginine-stimulated C-peptide test: This test measures the body's insulin production. The patient is injected with a liquid containing arginine, a normal constituent of food that increases insulin release from beta cells into the blood stream. After the injection, seven blood samples are collected over 10 minutes. - Mixed meal stimulated C-peptide test with acetaminophen: This test assesses the response of the beta cells to an ordinary meal and the time it takes for food to pass through the stomach. The patient drinks a food supplement and takes acetaminophen (Tylenol). Blood samples are then drawn through a catheter (plastic tube placed in a vein) every 30 minutes for 4 hours to measure levels of various hormones and the concentration of acetaminophen. - Euglycemic clamp: This test measures the body's sensitivity to insulin. The patient is admitted to the NIH Clinical Center the evening before the study and receives an insulin drip through an intravenous (IV) line overnight to maintain normal blood sugar levels. The next morning, another IV line is placed, glucose and insulin are being infused and frequent blood samples are being collected to measure blood sugar andinsulin levels. Test period A: Patients are randomly assigned to receive 1) AC2993 alone or 2) AC2993 plus immunosuppressive drugs (sirolimus and tacrolimus), along with an antibiotic to reduce the risk of fungal infections, for 6 months. If the patient receives immunosuppressive agents, blood is drawn twice a week to measure drug levels, then once a week for 1 month, and then every 2 weeks for the rest of the study. AC2993 is injected under the skin twice a day at first and then 4 times a day in increasing doses. Test period B: Patients who took immunosuppressive drugs in test period A continue to take them for the 6 months of test period B. Patients who took AC2993 in test period A do not take it in test period B, and those who did not take AC2993 in test period A do take it in test period B. Patients have three argininestimulated C-peptide tests during the last 3 months of test periods A and B and a euglycemic clamp study and mixed meal study at the end of each test period. Drug side effects are monitored throughout the study. Treatment and evaluation may be extended beyond the 20-month study period for patients who benefit from the treatment. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00064714 •

Efficacy, safety, tolerability and pharmacokinetics of Ro 205-2349 in patients with Type 2 diabetes mellitus Condition(s): Diabetes Study Status: This study is currently recruiting patients. Sponsor(s): Hoffmann-La Roche

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Purpose - Excerpt: The objectives of the study are: To determine the dose(s) of Ro 2052349 which, when compared to placebo, are efficacious, safe, and tolerable in improving glycemic control in patients with type 2 diabetes. Doses of 2 to 5 mg/day will be studied. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00057304 •

Evaluation of a Diabetes Vaccine in Newly Diagnosed Diabetics Condition(s): Insulin-Dependent Diabetes Mellitus; Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID); Immune Tolerance Network Purpose - Excerpt: Insulin dependent diabetes mellitus (also called type 1 diabetes mellitus or T1DM) is caused by the destruction of insulin-producing cells in the pancreas. People with T1DM do not produce enough insulin, which is necessary for proper regulation of blood sugar levels. T1DM is an autoimmune disease. An autoimmune disease is a disease in which the body's immune system attacks the body itself. In addition to regulating blood sugar, insulin may have the ability to protect cells in the pancreas from attack by the immune system. This study will evaluate whether an insulin-based vaccine can protect cells from autoimmune destruction. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00057499

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Evaluation of the Effect on Glucose Control and the Safety and Tolerability of AC2993 in Patients With Type 2 Diabetes Mellitus Condition(s): Diabetes Mellitus, Non-Insulin-Dependent Study Status: This study is currently recruiting patients. Sponsor(s): Amylin Pharmaceuticals Purpose - Excerpt: This is a multicenter, randomized, blinded, placebo-controlled, shortterm, dose-response study to examine the effects on glucose control of AC2993 as compared to placebo in patients with type 2 diabetes. Patients will be individuals with type 2 diabetes treated with metformin for at least 3 months prior to screening. Patients whose diabetes management consists of diet and exercise will also be eligible for this study. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00044694

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Genetic Studies of Insulin and Diabetes Condition(s): Diabetes Mellitus; Insulin Resistance Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The study will allow researchers to obtain blood, plasma, DNA, and RNA for genetic studies of insulin. There will be a focus on the causes of insulin resistance and diabetes mellitus. Insulin is a hormone found in the body that controls the level of sugar in the blood. Insulin resistance refers to conditions like diabetes when insulin does not work properly. In this study researchers would like to compare patients with diabetes and other forms of insulin resistance to normal individuals. The study will investigate how insulin attaches to cells. Researchers will take 4 to 6 ounces (100-150 ml) of blood from adult patients and may request up to 12 ounces (one unit) of blood if necessary. Skin samples may be taken for a biopsy if further genetic testing is necessary. In addition some patients may be asked not to eat for up to 72 hours prior to testing. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001987

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Gestational Diabetes Mellitus Trial Condition(s): Diabetes, Gestational Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Child Health and Human Development (NICHD) Purpose - Excerpt: Gestational diabetes mellitus (GDM) is a type of diabetes (high blood sugar) that occurs in pregnant women. This study will determine whether treating pregnant women with mild GDM improves the health of their babies. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069576

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Glycemic Control and Complications in Diabetes Mellitus Type 2 (VADT) Condition(s): Type 2 diabetes mellitus Study Status: This study is currently recruiting patients. Sponsor(s): Department of Veterans Affairs; Department of Veterans Affairs Cooperative Studies Program; ADA Purpose - Excerpt: This study is a prospective, 2-arm, randomized controlled trial to determine whether glycemic control, achieved through intensification of treatment, is effective in preventing clinical macrovascular complications in patients with type 2 DM who are no longer responsive to oral agents alone. The study consists of a two-year accrual period and five years of follow-up (7 years total) of 1700 patients across 20 centers. We have powered the study to detect a 25% reduction in the primary event rate. Additional study goals are to determine whether the expenditures, discomfort, and adverse effects associated with intensive intervention are justified in terms of their clinical benefits, considering both macrovascular and microvascular complications. Phase(s): Phase III

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Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00032487 •

Ingested Interferon Alpha: Prolongation or Permanence of the "Honeymoon" Phase in Newly Diagnosed Type 1 Diabetes Mellitus Condition(s): Diabetes Mellitus, Type 1 Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: We hypothesize that ingested human recombinant interferon-alpha (hrIFN-a) will prolong the "honeymoon" period and enhance B cell survival in type 1 diabetes in a phase II randomized, placebo-controlled, double-blind clinical trial. We have demonstrated that ingested IFN-a prevents type 1 diabetes in the NOD mouse, prolongs the "honeymoon" period in newly diagnosed type 1 diabetics, and delays murine islet allograft rejection. The natural history of type 1 diabetes is unique for a phase frequently referred as the "honeymoon," a period in which the insulin need becomes minimal and glycemic control improves. The B cell (the insulin producing cell) partially recovers. However, as with all honeymoons, they end and the patient becomes completely insulin-deficient. The general consensus of the international diabetes community is to test potential preventive therapies for type 1 diabetes in newly diagnosed patients. Prolongation of the honeymoon as the reversal of the disease is considered a positive result. In this phase II randomized, double-blind, parallel-design clinical trial we will determine whether ingested (oral) human recombinant IFN-a will prolong the "honeymoon" period and increase counterregulatory anti-inflammatory cytokine(s). We will determine the safety and efficacy of 30,000 units ingested hrIFN-a vs placebo in eighty patients with newly diagnosed type 1 diabetes in a phase II trial for one year. Primary outcome measures will be a 30% increase in C-peptide levels released after Sustacal stimulation at 3, 6, 9, and 12 months after entry. Secondary outcome will be decreasing titers of islet cell antibodies (ICA). If successful, a larger and longer phase III trial of prevention of type 1 diabetes in high risk patients will be undertaken. We will also determine if ingested hrIFN-a increases IL-4, IL-10 or IFN-a production in peripheral blood mononuclear cells (PMNC) from patients with recent onset type 1 diabetes. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005665

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Interferon-Alpha for Diabetes Mellitus Type 1 Condition(s): Insulin-Dependent Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: This study will examine whether interferon alpha can prevent or minimize the risk of complications from diabetes type 1. This type of diabetes results when the body's immune system attacks cells in the pancreas that produce insulin, a hormone that helps regulate blood sugar levels. Many common complications of

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diabetes, such as blindness, kidney failure, nerve damage and artery disease leading to heart attacks and strokes, are related to high blood sugar. This study will see if interferon alpha, given early in the disease, can stop or slow the immune attack on insulin-producing cells. Animal experiments have shown that interferon alpha taken by mouth may stop the development of diabetes. Patients between 3 and 25 years of age with type 1 diabetes mellitus of less than 6 weeks duration may be eligible for this study. Candidates undergo a medical history, physical examination, routine and research blood tests, a urine test and a Boost stimulation test. For the Boost test, patients fast overnight and do not take the next morning's insulin dose. A blood sample is drawn to measure fasting sugar and C-peptide levels. The patient then drinks a food supplement (Boost High Protein) and blood draws are repeated for sugar and C-peptide measurements at 15, 30, 60, 90 and 120 minutes after ingesting the liquid. Participants are randomly assigned to treatment with either interferon alpha or placebo (an inactive, look-alike substance) once a day by mouth for up to 12 months. The active compound consists of either 5,000 or 30,000 units of interferon alpha in a tablespoon of salt water; the placebo consists of salt water alone. Follow-up visits are scheduled at 1, 2, 3, 6, 9 and 12 months for a repeat Boost test, routine and research blood tests, and a physical examination to evaluate possible drug effects. A small blood sample will be drawn for HLA-typing, a genetic test similar to blood typing, to examine the makeup of genes thought to affect diabetes. The results of the genetic studies will be kept confidential. Patients who finish 12 months of treatment before the entire study ends may decide to continue treatment until all study patients completed the protocol. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00024518 •

Lactobacillus plantarum as therapy for NK-T cell deficiency Condition(s): Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: The etiology of immune-mediated diabetes mellitus (IMD) remains unclear. However, previous studies indicate that autoimmunity may be a result of dysfunction of natural killer T cells (NK-T cells). Newly diagnoses patients with IMD have been shown in our laboratory to have significantly lower NK-T cells than normal controls. Other studies have shown that oral administration of lactobacillus can boost NK-T cell activity in children with HIV without side effects. Our objective is to evaluate the effect of lactobacillus administration on NK-T cell activity in patients with IMD Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00011141

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LY333531 Treatment for Symptomatic Peripheral Neuropathy in Patients with Diabetes. Condition(s): Diabetic Neuropathies; Diabetes Mellitus, Insulin-Dependent; Diabetes Mellitus, Non-Insulin-Dependent

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Study Status: This study is currently recruiting patients. Sponsor(s): Eli Lilly and Company Purpose - Excerpt: The purpose of this protocol is to determine if an investigational drug known as LY333531 is effective in treating nerve malfunction in diabetes. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00044408 •

Pilot Study of Vedic Medicine for Type 2 Diabetes Condition(s): Diabetes Mellitus, Type 2 Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: The purpose of this study is to determine the feasibility and effectiveness of a multimodality Vedic Medicine treatment protocol for the management of newly diagnosed type 2 diabetes. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00065650

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Prevention of Type 2 Diabetes Mellitus in Children Condition(s): Diabetes Mellitus, Type 2 Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: This is a pilot study to examine the short-term effects of supervised exercise on metabolic risk factors for type 2 diabetes mellitus in children from a population that is at high risk for this disease. We hypothesize that exercise will significantly improve insulin sensitivity in all children, especially in children who are already insulin resistant, thereby lowering the risk that they will go on to develop type 2 diabetes mellitus. The specific hypotheses being tested are: 1. Insulin resistance will be most evident in overweight children while an impaired ability of the pancreas to release insulin will be most evident in children with a family history of type 2 diabetes mellitus. 2. Exercise will significantly improve insulin resistance (as measured by the fasting glucose/insulin ratio) with little or no effect on insulin secretory capacity (as measured by circulating insulin concentration at 1, 3, and 5 minutes following an intravenous glucose load) in children. 3. Participation in a school-based health, nutrition, and exercise education program will have long-term beneficial effects on health-related behaviors and on insulin resistance. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00073268

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Randomized Trial of Health Events Costs in Diabetic Blacks Condition(s): Diabetes Mellitus, Type 2 Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: 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. Prior work suggests two possible approaches aimed at prevention to enhance risk factor control in outpatients with type 2 diabetes. One approach uses Nurse Case Managers (NCMs) to coordinate care plans with the provider team following protocols/clinical guidelines and algorithms designed to guide treatment including initiating and adjusting drug therapy, enhancing continuity of care, promoting interventions and self-management which include educational and behavioral strategies incorporating feedback and selfregulation. Another approach uses Community Health Workers (CHWs) to enhance culturally sensitive outreach, linkage, and monitoring service; to provide important patient and family education; and to improve access to and continuity of care. Results indicate that this intensive team approach, compared to usual care alone, produces substantial improvements in metabolic control. However, the cost-effectiveness of such interventions is unknown in the ''real-world''. This has led to our current study, a randomized controlled trial within a managed care organization to determine the effects of a NCM/CHW team on metabolic control, on the occurrence of diabetes-related health events, health care utilization, and on direct health care costs. The participants will be African American adults with type 2 diabetes who receive primary care within a managed care organization in inner-city Baltimore. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00022750

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Safety and Efficacy of Human Insulin Inhalation Powder in Patients with Type 1 Diabetes Mellitus. Condition(s): Diabetes Mellitus, Type 1 Study Status: This study is currently recruiting patients. Sponsor(s): Eli Lilly and Company Purpose - Excerpt: This is a research study of a study drug known as LY041001 or human insulin inhalation powder (HIIP). HIIP is a powder form of insulin made to be inhaled through the mouth and into the lungs using a special handheld device. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00063128

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Safety and Pharmacokinetics (PK) of hOKT3g1 (Ala-Ala) in Type 1 Diabetes Mellitus (T1DM) Condition(s): Diabetes Mellitus, Insulin-Dependent Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: To assess the tolerability and safety of hOKT3g1 (Ala-Ala) after a 12day dosing regimen administered via intravenous infusion. To assess the pharmacokinetics of hOKT3g1 (Ala-Ala). Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00073255

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Screening adolescents for type 2 diabetes mellitus in a community clinic Condition(s): Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Duke University; Diabetes Trust Fund Purpose - Excerpt: The purpose of this study is to evaluate the prevalence of Type 2 diabetes or impaired glucose tolerance in a subset of children 10-19 years of age in an inner city community clinic. The demographics of the clinic are 75% African American, 20% Hispanic, 5% other. African American and Hispanic patients have a higher prevalence of diabetes with significant morbidity, predominantly from microvascular and macrovascular disease. Obesity is commonly seen in patients with Type 2 diabetes and contributes to the underlying insulin resistance seen in the disease. Obesity is an increasing health problem among adolescents. Since Type 2 diabetes can be present for several years before diagnosis, it is worrisome that younger children will have undiagnosed Type 2 diabetes for years. This will increase the risk of earlier complications in these patients as young adults. We hypothesize that the occurrence of abnormal glucose metabolism in 400 children with either a history of obesity, family history of diabetes mellitus, or symptoms suggestive of diabetes mellitus will be higher than the general pediatric population. We believe that a family based educational program can reduce fasting plasma glucose. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00042042

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Study Of Avandamet With Or Without Insulin In Type II Diabetes Mellitus Patients Condition(s): Non-Insulin-Dependent Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): (Sponsor Name Pending) Purpose - Excerpt: The purpose of this study is to test the safety and efficacy (how well it works) of Avandamet in combination with insulin in improving the control of blood sugar when compared with taking insulin on its own. Avandamet capsules contain a

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fixed dose of Avandia and metformin. Both Avandia and metformin are medicines which are individually licensed for the treatment of type II diabetes mellitus. Because they act in different ways, it is thought that combining them may give an increased benefit of treating diabetes and reducing blood sugar. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069836 •

Study Of Subjects With Type II Diabetes Mellitus Who Are Inadequately Controlled On Insulin Condition(s): Non-Insulin-Dependent Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): (Sponsor Name Pending) Purpose - Excerpt: This 24-week study will compare the effects of adding the drug rosiglitazone (2mg and 4mg) or placebo to insulin in patients with Type 2 diabetes mellitus (non-insulin-dependent) who have not achieved their blood glucose goal using insulin alone. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00054782

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The ORIGIN Trial (Outcome Reduction with Initial Glargine Intervention) Condition(s): Diabetes Mellitus, Non-Insulin-Dependent Study Status: This study is currently recruiting patients. Sponsor(s): Aventis Pharmaceuticals Purpose - Excerpt: To determine whether insulin glargine-mediated normoglycemia can reduce cardiovascular morbidity and/or mortality in people at high risk for vascular disease with either IFG, IGT or early type 2 diabetes; To determine whether omega-3 fatty acids can reduce cardiovascular mortality in people with IFG, IGT or early type 2 diabetes. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069784

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A Research Study to Assess the Mechanism By Which Glucovance, Metformin, and Glyburide Work To Control Glucose Levels In Patients With Type 2 Diabetes Condition(s): Diabetes Mellitus, Non-Insulin-Dependent Study Status: This study is no longer recruiting patients. Sponsor(s): Bristol-Myers Squibb

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Purpose - Excerpt: The purpose of this clinical research study is to support earlier observations that Glucovance controls glucose levels after a mean, and improves overall glucose control better than metformin or glyburide therapy alone in adults with type 2 diabetes. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00035568 •

A Research Study to determine the safety and efficacy of Glucovance Compared to Metformin and Glyburide in Children and Adolescents with Type 2 Diabetes. Condition(s): Diabetes Mellitus, Non-Insulin-Dependent Study Status: This study is no longer recruiting patients. Sponsor(s): Bristol-Myers Squibb Purpose - Excerpt: The purpose of this clinical research study is to see if Glucovance, a medication currently approved for use in adults with type 2 diabetes, can control type 2 diabetes safely and effectively in children 9 to 16 years of age. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00035542

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Dyslipidemia and Risk of Cardiovascular Disease in Diabetic Men and Women Condition(s): Cardiovascular Diseases; Diabetes Mellitus, non-insulin dependent; Heart Diseases; Atherosclerosis; Diabetes Mellitus Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the role of dyslipidemia, markers of endothelial dysfunction genetic susceptibility, and dietary fat intake on the development of cardiovascular disease (CVD) complications in Type II diabetes mellitus. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00037258

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Evaluation of the Bioavailability of Pramlintide Condition(s): Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2 Study Status: This study is no longer recruiting patients. Sponsor(s): Amylin Pharmaceuticals Purpose - Excerpt: This is a randomized, open-label, crossover study to examine the bioavailability of pramlintide in normal weight and overweight subjects with type 1 and type 2 diabetes mellitus using insulin. Phase(s): Phase II

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Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00042471 •

Evaluation of the Effect on Glucose Control of AC2993 in Patients With Type 2 Diabetes Mellitus Condition(s): Diabetes Mellitus, Type 2 Study Status: This study is no longer recruiting patients. Sponsor(s): Amylin Pharmaceuticals Purpose - Excerpt: This is a multicenter, randomized, blinded, placebo-controlled study to assess the effects on glucose control of AC2993 as compared to placebo in patients with type 2 diabetes. Patients will be randomized into one of two AC2993 treatment arms or to placebo treatment and will continue with their required existing diabetes medications (metformin and a sulfonylurea) throughout the study. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00035984

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Evaluation of the Effect on Glucose Control of AC2993 in Patients With Type 2 Diabetes Mellitus Treated With a Sulfonylurea Condition(s): Diabetes Mellitus, Non-Insulin-Dependent Study Status: This study is no longer recruiting patients. Sponsor(s): Amylin Pharmaceuticals Purpose - Excerpt: This is a multicenter, randomized, blinded, placebo-controlled study to assess the effects on glucose control of AC2993 as compared to placebo in patients with type 2 diabetes. Patients will be randomized into one of two AC2993 treatment arms or to placebo treatment and will continue with their required existing diabetes medication (sulfonylurea) throughout the study. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00039026

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Evaluation of the Effect on Glucose Control of AC2993 in Patients With Type 2 Diabetes Mellitus Treated With Metformin Condition(s): Diabetes Mellitus, Type 2 Study Status: This study is no longer recruiting patients. Sponsor(s): Amylin Pharmaceuticals Purpose - Excerpt: This is a multicenter, randomized, blinded, placebo-controlled study to assess the effects on glucose control of AC2993 as compared to placebo in patients with type 2 diabetes. Patients will be randomized into one of two AC2993 treatment

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arms or to placebo treatment and will continue with their required existing diabetes medication (metformin) throughout the study. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00039013 •

Markers and Mechanisms of Macrovascular Disease in IDDM Condition(s): Cardiovascular Diseases; Diabetes Mellitus; Atherosclerosis; Heart Diseases; Diabetes Mellitus, Insulin-Dependent Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To elucidate the biochemical, metabolic, and genetic markers and mechanisms of macrovascular disease in insulin dependent diabetes mellitus (IDDM). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005474

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Mechanisms of Pro-Thrombosis in Diabetes Mellitus -- Ancillary to BARI 2D Condition(s): Cardiovascular Diseases; Heart Diseases; Diabetes Mellitus, non-insulin dependent; Coronary Disease; Thrombosis; Diabetes Mellitus Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the effect of the method of hyperglycemic management on pro- thrombotic potential in diabetic subjects. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00041405

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Non-Traditional Cardiovascular Risk Factors in Type 2 Diabetes Mellitus - Ancillary to VA Study of Glycemic Control Condition(s): Atherosclerosis; Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, non-insulin dependent; Heart Diseases Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To test whether novel cardiovascular risk factors are related to the presence and development of atherosclerosis and macrovascular events in Type 2 diabetes mellitus and to determine whether intensive glucose lowering therapy will reduce the levels of these cardiovascular risk factors. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00021944

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Solitary Islet Transplantation for Type 1 Diabetes Mellitus Using Steroid Sparing Immunosuppression Condition(s): Insulin Dependent Diabetes Mellitus Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: This study will test whether a new islet transplant procedure will enable patients with type 1 diabetes mellitus to stop insulin therapy. Islets are cell clusters in the pancreas that contain insulin-producing cells. The new procedure features three important advances, first developed by a group in Edmonton, Canada, over the way islet transplants have traditionally been performed: 1) the islets are transplanted immediately after they are removed from the donor; 2) islets are transplanted from two different donors in order to obtain the number of islets in a normal pancreas; and 3) the anti-rejection drug regimen is designed to reduce the harmful side effects of "conditioning" chemotherapy. (In the standard transplant procedure, patients receive intensive chemotherapy following the transplant. This study will use no radiation and lower-dose chemotherapy.) Patients between the ages of 18 and 65 with the diagnosis of type 1 diabetes mellitus for at least 5 years may be eligible for this study. Candidates will be screened with a medical history and physical examination, blood tests, chest Xray and tuberculin skin test, electrocardiogram and exercise test for heart function, abdominal ultrasound, psychological evaluation, and an arginine stimulated c-peptide test. The latter test determines if the patient is producing any insulin. Eligibility is restricted to patients who make no insulin at all. The study has an active phase lasting 15 months and follow-up that continues indefinitely. Patients will receive 10,000 "islet equivalents" per kilogram (2.2 pounds) of body weight. This will likely require two separate transplant procedures from two donors. Before the first surgery, patients will be given anti-rejection (immune suppressing) drugs, including FK506 and rapamycin (orally) and daclizumab (intravenously). The islets will be infused through a tube placed in the portal vein (the large vein that feeds the liver). After surgery, patients will receive insulin intravenously for 24 hours. They will then have an abdominal ultrasound and blood tests to determine liver function. If fewer than 10,000 islets were transplanted, patients will continue insulin treatment, with the dosages adjusted to account for the transplanted islets. They will take Daclizumab every 2 weeks, and FK506 and rapamycin daily. Blood tests to follow how much of these drugs are in the blood stream will be performed daily at first and then weekly after blood levels of these drugs stabilize. They will be given antibiotics to prevent infections. The arginine test will be repeated 2 weeks after the transplant and periodically thereafter. Blood will be drawn weekly to check drug levels, and monthly for other tests. The investigators will track daily insulin requirements, and these will be recorded monthly. Patients who require a second transplant to achieve the required amount of islets will return for the procedure when a compatible organ is donated. The second procedure will be done as described above. As before, insulin will be infused for 24 hours following surgery. It will then be stopped, however, and will not be resumed unless blood glucose levels reach above 180 milligrams/deciliter. Patients will continue taking FK506 and rapamycin indefinitely. Daclizumab will be given every 2 weeks for 4 doses following the second transplant, and then stopped. Patients will take an antiviral called ganciclovir for 14 weeks and another antibiotic for 1 year following surgery. For the first year after surgery, patients will have frequent blood tests to monitor drug levels and immune function. They will return to NIH for a complete history and physical examination 2 and 3 years after the final islet transplant and will be contacted yearly by phone to ascertain their general health status and whether they remain insulin independent.

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Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006505 •

Subclinical Heart Disease in Insulin-Dependent Diabetes Condition(s): Cardiovascular Diseases; Heart Diseases; Coronary Disease; Diabetes Mellitus; Diabetes Mellitus, Insulin-Dependent Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To investigate the occurrence and associated risk factors for subclinical heart disease in persons with insulin-dependent diabetes mellitus (IDDM). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005754

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Achilles Tendon Lengthening in Patients with Diabetes to Prevent Foot Ulcers Condition(s): Diabetes Mellitus; Foot Ulcer; Peripheral Neuropathy Study Status: This study is completed. Sponsor(s): National Institute of Child Health and Human Development (NICHD) Purpose - Excerpt: People with diabetes often develop severe skin problems (ulcers) on their feet. Sometimes these are treated with surgery and other times by temporarily immobilizing the foot in a cast. This study compares the effect of surgery to lengthen the Achilles tendon and put the foot in a cast, to using a cast alone. The study will also examine how foot strength, joint movement, and overall ability to walk, balance and climb stairs is affected. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006426

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Automated Calls with Nurse Follow-Up to Improve Diabetes Ambulatory Care Condition(s): Diabetes Mellitus Study Status: This study is completed. Sponsor(s): Department of Veterans Affairs; Department of Veterans Affairs Health Services Research and Development Service Purpose - Excerpt: Regular outpatient follow-up is important for all diabetes patients, with some needing frequent attention because their health is unstable, their treatment regimen is complex, or their social supports are inadequate. However, many patients live with access barriers that limit their use of outpatient services, fail to attend outpatient appointments, and experience worse outcomes than trials of aggressive management suggest is possible. Although labor-intensive, telephone care programs are one potential strategy for bringing diabetes management services into patients? homes

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and improving their glycemic control. Automated telephone disease management (ATDM) systems can augment telephone care by providing frequent monitoring and health education to large patient panels while focusing clinicians? attention on individuals who need it most. Although this technology has shown some promise, it has not been rigorously evaluated, particularly in VA. This study evaluated Automated Telephone Disease Management (ATDM) calls with telephone nurse follow-up as a means of improving the quality of VA diabetes care. Specifically, we will determine whether this service improves patients' glucose control; improves other important outcomes such as their quality of life, satisfaction with care, and health service use; improves health behaviors such as self-monitoring of blood glucose, fat intake, and medication adherence; and has effects that vary across patient subgroups. Patients with diabetes mellitus using hypoglycemic medication were enrolled during outpatient visits to a university-affiliated VA health care system and randomized to usual care or bi-weekly ATDM assessment and self-care education calls with follow-up by a nurse educator. The intervention process was evaluated by examining patients? patterns of ATDM use and the reliability and validity of information they provided. Telephone surveys were used to measure intervention effects at 12-months on patients? self-care, symptoms, satisfaction with care, and perceived access barriers. The impact on VA utilization was evaluated using electronic utilization databases, and glycemic control was measured using laboratory tests. A total of 292 patients were randomized and 272 (93%) provided data at 12-months. Intervention patients completed ATDM assessments consistently throughout the observation period and the assessments identified groups of intervention patients with varying degrees of health risk at baseline. Compared to control patients, intervention patients at 12-months reported more frequent glucose selfmonitoring, fewer access problems, and greater satisfaction with care (all p = 0.05). Intervention patients were more likely than controls to have been seen in podiatry clinics (53% versus 31%, p = 0.003) and diabetes specialty clinics (31% versus 17%, p = 0.03) during the study. The intervention did not influence mean endpoint HgA1c levels overall. However, among patients with baseline HgA1c = 8%, mean endpoint values among intervention and control patients were 8.7% and 9.2%, respectively (p = 0.05); intervention effects were even greater among patients with baseline HgA1c = 9%. Moreover, intervention patients at follow-up reported fewer symptoms of poor glycemic control than patients receiving usual care (3.6 versus 4.4, p = 0.03). Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00012753 •

Continuous Glucose Monitors for Children With Diabetes Mellitus Condition(s): Diabetes Mellitus, Insulin-Dependent Study Status: This study is completed. Sponsor(s): National Institute of Child Health and Human Development (NICHD); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: Good control of blood glucose levels is important in preventing complications from diabetes. This study assessed the accuracy and reliability of two FDA-approved continuous glucose monitors, the Continuous Glucose Monitoring System (CGMS) and the GlucoWatch G2 Biographer (GW2B), in children with type 1 diabetes mellitus (T1DM).

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Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069537 •

Diabetes, Lipoproteins and Accelerated Vascular Disease Condition(s): Cardiovascular Diseases; Heart Diseases; Coronary Disease; Atherosclerosis; Carotid Artery Diseases; Diabetes Mellitus, non-insulin dependent; Diabetes Mellitus Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To better understand the excess cardiovascular disease associated with diabetes mellitus. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005479

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Education and Group Support for Diabetic Hispanics Condition(s): Diabetes Mellitus, Non-Insulin-Dependent Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The purpose of this ongoing work in Starr County, located on the Texas-Mexico border, is to conduct clinical studies to determine the effectiveness of diabetes self-management programs designed specifically for Mexican Americans. The programs meet national standards for diabetes self-management education. They are provided in community settings with the primary purpose of improving the health of Mexican Americans with diabetes and their family members, who either have diabetes or are at risk for developing diabetes. The diabetes self-management programs are provided in Spanish and are directed by bilingual Hispanic clinical nurse specialists, dietitians, and community health workers. Key elements of the programs include instruction on nutrition, self-monitoring of blood glucose, exercise, and other diabetes self-management topics, as well as group support to promote behavioral changes. In the original study (1994-1998), 256 Mexican American adults diagnosed with type 2 diabetes and 256 family members or other support persons were enrolled. For one year, the people with diabetes, along with their family members, attended small group sessions held in churches, community health clinics, adult day care centers, and schools. Information on the effectiveness of the program was collected at 3, 6, and 12 months; and annually thereafter. Findings of the original study suggested that the program had a positive impact on diabetes metabolic control. Levels of diabetes knowledge and rates of glucose self-monitoring and attendance suggested that a shorter program - one that incorporated critical elements of the previous successful strategy - might result in similar improvements. Thus, the goal of the new study, funded in June 1999, was to shorten the original program and to compare it to the previous successful program in terms of short- and long-term health outcomes. To identify key components of the previous program, we are exploring differences between subjects who successfully integrated self-care components of the program and who experienced significant

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improvements in metabolic control and those who were not as successful. The program is being revised and shortened, based on this information. Beginning in April 2000, we will start recruiting participants for the clinical trial of the revised program. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004983 •

Evaluate the Role of Adding Amaryl to Non-Insulin Dependent Diabetes Mellitus Patients unresponsive to Maximum Dose Metformin & Thiazolidinedione Condition(s): Diabetes Mellitus, Non-Insulin-Dependent Study Status: This study is completed. Sponsor(s): Aventis Pharmaceuticals Purpose - Excerpt: Assess the efficacy and safety of Amaryl when added to Metformin and TZD Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00044447

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Finding Diabetes Mellitus Among Veterans Condition(s): Diabetes Mellitus Study Status: This study is completed. Sponsor(s): Department of Veterans Affairs; Department of Veterans Affairs Cooperative Studies Program Purpose - Excerpt: Population-based screening for diabetes mellitus in non-pregnant adults remains controversial. For a screening strategy to be successful, patients identified by surveillance will have to have better outcomes than if they had been diagnosed at a later, more symptomatic phase of disease. However, little is known about the fate of patients diagnosed with diabetes by screening. Additionally, while about half of the cases of diabetes among the general population at any given time are undiagnosed, the prevalence of undiagnosed diabetes among veterans is unknown. The annual incidence of diabetes among veterans is also unknown. Assessing risk factors prior to blood testing will improve the specificity, with little cost in sensitivity, of screening for diabetes in a medical center setting. The target population which optimizes the potential value of diabetes screening is patients with at least 1 of the above 3 risk factors for diabetes (obesity, hypertension, family history). Hypertension is strongly associated with unrecognized diabetes in veterans. VA and other health care providers considering whether to perform systematic screening for diabetes should use known risk factors to identify an appropriate target population for screening. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00007696

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Genetic Influence on Susceptibility to Type 1 Diabetes Mellitus Condition(s): Diabetes Mellitus; Healthy Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: Type 1 diabetes mellitus is an autoimmune disease in which the body's immune cells attack the insulin-producing cells of the pancreas. Several environmental and genetic factors may predispose individuals to developing this disease, including changes in a gene called CD152. This study will examine how this gene may influence the development of insulin-dependent diabetes. Patients with Type 1 diabetes mellitus enrolled in clinical trials at the National Institutes of Health and at the University of Florida and healthy normal volunteers may participate in this study. Participants will have up to three blood samples drawn over a period of less than 1 year. The first sample (about 20 milliliters, or 4 teaspoons), will be examined for changes in the structure of the CD152 gene. If the CD152 structure is different from that normally seen in the general population, a second sample (about 90 ml, or 6 tablespoons of blood) will be drawn. This sample will be used to study the function of specialized immune system cells (T cells), including their growth and survival, chemicals they produce when stimulated, and other factors. If these cells function differently from what is generally seen in the population, a third sample (90 ml) will be drawn for more detailed studies. This investigation may help explain what makes certain individuals susceptible to Type 1 diabetes mellitus and may contribute to the development of improved treatments for the disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001985

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Islet Cell Transplantation Alone and CD34+ Enriched Bone Marrow Cell Infusion in Patients with Diabetes Mellitus: Steroid-Free Regimen Condition(s): Type 1 Diabetes Mellitus Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The goal of islet cell transplantation in Type 1 diabetics is to provide those affected with constant normal blood glucose levels, thereby reducing or eliminating altogether the need for injected insulin. This normalization may prevent or slow progression of diabetic complications, result in a healthier lifestyle, and lead to a better quality of life. Participants who meet the inclusion criteria will undergo an extensive screening process which typically includes a series of blood tests, EKG, chest x-rays, and a psychological evaluation, among others. Those who are eligible for and chose to participate in the trial will receive an islet cell transplant and bone marrow infusion from the same donor, together with following immunosuppressive medications: tacrolimus, sirolimus, daclizumab and infliximab. Because the bone marrow infusion may successfully prevent the transplanted islet cells from rejecting, some participants may be able to stop taking the immunosuppressive medications after a year. The islet cell transplant is done under local anesthesia in a special procedure radiology room. Several days after the islet cell transplant, the participant is admitted to the hospital as an outpatient in order to receive bone marrow via a simple intra-venous infusion procedure. All participants will need to be seen at the Diabetes Research Institute after the transplant for follow-up testing and post-islet cell transplant care.

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Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00021801 •

Islet Cell Transplantation Alone in Patients with Type I Diabetes Mellitus: steroidfree immunosuppression Condition(s): Diabetes Mellitus, Type 1 Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The goal of islet cell transplantation in patients with Type 1 Diabetes Mellitus is to provide constant normal blood glucose levels. This may eliminate the need for insulin altogether or provide a significant reduction in the amount of insulin necessary to maintain constant normal blood glucose levels. This normalization may prevent or slow progression of diabetic complications. Furthermore, the participant may enjoy a healthier lifestyle and a better quality of life. If you meet the initial inclusion criteria for the trial, you must be able to give informed consent personally. Then you will need to participate in an extensive screening process that involves many standard tests and collection of laboratory samples to make sure that the transplant is suitable and safe for you. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00021788

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Native Hawaiian Diabetes Intervention Program Condition(s): Diabetes Mellitus, Type 2 Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The Native Hawaiian Diabetes Intervention Program is a project focused on determining whether a cultural-based, healthy lifestyles program with family support will have a positive effect on lifestyle behaviors and psychosocial and clinical outcomes. A culturally sensitive, lifestyle intervention program was administered via community peer educators to a population of Native Hawaiians with or at risk for diabetes. The effect of this intervention program on selected outcomes is being compared to a ''standard'' program given to a similar population in a second Native Hawaiian community. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006165

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Proactive Diabetes Case Management Condition(s): Diabetes Mellitus

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Study Status: This study is completed. Sponsor(s): Department of Veterans Affairs; Department of Veterans Affairs Health Services Research and Development Service Purpose - Excerpt: The consequences of current deficiencies in type 2 diabetes mellitus (T2DM) care are staggering, and conventional approaches to improve care have failed. Treatment guidelines and case management have been advocated as solutions to this problem. However, traditional approaches to guideline implementation have been discouraging and the cost-effectiveness of case management has not been rigorously evaluated. This study addresses two VA HSR&D priority areas: (1) guideline dissemination; and (2) evaluating managed care techniques for use in VA. The study has the following specific aims: (1) to evaluate the impact of a targeted, proactive T2DM case management intervention on: (a) glycemic control, (b) adherence to minimum standards, (c) short-term resource utilization, (d) veteran satisfaction, and (e) short-term patient physiologic and functional outcomes; and (2) using Monte Carlo simulations, estimate the expected impact of changes in key processes of care and intermediate outcomes on end-stage outcomes and long-term costs. The study is a randomized controlled trial. Veterans (n = 246) at two VAMCs who met specific eligibility criteria were recruited to participate in the study and randomly assigned to the intervention or control groups. Study participants are being followed for approximately 18 months. The intervention consists of two nurse practitioners who are actively monitoring and coordinating patient care, guided by approved treatment algorithms. Primary data sources include: (1) a baseline and exit examination; (2) a baseline and exit survey; and (3) the VA medical information system. The primary outcome measure is glycemic control as measured by hemoglobin A1c (HbA1c). Secondary outcomes include serum LDL, veteran satisfaction, functional status, eye and kidney screening, foot integrity, blood pressure, resource utilization and costs. The data will be analyzed using the change in the primary and secondary outcome measures over the study period as dependent variables. A subgroup analysis also will be conducted to examine those with poorer glycemic control at baseline (HbA1c > 9.5%) vs. those with better baseline control. A Monte Carlo simulation model will be used to estimate the expected longterm benefits of the intervention. Cost estimates also will be incorporated to evaluate the long term cost-effectiveness of the intervention. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00013208 •

The GlucoWatch G2 Biographer for the Management of Type 1 Diabetes in Children Condition(s): Diabetes Mellitus, Insulin-Dependent Study Status: This study is completed. Sponsor(s): National Institute of Child Health and Human Development (NICHD); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: Devices such as the GlucoWatch G2 Biographer (GW2B), which constantly measure blood sugar levels, may improve the treatment of Type 1 diabetes mellitus in children. This study evaluated the GWB when used by children in their homes. Phase(s): Phase IV Study Type: Interventional

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069615

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 “diabetes mellitus” (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: •

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 6. PATENTS ON DIABETES MELLITUS 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 “diabetes mellitus” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on diabetes mellitus, we have not necessarily excluded nonmedical patents in this bibliography.

Patents on Diabetes Mellitus By performing a patent search focusing on diabetes mellitus, 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. 9Adapted

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

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The following is an example of the type of information that you can expect to obtain from a patent search on diabetes mellitus: •

Aryloxyacetic acids for diabetes and lipid disorders Inventor(s): Jones; A. Brian (Clavering, GB), Liu; Kun (Edison, NJ), Xu; Libo (Dayton, NJ) Assignee(s): Merck & Co., Inc. (Rahway, NJ) Patent Number: 6,569,879 Date filed: August 17, 2001 Abstract: A class of aryloxyacetic acids 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 aryloxyacetic acids and pharmaceutically acceptable salts and prodrugs thereof which are useful as therapeutic compounds, particularly in the treatment 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 insulindependent 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 insulin-sensitive 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=US06569879__

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Attenuation of rejected cells transformed with adenovirus E3 Inventor(s): Brownlee; Michael (New York, NY), Efrat; Shimon (Bronx, NY), Federoff; Howard J. (Rochester, NY), Horwitz; Marshall S. (Larchmont, NY) Assignee(s): Albert Einstein College of Medicine of Yeshiva University (Bronx, NY) Patent Number: 6,491,909 Date filed: August 1, 2000 Abstract: The invention provides a method and vectors to express a gene or genes, derived from a virus, which block allograft rejection. One class of genes blocks the intracellular transport and/or intracellular maturation within the cells of proteins called MHC class I products. Without limitation as to theory, it is believed that blocking the appearance of this class of proteins on the transplanted cell's surface, prevents the host's immune system from rejecting the graft. Another class of proteins acts to permit TNF.alpha.-mediated cell cytolysis. In one embodiment, the invention is directed towards engrafting the cells that secrete insulin, which are called alternatively, pancreatic.beta.-cells and islet cells, and thereby provide a treatment of diabetes mellitus. Excerpt(s): This invention concerns an improvement in the art of the transplantation of tissue for medical purposes. Specifically it concerns methods, vectors and compounds useful in preventing the expression of certain transplantation antigens on the surface of cells to be transplanted. More specifically it concerns the blockage of the cell surface expression of one particular class of proteins the genes for which are located in the major histocompatibility complex (MHC). In cases of extreme and life threatening conditions such as renal, liver and cardiac failure, physicians have successfully transplanted tissues between genetically distinct individuals. Even when care is taken to reduce the genetic differences between the host and donor, the recipients of these grafts must usually be given drugs that reduce the activity of their immune system so that the graft is not rejected. Such immuno-suppression entails substantial risks. Even when such immuno-suppression is well tolerated, there are considerable difficulties attendant in minimizing the antigenic differences (matching) between the donor and the recipient that increases the costs and reduces the availability of this mode of therapy. Furthermore, not all tissues can be successfully transplanted between genetically distinct persons. In principle, for example, diabetes mellitus, one of the most common and, in the longterm, one of the most debilitating chronic diseases, could be "cured" by a successful transplant of the tissue that secrete insulin, the islets of Langerhans. Despite the magnitude of the problem, the availability of islets from cadaveric donors and the successful experience in other situations, e.g., renal, cardiac and hepatic transplantation, there is presently no practical protocol that routinely provides for the survival of histoincompatible islet cells. Web site: http://www.delphion.com/details?pn=US06491909__

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Cardioprotective phosohonates and malonates Inventor(s): Haque; Wasimul (Edmonton, CA) Assignee(s): Medicure International Inc. (St. James, BB) Patent Number: 6,605,612 Date filed: February 28, 2001

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Abstract: The present invention provides for pyridoxine phosphonate analogues such as, for example, ((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)alkylphosphonates, and and (2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)azaalkylphosphonates) and to pyridoxine malonate analogues, such as, for example, ((2-methyl-3-hydroxy-4hydroxymethyl-5-pyridylmethyl)malonates), pharmaceutical compositions, and methods for treatment of cardiovascular and related diseases, and diabetes mellitus and related diseases. Excerpt(s): This invention relates to pyridoxine phosphonate analogues, to pyridoxine malonate analogues, to their preparation, to pharmaceutical compositions thereof, and to treatments for cardiovascular and related diseases, for example, hypertrophy, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, heart failure subsequent to myocardial infarction, myocardial infarction, ischemia reperfusion injury, and diseases that arise from thrombotic and prothrombotic states in which the coagulation cascade is activated; and treatments for diabetes mellitus and related diseases, for example, hyperinsulinemia, diabetes-induced hypertension, obesity, insulin resistance, and damage to blood vessels, eyes, kidneys, nerves, autonomic nervous system, skin connective tissue, or immune system. Pyridoxal-5'-phosphate (PLP), an end product of vitamin B.sub.6 metabolism, plays a vital role in mammalian health. In previous patents (U.S. Pat. Nos. 6,051,587 and 6,043,259, herein incorporated by reference) the role of pyridoxal-5'-phosphate, and its precursors pyridoxal and pyridoxine (vitamin B.sub.6), in mediating cardiovascular health and in treating cardiovascular related diseases is disclosed. The major degradation pathway for pyridoxal-5'-phosphate in vivo is the conversion to pyridoxal, catalysed by alkaline phosphatase. Thus, there is a need to identify and administer drugs that are functionally similar to pyridoxal-5'-phosphate such as pyridoxine phosphonate analogues or pyridoxine malonate analogues, that elicit similar or enhanced cardiovascular benefits, and that beneficially affect PLP-related conditions, but are stable to degradation by phosphatase. Web site: http://www.delphion.com/details?pn=US06605612__ •

Combination therapeutic compositions and method of use Inventor(s): Chen; Jin-Long (Foster City, CA), Jaen; Juan C. (Burlingame, CA) Assignee(s): Tularik Inc. (South San Francisco, CA) Patent Number: 6,653,332 Date filed: May 2, 2001 Abstract: The present invention provides pharmaceutical compositions and methods for the treatment of diabetes mellitus using combination therapy. The compositions relate to a compound of Formula I and an antidiabetic agent such as sulfonylureas, biguanides, glitazones,.alpha.-glucosidase inhibitors, potassium channel antagonists, aldose reductase inhibitors, glucagon antagonists, activators of RXR, insulin therapy or other anti-obesity agent. The methods include the administration of the combination of compound of Formula I with antidiabetic agent where the two components are delivered in a simultaneous manner, where the compound of Formula I is administered first, followed by the antidiabetic agent, as well as wherein the antidiabetic agent is delivered first followed by the compound of Formula I. Excerpt(s): In general, the present invention relates to pharmaceutical compositions, and more particularly, to pharmaceutical compositions for the treatment of diabetes

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mellitus using combination therapy. Diabetes mellitus is a term generally used to refer to various pathological states characterized by hyperglycemia and altered metabolism of lipids, carbohydrates and proteins. These conditions are also often associated with other co-morbidities, such as obesity and an increased risk of cardiovascular disease. By some estimates, as many as 600,000 new individuals become clinically diabetic every year in the United States. Diabetic conditions are generally classified as either insulindependent diabetes mellitus (IDDM, Type I diabetes) or non-insulin-dependent diabetes mellitus (NIDDM, Type II diabetes). There are also less common clinical pathologies that are associated with diabetic conditions, such as gestational maturityonset diabetes of youth (MODY), tropical diabetes secondary to chronic pancreatis, diabetes secondary to pancreatic disease or surgery, and diabetes secondary to endocrinopathies. Web site: http://www.delphion.com/details?pn=US06653332__ •

Diagnostic assay for diabetes mellitus based on mutational burden Inventor(s): Davis; Robert E. (San Diego, CA), Herrnstadt; Corinna (San Diego, CA) Assignee(s): MitoKor, Inc. (San Diego, CA) Patent Number: 6,544,745 Date filed: June 27, 2001 Abstract: The present invention relates to genetic mutations in mitochondrial genes that segregate with diabetes mellitus. The invention provides methods for detecting such mutations, as a diagnostic for diabetes mellitus, either before or after the onset of clinical symptoms. Examples of specific mutations in the ATP synthase 8/6 sequence and tRNA.sup.Lys sequence are given. The invention also provides treatments for dysfunctions due to genes for mitochondrial functions that segregate with diabetes mellitus. Cybrid cell lines are described which are useful as model systems for the study of the mitochondrial metabolic disorders that are associated with diabetes mellitus, and for identifying therapeutic compounds and treatments for this disease. Excerpt(s): The present invention relates generally to model systems for diseases that involve defects in the function of mitochondria and specific mutational burdens. The invention also relates to the use of these model systems for screening drugs and evaluating the efficacy of treatments for those diseases. In particular, the invention relates to the diagnosis and treatment of late onset diabetes mellitus and related pathologies, such as impaired glucose tolerance and insulin dependent or non-insulin dependent diabetes. Diabetes mellitus is a common degenerative disease affecting 5 to 10 percent of the population in developed countries. It is a heterogeneous disorder with a strong genetic component; monozygotic twins are highly concordant and there is a high incidence of the disease among first degree relatives of affected individuals. The propensity for developing diabetes mellitus is reportedly maternally inherited, suggesting a mitochondrial genetic involvement. (Alcolado, J. C. and Alcolado, R., Br. Med. J. 302:1178-1180 (1991); Reny, S. L., International J. Epidem. 23:886-890 (1994)). Studies have shown that diabetes mellitus may be preceded by or associated with certain related disorders. For example, it is estimated that forty million individuals in the U.S. suffer from late onset impaired glucose tolerance (IGT). IGT patients fail to respond to glucose with increased insulin secretion. A small percentage of IGT individuals (5-10%) progress to insulin deficient non-insulin dependent diabetes (NIDDM) each year. Some of these individuals further progress to insulin dependent diabetes mellitus (IDDM). This form of NIDDM or IDDM is associated with decreased

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release of insulin by pancreatic beta cells and/or a decreased end-organ response to insulin. Other symptoms of diabetes mellitus and conditions that precede or are associated with diabetes mellitus include: obesity, vascular pathologies, peripheral and sensory neuropathies, blindness, and deafness. Web site: http://www.delphion.com/details?pn=US06544745__ •

Diagnostic screens for type 1 diabetes (IDDM) Inventor(s): Corkey; Barbara E. (Boston, MA), Husni; Nicholas R. (Boston, MA) Assignee(s): Boston Medical Center Corporation (Boston, MA) Patent Number: 6,620,583 Date filed: July 9, 2002 Abstract: The present invention features a method for identifying genes or proteins important in insulin-dependent diabetes mellitus (IDDM). The genes or proteins are useful in identifying IDDM-susceptible individuals, and in identifying and testing potential therapeutic agents for the treatment of IDDM. Excerpt(s): Approximately 16 million people (roughly 6% of the population) in the United States suffer from diabetes. Diabetes is the seventh leading cause of death (sixth leading cause of death by disease) in the United States claiming approximately 200,000 lives each year. Moreover, diabetes is one of the most costly health problems in America, running upwards of $92 billion in health care costs annually. Life-threatening complications associated with diabetes include cardiovascular disease and stroke, high blood pressure, blindness, kidney disease, nerve disease and amputation. Of the 16 million diabetics in the United States, approximately 5-10% suffer from IDDM (InsulinDependent Diabetes Mellitus) otherwise known as Type 1 diabetes. At least 30,000 new cases of IDDM are diagnosed each year. Persons with IDDM fail to produce insulin and, accordingly, are required to take daily insulin injections in order to stay alive. Many people are unaware that they have diabetes until they develop one or more of its lifethreatening complications. Accordingly, much biomedical research has focussed on the cause and development of diabetes with the hope that having a better understanding of the disease will ultimately aid in earlier detection and/or better therapeutic treatments. With regards to IDDM or Type 1 diabetes, three major theories have been advanced to account for the pathogenesis of the disease. The first is that IDDM is an inherited, or genetic disease. The second, that IDDM results from autoimmunity. The third theory states that IDDM is brought about by an environmental insult, presumably viral (Cotran (1989) Robbins Pathologic Basis of Disease 994-1005; Foster (1991) Harrison's Principles of Internal Medicine 1739-1759). Most agree however, that it is a combination of elements of all three theories that eventuates in IDDM, rather than each of the three acting independently in different individuals. There is much evidence to support the theory that IDDM is an inherited disease. IDDM tends to aggregate in families, meaning that if one individual in a given family has the disease, each other member of the family has a greater chance of developing it. Certain HLA types, notably those of the D region of chromosome 6, carry an increased risk of IDDM (Cox et al. (1994) Diabetologia 37:500503). Despite the presence of this genetic evidence, the facts remain that IDDM has a low prevalence of direct vertical transmission, and that the concordance rate of IDDM in monozygotic twins is only 20% (Cotran supra; Foster supra). This indicates that something more complex than simple Mendelian genetics is operating to cause the disease.

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Web site: http://www.delphion.com/details?pn=US06620583__ •

Effectors of dipeptidyl peptidase IV Inventor(s): Demuth; Hans-Ulrich (Halle/Saale, DE), Glund; Konrad (Halle/Saale, DE), Kruber; Susanne (Halle/Saale, DE), Schlenzig; Dagmar (Halle/Saale, DE) Assignee(s): Probiodrug AG (Halle/Salle, DE) Patent Number: 6,548,481 Date filed: November 28, 2000 Abstract: Dipeptide compounds and compounds analogous to dipeptide compounds that are formed from an amino acid and a thiazolidine or pyrrolidine group, and salts thereof used in the treatment of impaired glucose tolerance, glycosuria, hyperlipidaemia, metabolic acidoses, diabetes mellitus, diabetic neuropathy and nephropathy and also of sequelae of diabetes mellitus in mammals. Excerpt(s): According to the current state of the art, hyperglycaemia and associated causes and sequelae (including diabetes mellitus) are treated by the administration of insulin (e.g. material isolated from bovine pancreas or obtained by genetic engineering techniques) to the diseased organisms in various forms of administration. All methods known hitherto, including more modern procedures, are distinguished by the requirement of a large amount of material, by high costs and often by a distinct impairment of the quality of life of the patients. The conventional method (daily i.v. insulin injection, customary since the 1930s) treats the acute symptoms of the disease, but after prolonged use leads inter alia to serious vascular changes (arteriosclerosis) and nerve damage. More recently the installation of subcutaneous depot implants (the insulin is released in metered amounts, and daily injections are unnecessary) and implantation (transplantation) of intact Langerhan's cells into the functionally impaired pancreatic gland or into other organs and tissues have been proposed. Such transplants require a high level of technical resources. Furthermore, they involve a surgical intervention into the recipient organism, which is associated with risks, and even in the case of cell transplants require methods of suppressing or circumventing the immune system. The use of alanyl pyrrolidide and isoleucyl thiazolidide as inhibitors of DP IV or of DP IV-analogous enzyme activity is already known from PCT/DE 97/00820 and the use of isoleucyl pyrrolidide and isoleucyl thiazolidide hydrochloride is already known from DD 296 075. Isoleucyl thiazolidide, which is used in the latter prior art, is a natural, that is to say L-threo-isoleucyl thiazolidide: on the priority date and also on the application date of the two specifications, only that form, the natural form, of isoleucyl thiazolidide was available. Web site: http://www.delphion.com/details?pn=US06548481__

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Extracellular signal-regulated kinase, sequences, and methods of production and use Inventor(s): Lechner; Cornelia (Unterschleissheim, DE), M.o slashed.ller; Niels Peter (Copenhagen, DK), Ullrich; Axel (Martinsreid, DE) Assignee(s): Max-Planck-Gesellschaft zur Forderung der Wissenschaften, e.V. (Munich, DE) Patent Number: 6,579,972 Date filed: September 9, 1999

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Abstract: The present invention relates, in general, to an extracellular signal regulated kinase, ERK-5. In particular, the present invention relates to nucleic acid molecules coding for ERK-5; ERK-5 polypeptides; recombinant nucleic acid molecules; cells containing the recombinant nucleic acid molecules; antisense ERK-5 nucleic acid constructs; antibodies having binding affinity to an ERK-5 polypeptide; hybridomes containing the antibodies; nucleic acid probes for the detecting of ERK-5 nucleic acid; a method of detecting ERK-5 nucleic acid or polypeptide in a sample; kits containing nucleic acid probes or antibodies; a method of detecting a compound capable of binding to ERK-5 or a fragment thereof; a method of detecting an agonist or antagonist of ERK-5 activity; a method of agonizing or antagonizing ERK-5 associated activity in a mammal; a method of treating diabetes mellitus, skeletal muscle diseases, Alzheimer's disease, or peripheral neuropathies in a mammal with an agonist or antagonist of ERK-5 activity; and a pharmaceutical composition comprising an ERK-5 agonist or antagonist. Excerpt(s): The present invention relates to the field of extracellular signal regulated kinases (ERKs), which are also referred to as mitogen-activated protein (MAP) kinases. None of the following discussion of the background of the invention is admitted to be prior art to the invention. Cellular signal transduction is a fundamental mechanism whereby external stimuli that regulate diverse cellular processes are relayed to the interior of cells. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of tyrosine residues on proteins. The phosphorylation state of a protein is modified through the reciprocal actions of tyrosine phosphatases (TPs) and tyrosine kinases (TKs), including receptor tyrosine kinases and non-receptor tyrosine kinases. Web site: http://www.delphion.com/details?pn=US06579972__ •

Fructosamine oxidase: antagonists and inhibitors Inventor(s): Baker; John Richard (Auckland, NZ) Assignee(s): Protemix Corporation Limited (Auckland, NZ) Patent Number: 6,610,693 Date filed: October 10, 2001 Abstract: The present invention relates to methods of treating an individual with diabetes mellitus by administering to said individual an effective amount of copper chelators, hydrazine compounds, and/or substrate analogues. The invention also relates to methods of treating an individual with diabetes mellitus by lessening fructosamine odixase activity in said individual. Provided within is disclosure pertaining to treatment, pharmaceutical compositions, dosage ranges, and uses of fructosamine oxidase enzyme inhibitors to lessen fructosamine oxidase activity. Excerpt(s): The present invention is in the field of biochemistry. More specifically, the invention involves fructosamine oxidase enzyme inhibitors. Methods of treatment, pharmaceutical compositions, dosage forms, uses of fructosamine oxidase enzyme inhibitors in medicine or for manufacturing pharmaceutical compositions, treatment regimes, and related combinations, methods and products are disclosed herein. Diabetes mellitus is a common disorder affecting nearly 16 million Americans. See, for example, Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 20; 1183-97 (1997). Diabetic individuals are prone to complications which are a major threat to both the quality and the quantity of life. Almost half those diagnosed with diabetes before the age of 31 years die before they

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reach 50 years largely as a result of cardiovascular or renal complications, often with many years of crippling and debilitating disease beforehand. See, Deckert T., Poulsen J., Larsen M. Diabetologia 14:363-70 (1978). It is estimated that diabetic individuals have a 25-fold increase in the risk of blindness, a 20-fold increase in the risk of renal failure, a 20-fold increase in the risk of amputation as a result of gangrene, and a 2- to 6-fold increased risk of coronary heart disease and ischemic brain damage. See, Klein R., Klein B., Moss S., Davis M., DeMets D. Diabetes Care 8;311-5 (1985). Largely because of these long-term complications, the cost of diabetes in the US was estimated as $98 billion in 1997 comprising $44 billion for direct medical costs such as inpatient and outpatient care plus $54 billion for indirect costs such as lost earnings and productivity, and premature death. Medical innovations that can slow the progression of diabetes have tremendous potential to mitigate the associated clinical and cost repercussions See, American Diabetes Association, "Economic consequences of diabetes in the US in 1997," Diabetes Care 21:296-309(1998). Web site: http://www.delphion.com/details?pn=US06610693__ •

Glucose measurement utilizing non-invasive assessment methods Inventor(s): Berman; Herbert L. (Los Altos Hills, CA), Blair; Robert N. (San Jose, CA), Roe; Jeffrey N. (San Ramon, CA) Assignee(s): MedOptix, Inc. (Cupertino, CA) Patent Number: 6,522,903 Date filed: October 19, 2000 Abstract: This involves non-invasive glucose measurement processes for determining blood glucose level in the human body. After achieving a static level of glucose at a surface of the skin over some period of time, the glucose may then be measured by a variety of different processes. A sample of the glucose may also first be extracted from the skin and this sample may then be measured. Clearly, these processes are especially suitable for monitoring glucose levels in the human body, and is especially beneficial to users having diabetes mellitus. These procedures may be used for other analyte materials that are found in appropriate regions of the outer skin. Excerpt(s): This invention involves non-invasive glucose measurement and a process for determining blood glucose levels in the human body. Preferably, the process is used on a fingertip or other part of the body, typically a skin surface of the body. The American Diabetes Association reports that nearly 6% of the population in the United States, a group of 16 million people, has diabetes. The Association further reports that diabetes is the seventh leading cause of death in the United States, contributing to nearly 200,000 deaths per year. Diabetes is a chronic disease having no cure. The complications of the disease include blindness, kidney disease, nerve disease, and heart disease, perhaps with stroke. Diabetes is said to be the leading cause of new cases of blindness in individuals in the range of ages between 20 and 74; from 12,000-24,000 people per year lose their sight because of diabetes. Diabetes is the leading cause of end-stage renal disease, accounting for nearly 40% of new cases. Nearly 60-70% of people with diabetes have mild to severe forms of diabetic nerve damage which, in severe forms, can lead to lower limb amputations. People with diabetes are 2-4 times more likely to have heart disease and to suffer strokes. Diabetes is a disease in which the body does not produce or properly use insulin, a hormone needed to convert sugar, starches, and the like into energy. Although the cause of diabetes is not completely understood, genetics, environmental factors, and viral causes have been partially identified.

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Web site: http://www.delphion.com/details?pn=US06522903__ •

Hepatocyte growth factor for treatment of diabetes Inventor(s): Ichihara; Junji (Takatsuki, JP), Kishino; Michiko (Suita, JP), Nakayama; Chikao (Sanda, JP), Noguchi; Hiroshi (Kawanishi, JP), Taiji; Mutsuo (Takatsuki, JP) Assignee(s): Sumitomo Pharmaceuticals Company, Limited (Osaka-fu, JP) Patent Number: 6,472,366 Date filed: January 25, 2002 Abstract: The present invention provides a therapeutic agent for treatment of diabetes and hyperlipemia, especially a therapeutic agent for treatment of type II diabetes mellitus, which comprises as the active ingredient a neurotrophic factor such as BDNF (brain-derived neurotrophic factor), ligands of trkB or trkC receptors, NGF, NT-3, NT4/5, CNTF, GDNF, HGF, etc. Different from conventional oral hypoglycemic agents being mainly used in the treatment of type II diabetes mellitus, the agent of the present invention exhibit blood lipid regulating effects and body fat accumulation regulating effects, in addition to the blood glucose regulating effects. Thus, the agent of the present invention are novel, and can reduce the risk factors in diabetes accompanied by hyperlipemia or obesity, without using any other agent. Excerpt(s): The present invention relates to a therapeutic agent for treating a patient of diabetes or hyperlipemia, more particularly, a therapeutic agent for treating a patient of diabetes or hyperlipemia which comprises a neurotrophic factor as an active ingredient. Recently, the number of patients afflicted with degenerative diseases, especially diabetes mellitus, diabetic complications, or hyperlipemia, has been increased, due to an improvement in a living standard, and/or change of the dietary life into the Western style, or increase in lack of exercise. Hyperlipemia is a very important underlining disease, which causes arteriosclerosis, and as a result, further leads to ischemic heart diseases, and occasionally, may lead to the onset of acute pancreatitis. In addition, there is a tendency of increasing numbers of patients afflicted with these diseases in the young generation. Diabetes is classified into insulin dependent diabetes mellitus (type I, IDDM) and non insulin dependent diabetes mellitus (type II, NIDDM), and more than 90% of patients of diabetes mellitus are patients afflicted with the latter one. Insulin injections are used for the treatment of IDDM, and an oral antidiabetic agent such as sulfonyl urea or a biguanide compound is employed for the treatment of NIDDM, together with exercise therapy or dietary therapy (cf. Today's Therapy 1993, supervised by Shigeaki HINOHARA, Masakazu ABE, published by IGAKU SHOIN, pages 494498). These drugs are commonly used in order to control the blood glucose level, which is the most important indicator in the treatment of diabetes, but their effects are not sufficient enough, and in fact, continuous hyperglycemia causes various diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiovascular diseases, or delay in healing or ulceration of wound. Besides, various risk factors such as an acute hypoglycemia by insulin injection, prolonged hypoglycemia by an insulin secretagogue, sulfonylurea, lactic acidosis by anaerobic inhibitor of glycolysis, biguanide, affect the quality of life of patients afflicted with diabetes. Web site: http://www.delphion.com/details?pn=US06472366__

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Herbal composition and medicament against diabetes mellitus type II manufactured thereof Inventor(s): Leko; Vladimir (Josipa Kozarca 4, 34310 Pleternica, HR) Assignee(s): none reported Patent Number: 6,576,270 Date filed: September 11, 2001 Abstract: The invention relates to the herbal composition which consists of: Centaurii umbellatum, Gentianaceae (centaury plant), Teraxacum officinale, Asteraceae (dandelion root), Juniperi communis L, Cupresaceae (juniper berry), Urticae dioica L, Urticeae (nettle plant), Urticae dioica L, Urticaceae (nettle root), Cichorium intybus L, Cichoriaceae (chicory root), Morus nigra L, Moraceae, (mulberry leaf), Achilleae millefolium L, Asteraceae (yarrow flower), Vaccinium myrtillus L, Ericaceae (bilberry leaf), Phaseolus vulgaris L, Fabaceae (bean pods), Valeriana officinalis L, Valerlanaceae (Valerian root). Excerpt(s): This invention refers to the field of pharmacy, and more closely, it refers to the medicament against diabetes mellitus type II, and even more precisely, it refers to the medicament against diabetes mellitus type based on a herbal composition as an active substance. According to the International Classification of Patents, the subject invention is marked with the classification symbol A 61 K 35/78--Medical preparations containing substances or products of their reactions with undefined composition, whereby substances from herbs are in question. The technical problem, the solution of which is disclosed in this patent application, consists in finding a medicament for diabetes mellitus type II which will have the following characteristics: 1) that it is suitable for peroral application; 2) that even very high values of glucose concentration in blood can be reduced to or near its normal value; 3) no evident harmful side effects occur even in case of large daily doses, and even in case of a long-time use; and 4) that its effectivess is not caused by a strict diet. Insulin, a hormone produced by the pancreas, makes glucose available to cells in the human body for the purpose of obtaining energy. In case of diabetes mellitus type I the pancreas produces little insulin or it does not produce it at all and insulin must be injected daily so that a diabetic would survive. With diabetes mellitus type II the pancreas produces insulin, but the quantity of insulin is insufficient or it is less effective due to the cellular resistence, or both. In each of these forms there are various abnormalities, but the basic defects to which these abnormalities can be attributed are: 1) the reduced entering of glucose into various "peripheral" tissues; and 2) the increased releasing of glucose from the liver into the bloodstream (increased liver glucogenesis). Therefore, there is an extracellular surplus of glucose and an intracellular lack of glucose, which can be called "starving amidst abundance". Web site: http://www.delphion.com/details?pn=US06576270__

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Identification of transcription factor within a cAMP-responsive transcriptional enhancer binding protein (CREB), and uses therefore Inventor(s): Montminy; Marc R. (Wellesley, MA) Assignee(s): The Salk Institute for Biological Studies (La Jolla, CA) Patent Number: 6,646,115 Date filed: October 10, 2000

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Abstract: In accordance with the present invention, it has been discovered that CREB binding protein (CBP) cooperates with upstream activators involved in the activation of transcription of such signal dependent transcription factors as c-Jun (responsive to phorbol ester), serum response factor, and the like. It has also been discovered that CBP can be employed in an assay to identify compounds which disrupt the ability of such signal dependent transcription factors to activate transcription. In another aspect, it has been discovered that CBP can be employed in an assay to identify new signal dependent transcription factors. In yet another aspect of the present invention, it has been discovered that CBP can be employed in an assay to identify novel co-factor protein(s) which mediate the interaction between signal dependent transcription factors and inducer molecules involved in the activation of transcription. Accordingly, the present invention provides methods for the identification of compounds which inhibit activation of cAMP and mitogen responsive genes and methods for the identification of novel signal dependent transcription factors and co-factor proteins. In still another aspect, methods employing compounds which inhibit intracellular signal-induced response pathways have been developed for the treatment of diabetes mellitus. Excerpt(s): The present invention relates to analytical methods. In a particular aspect, the present invention relates to methods for the identification of compounds which mediate the interaction between signal dependent transcription factors and co-factor protein(s) involved in the activation of transcription. In another aspect, the present invention relates to methods for the identification of new signal dependent transcription factors. In yet another aspect, the present invention relates to methods for the identification of novel co-factor protein(s) which mediate the interaction between signal dependent transcription factors and inducer molecules involved in the activation of transcription. In yet another aspect, the present invention relates to methods for treating diabetes mellitus. Many eukaryotic genes are regulated in an inducible, cell typespecific fashion. Genes expressed in response to heat shock, steroid/thyroid hormones, phorbol esters, cyclic adenosine monophosphate (cAMP), growth factors. and heavy metal ions are examples of this class. The activity of cells is controlled by external signals that stimulate or inhibit intracellular events. The process by which an external signal is transmitted into and within a cell to elicit an intracellular response is referred to as signal transduction. Signal transduction is generally initiated by the interaction of extracellular factors (or inducer molecules, i.e., growth factors, hormones, adhesion molecules, neurotransmitters, and other mitogens) with receptors at the cell surface. Extracellular signals are transduced to the inner face of the cell membrane, where the cytoplasmic domains of receptor molecules contact intracellular targets. The initial receptor-target interactions stimulate a cascade of additional molecular interactions involving multiple intracellular pathways that disseminate the signal throughout the cell. Many of the proteins involved in signal transduction contain multiple domains. Some of these domains have enzymatic activity and some of these domains are capable of binding to other cellular proteins, DNA regulatory elements, calcium, nucleotides, lipid mediators, and the like. Web site: http://www.delphion.com/details?pn=US06646115__

Patents 191

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Indicators of altered mitochondrial function in predictive methods for determining risk of type 2 diabetes mellitus Inventor(s): Anderson; Christen M. (Encinitas, CA), Davis; Robert E. (San Diego, CA) Assignee(s): Mitokor, Inc. (San Diego, CA) Patent Number: 6,653,094 Date filed: August 7, 2001 Abstract: The present invention relates to improved diagnostic methods for early detection of a risk for developing type 2 diabetes mellitus in humans, and screening assays for therapeutic agents useful in the treatment of type 2 diabetes mellitus, by comparing the levels of one or more indicators of altered mitochondrial function. Indicators of altered mitochondrial function include enzymes such as mitochondrial enzymes and ATP biosynthesis factors. Other indicators of altered mitochondrial function include mitochondrial mass, mitochondrial number and mitochondrial DNA content, cellular responses to elevated intracellular calcium and to apoptogens, and free radical production. Methods of treating, and of stratifying, human patients as such methods relate to disclosed indicators of altered mitchondrial function are also provided. Excerpt(s): The present invention relates generally to diabetes mellitus, and in particular to compositions and methods for the diagnosis, prognosis and treatment of type 2 diabetes. Type 2 diabetes mellitus, or "late onset" diabetes, is a common, degenerative disease affecting 5 to 10 percent of the population in developed countries. The propensity for developing type 2 diabetes mellitus ("type 2 DM") is reportedly maternally inherited, suggesting a mitochondrial genetic involvement. (Alcolado, J. C. and Alcolado, R., Br. Med. J. 302:1178-1180 (1991); Reny, S. L., International J. Epidem. 23:886-890 (1994)). Diabetes is a heterogeneous disorder with a strong genetic component; monozygotic twins are highly concordant and there is a high incidence of the disease among first degree relatives of affected individuals. Current pharmacological therapies for type 2 DM include injected insulin, and oral agents that are designed to lower blood glucose levels. Currently available oral agents include (i) the sulfonylureas, which act by enhancing the sensitivity of the pancreatic beta cell to glucose, thereby increasing insulin secretion in response to a given glucose load; (ii) the biguanides, which improve glucose disposal rates and inhibit hepatic glucose output; (iii) the thiazolidinediones, which improve peripheral insulin sensitivity through interaction with nuclear peroxisome proliferator-activated receptors (PPAR, see, e.g., Spiegelman, 1998 Diabetes 47:507-514; Schoonjans et al., 1997 Curr. Opin. Lipidol. 8:159166; Staels et al., 1997 Biochimie 79:95-99), (iv) repaglinide, which enhances insulin secretion through interaction with ATP-dependent potassium channels; and (v) acarbose, which decreases intestinal absorption of carbohydrates. Web site: http://www.delphion.com/details?pn=US06653094__

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Isoxazole derivatives to be used as phosphodiesterase VII inhibitors Inventor(s): Eggenweiler; Hans-Michael (Weiterstadt, DE), Gassen; Michael (Griesheim, DE), Jonas; Rochus (Darmstadt, DE), Welge; Thomas (Alsbach, DE), Wolf; Michael (Darmstadt, DE) Assignee(s): Merck Patentgesellschaft (Darmstadt, DE) Patent Number: 6,531,498 Date filed: May 3, 2002 Abstract: The invention relates to compounds of formula I and to their physiologically acceptable salts and solvates which act as phosphodiesterse VII inhibitors and are thus useful for the treatment of allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases, rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumor growth, tumor metastases, sepsis, memory disturbances, atherosclerosis and AIDS. Excerpt(s): and their physiologically acceptable salts and/or solvates as phosphodiesterase VII inhibitors. The invention further relates to the use of the compounds of the formula I for producing a pharmaceutical for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as, for example, rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastases, sepsis, memory disturbances, atherosclerosis and AIDS. Compounds of the formula I are described by Bionet. Web site: http://www.delphion.com/details?pn=US06531498__

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Kv2.1 antagonists Inventor(s): Bubacz; Dulce Garrido (Cary, NC), Dukes; Iain David (Durham, NC), McLean; Ed Williams (Raleigh, NC), Noe; Robert Anderson (Hurdle Mills, NC), Peat; Andrew James (Apex, NC), Szewczyk; Jerzy Ryszard (Chapel Hill, NC), Thomson; Stephen Andrew (Durham, NC), Worley, III; Jennings Franklin (Durham, NC) Assignee(s): SmithKline Beecham Corporation (Philadelphia, PA) Patent Number: 6,589,934 Date filed: June 13, 2000 Abstract: The invention relates to methods of treatment of non insulin dependent diabetes mellitus, antagonists of the delayed rectifier potassium channel Kv2.1, methods of using and preparing the antagonists and assays for identifying such antagonists. Excerpt(s): This application is filed pursuant to 35 U.S.C.sctn.371 as a United States National Phase Application of International Application No. PCT/EP98/08085 filed Dec. 16, 1998, which claims priority from GB 9726630.8 filed Dec. 18, 1997. The present invention relates to methods for treating diabetes mellitus. The present invention also relates to antagonists of the potassium channel Kv2.1, methods for using and preparing the antagonists, and assays for identifying such antagonists. The secretion of insulin by the pancreatic.beta.-cell plays a critical role in regulating glucose metabolism. Derangement in insulin secretion can therefore lead to impaired regulation of blood

Patents 193

glucose, manifesting as hypoglycemia or hyperglycemia resulting in for example insulin-dependent (Type 1) diabetes mellitus or non-insulin dependent (Type 2) diabetes mellitus (NIDDM). Unlike type 1 diabetes, with NIDDM there is no autoimmune destruction of pancreatic.beta.-cells. Web site: http://www.delphion.com/details?pn=US06589934__ •

Method for culturing langerhans islets and islet autotransplantation islet regeneration Inventor(s): Yoon; Tai-Wook (51-72 Ho Yeonhee 3-Dong, Seodaemoon-Ku Seoul, KR) Assignee(s): none reported Patent Number: 6,506,599 Date filed: October 15, 1999 Abstract: A method for culturing Langerhans islets to obtain an amount sufficient for transplant and autotransplant is disclosed. The islets are cultured in a culture serum (rat/human) medium which is supplemented with radical scavengers, growth factors, a matrix material, nerve growth factor, cell migrating/scattering factors and antiintegrin.beta.1 antibody at proper the time during the culturing process. The medium is supplemented with radical scavengers and growth factors for the first time and then further supplemented with matrix material, radical scavengers, nerve growth factor and the growth factors around 12-24 hours after culturing. Thereafter, the medium is supplemented with growth factors, cell migrating/scattering factors and antiintegrin.beta.1 antibody at 4-5 days into the culturing process. The culturing process is conducted for an extended period of time, so that any latent red blood cells are eliminated from the islet culture. The islets then continue to proliferate to produce an amount of islets which is sufficient for transplantation into a diabetic patient, including a human, to provide extended normoglycaemia and islet regeneration to fully treat diabetes mellitus without the growth of fibroblasts. Excerpt(s): The present invention relates to a method for culturing the Langerhans islets suitable for transplantation. More particularly, the present invention relates to a culturing method by which the Langerhans islets can be proliferated in volume, and the fact that proliferated islet autotransplantation can stimulate islet regeneration via islet replication and neogenesis, leads to a perfect diabetes cure. Diabetes mellitus (usually referred to simply as diabetes) is a complex disease characterized by a grossly abnormal pattern of carbohydrate metabolism resulting from impaired insulin secretion and/or effectiveness. The incidence of diabetes in industrialized countries is about 10%. Indeed, diabetes is the most common serious metabolic disease in the world, it affects hundreds of millions. Diabetes may be classified as insulin-dependent diabetes or noninsulindependent diabetes. An absence of or insufficient intrinsic insulin is a characteristic of insulin-dependent diabetes. Some diabetics have a normal or even higher than normal level of insulin in their blood, but they are quite unresponsive to the hormone. This form of the disease, known as non-insulin-dependent diabetes, typically develops later in life than does the insulin-dependent form. However, the diabetes-causing mechanism with which these two types can be discriminated has yet to be revealed. Web site: http://www.delphion.com/details?pn=US06506599__

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Method for the improvement of islet signaling in diabetes mellitus and for its prevention Inventor(s): Demuth; Hans-Ulrich (Halle, DE), Glund; Konrad (Halle, DE) Assignee(s): Probiodrug AG (DE) Patent Number: 6,500,804 Date filed: April 2, 2001 Abstract: The present invention discloses a method for therapeutically treating mammals, including but not limited to humans, to increase the relative insulin producing performance of endogenous pancreatic.beta.-cells and to cause differentiation of pancreatic epithelial cells into insulin producing.beta.-cells. Oral administration a DP IV inhibitor causes the active form of GLP-1 to be preserved longer under physiological conditions. The extended presence of GLP-1, in particular in the pancreatic tissue facilitates differentiation and regeneration of the.beta.-cells already present that are in need of repair. These repaired insulin producing cells can contribute to the correction and maintenance of normal physiological glycemic levels. Excerpt(s): The pancreas comprises two glandular tissues, one, is a collection of cells that form the exocrine function of the pancreas where these exocrine cells synthesize and release digestive enzymes into the intestine; the second tissue comprises the endocrine function of the pancreas which synthesize and release hormones into the circulation. Of prime importance in the endocrine function of the pancreas, are the.beta.-cells. These cells synthesize and secrete the hormone insulin. The hormone insulin plays a vital role in maintaining normal physiological glycemic levels. There are molecules that are effectors of the endocrine cells of the pancreas. Incretins are an example of such molecules. Incretins potentiate glucose-induced insulin secretion from the pancreas. Incretins such as glucagon-like peptide-1 (7-36) amide ("GLP-1"; or the lizard analog Exendin-4) and gastric inhibitory polypeptide ("GIP") have been demonstrated to be insulinotropic, i.e., their presence or stabilization can maintain acute glycemic control by their insulin-secretive effects (Demuth, H. U., et al., DE 196 16 486:1-6, 1996; Pauly, R. P. et al., Regul. Pept. 64 (1-3): 148, 1996, the teachings of which are incorporated herein by reference in their entirety). Additionally, it has been demonstrated that GLP-1 acts, as an islet growth hormone by stimulating.beta.-cell proliferation, cell mass increase and by promoting undifferentiated pancreatic cells in specialized cells of the islet of Langerhans. Such cells show improved secretion of insulin and glucagon (Yaekura, K. et al., IN: VIP, PACAP, and Related Peptides, W. G. Forssmann and S. I. Said (eds.), New York: New York Academy of Sciences, 1998, p. 445-450; Buteau, J. et al., Diabetologia 42(7): 856-864, 1999, the entire teachings of which are herein incorporated by reference). It has been previously proposed to apply exogenous bioactive GLP-1, or its analogs, to either stimulate islet cell regeneration in vivo, or to obtain pancreatic cells from diabetes mellitus patients and to treat such cells ex vivo in tissue culture using bioactive GLP-1. This ex vivo treatment was considered to facilitate regeneration and/or differentiation of islet cells which could then synthesis and secrete insulin or glucagon (Zhou, J. et al., Diabetes, 48(12):2358-2366, 1999; Xu, G. et al., Diabetes, 48(12):2270-2276, 1999, the entire teachings of which are herein incorporated by reference). Web site: http://www.delphion.com/details?pn=US06500804__

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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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Method for treating, controlling, and preventing Diabetes Mellitus Inventor(s): Farouqi; Hafez Taji (Amman, JO), Murad; Osama Mansour (Amman, JO), Seir; Husni Abu (Amman, JO) Assignee(s): Diabex, Inc. (Wake Forest, NC) Patent Number: 6,555,126 Date filed: January 2, 2001 Abstract: This invention pertains to a method that can control, treat, and prevent Diabetes Mellitus. The method includes means of administering a potent product, including mainly the active ingredient Linalool, in any one of several forms, alone or with other additives and catalysts, such as vitamin E to enable the body to handle and control, then correct the complications of Diabetes Mellitus. A modest percentage of users suffering from this disease can be cured completely while the majority of others improve remarkably and experience lower blood glucose and reduce the glycated hemoglobin HbAlc readings to what are medically acceptable and healthy levels. Others, who are vulnerable to the disease due to hereditary factors, or other reasons, can

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help prevent it. The method works in several ways, including activation of the pancreas and re-establishing the ability of body cells to utilize and handle better and well, the glucose in the blood, and regulate the level of natural insulin in the body. The method employs Linalool in any one of its forms that can be found naturally or synthetically. Excerpt(s): This invention relates to a method that can be used to treat, control, cure, and prevent Diabetes Mellitus, of all types, through the administration of Linalool, alone, in any form, and possibly with other hypoglycemic additives in several forms, and by various means. The method does not cause any harmful or unpleasant side effects. Diabetes Mellitus is a feared and complex disorder. It has been a most distressing disease that can develop to a seriously life threatening condition. For ages, society was resigned to accepting various methods and medications that became a standard with no real hope for a cure, or drastic eradication of the disease. In fact, many of the drugs used cause serious side effects. A most important indicator of the ability of the body to deal with the complications of diabetes is the glycated hemoglobin HbAlc, that gives an integrated reading of the level of blood glucose. While all other known methods and medications help lower the glucose level at limited periods of the day or night time, the HbAlC remains higher than the normal 4.3 to 6.7 range regardless of the insulin dosage and other medicines. No full cure is expected or hoped for by the present regimens. The described method herein is new and unique, and actually reduces the HbAlc reading to the normal levels and for all patients. This method has actually cured some patients of both types I and II diabetes to such a degree that they stopped taking any medication while leading normal lives. Web site: http://www.delphion.com/details?pn=US06555126__ •

Mitochondria protecting agents for treating mitochondria associated diseases Inventor(s): Davis; Robert E. (San Diego, CA), Ghosh; Soumitra S. (San Diego, CA), Miller; Scott W. (San Marcos, CA), Moos; Walter H. (Oakland, CA) Assignee(s): MitoKor (San Diego, CA) Patent Number: 6,498,191 Date filed: December 7, 2000 Abstract: The present invention relates generally to mitochondria protecting agents for treating diseases in which mitochondrial dysfunction leads to tissue degeneration and, more specifically, to compounds, compositions and methods related to the same. The methods of this invention involve administration of a pharmaceutically effective amount of a mitochondria protecting agent to a warm-blooded animal in need thereof, and composition of this invention contain a mitochondria protecting agent in combination with a pharmaceutically acceptable carrier or diluent. Mitochondrial associated diseases which may be treated by the present invention include (but are not limited to) Alzheimer's Disease, diabetes mellitus, Parkinson's Disease, neuronal and cardiac ischemia, Huntington's disease and stroke. Excerpt(s): The present invention relates generally to mitochondria protecting agents for treating diseases in which mitochondrial dysfunction leads to tissue degeneration and, more specifically, to compounds, compositions and methods for treating such diseases. Mitochondria are the subcellular organelles that manufacture essential adenosine triphosphate (ATP) by oxidative phosphorylation. A number of degenerative diseases may be caused by or associated with either direct or indirect alterations in mitochondrial function. These include Alzheimer's Disease, diabetes mellitus, Parkinson's Disease,

Patents 197

neuronal and cardiac ischemia, Huntington's disease and other related polyglutamine diseases (spinalbulbar muscular atrophy, Machado-Joseph disease (SCA-3), dentatorubro-pallidoluysian atrophy (DRPLA) and spinocerebellar ataxias 1, 2 and 6), dystonia, Leber's hereditary optic neuropathy, schizophrenia, and myodegenerative disorders such as "mitochondrial encephalopathy, lactic acidosis, and stroke" (MELAS), and "myoclonic epilepsy ragged red fiber syndrome" (MERRF). Defective mitochondrial activity, including but not limited to failure at any step of the elaborate multi-complex mitochondrial assembly, known as the electron transport chain (ETC), may result in 1) decreases in ATP production, 2) increases in the generation of highly reactive free radicals (e.g., superoxide, peroxynitrite and hydroxyl radicals, and hydrogen peroxide), 3) disturbances in intracellular calcium homeostasis and/or 4) release of apoptosis inducing factors such as, e.g., cytochrome c. Because of these biochemical changes, mitochondrial dysfunction has the potential to cause widespread damage to cells and tissues For example, oxygen free radical induced lipid peroxidation is a well established pathogenetic mechanism in central nervous system (CNS) injury such as that found in a number of degenerative diseases, and in ischemia (i.e., stroke). Web site: http://www.delphion.com/details?pn=US06498191__ •

Receptor Inventor(s): Caskey; Charles T. (6402 Bellmont, Houston, TX 66005), Cox; Roger D (7 Park Road, Banbury, Oxon, GB OX16 0DW), Gerhold; David (730 Tranquility La., Lansdale, PA 19446), Hammond; Holly (621 Melvins Rd., Telford, PA 18969), Hess; John W. (566 Constitution Rd., Lansdale, PA 19446), Hey; Patricia (1133 Bloomfield Cir., Lansdale, PA 19446), Kawaguchi; Yoshihiko (Yamadanishi 3-33-B-206, Suita Shi, Osaka, JP 565), Merriman; Tony R. (16 A Cromwell Close, Marston, Oxford, GB OX3 0RX), Metzker; Michael L. (7400 Encampment Rd., Lansdale, PA 19446), Nakagawa; Yusuke (17 Latimer Grange, Latimer Road, Headington, Oxford, GB OX3 7PQ), Phillips; Michael S. (608 Poplar Ct., Lansdale, PA 19446), Todd; John A. (64 Rousham Road, Tackley, Oxon, GB OX5 3AJ), Twells; Rebecca C.J. (75 Park Street, Thame, Oxon, GB OX9 3HU) Assignee(s): none reported Patent Number: 6,545,137 Date filed: April 15, 1998 Abstract: A novel receptor, "LDL-receptor related protein-3" ("LRP-3"), is provided, along with encoding nucleic acid. The gene is associated with type 1 diabetes (insulin dependent diabetes mellitus), and experimental evidence provides indication that it is the IDDM susceptibility gene IDDM4. In various aspects the invention provides nucleic acid, including coding sequences, oligonucleotide primers and probes, polypeptides, pharmaceutical compositions, methods of diagnosis or prognosis, and other methods relating to and based on the gene, including methods of treatment of diseases in which the gene may be implicated, including autoimmune diseases, such as glomerulonephritis, diseases and disorders involving disruption of endocytosis and/or antigen presentation, diseases and disorders involving cytokine clearance and/or inflammation, viral infection, elevation of free fatty acids or hypercholesterolemia, osteoporosis, Alzheimer's disease, and diabetes. Excerpt(s): The present invention relates to nucleic acids, polypeptides, oligonucleotide probes and primers, methods of diagnosis or prognosis, and other methods relating to and based on the identification of a gene, which is characterised as a member of the LDL-receptor family and for which there are indications that some alleles are associated

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with susceptibility to insulin-dependent diabetes mellitus ("IDDM"), also known as type 1 diabetes. More particularly, the present invention is based on cloning and characterisation of a gene which the present inventors have termed "LDL-receptor related protein-5 (LRP5)" (previously "LRP-3"), based on characteristics of the encoded polypeptide which are revealed herein for the first time and which identify it as a member of the LDL receptor family. Furthermore, experimental evidence is included herein which provides indication that LRP5 is the IDDM susceptibility gene IDDM4. Diabetes, the dysregulation of glucose homeostasis, affects about 6% of the general population. The most serious form, type 1 diabetes, which affects up to 0.4% of European-derived population, is caused by autoimmune destruction of the insulin producing.beta.-cells of the pancreas, with a peak age of onset of 12 years. The.beta.-cell destruction is irreversible, and despite insulin replacement by injection patients suffer early mortality, kidney failure and blindness (Bach, 1994; Tisch and McDevitt, 1996). The major aim, therefore, of genetic research is to identify the genes predisposing to type 1 diabetes and to use this information to understand disease mechanisms and to predict and prevent the total destruction of.beta.-cells and the disease. Web site: http://www.delphion.com/details?pn=US06545137__ •

Recombinant vector for use in gene therapy for insulin-dependent diabetes mellitus and therapeutic composition thereof Inventor(s): Suh; Dongsang (Department Genetic Engineering, Sungkyunkwan University, Chunchun-dong, Jangan-ku, Suwon, Kyonggi-do, KR 440-746) Assignee(s): none reported Patent Number: 6,596,515 Date filed: February 5, 2001 Abstract: Disclosed are a recombinant vector for use in gene therapy for insulindependent diabetes mellitus and a therapeutic composition thereof. Following the injection of a.beta.-galactosidase expression vector having a K14 promoter gene, along with a Drosophola's P transposase expression helper vector, into murine skin in a liposome-mediated manner, the.beta.-galactosidase gene is expressed in the keratinocyte layer from 24 hours to 20 weeks after injection as measured by X-gal staining. With the enhancement effect and tissue specificity, the K14 promoter is applied for the expression of a human insulin gene in keratinocytes, thereby suggesting a new gene therapy method for treating insulin-dependent diabetes mellitus. When, in combination with the P-element expression helper vector, a human insulin expression vector with the K14 promoter is injected into the skin of diabetic mice, which lack insulin-producing.beta.cells of the pancreas, their blood glucose levels are maintained in a normal range. Excerpt(s): The present invention relates to a recombinant vector suitable for use in gene therapy for insulin-dependent diabetes mellitus and a pharmaceutical composition comprising the recombinant vector as an effective ingredient. More particularly, the present invention relates to a gene therapy system for effectively and safely treating insulin-dependent diabetes mellitus by taking advantage of the gene delivery capacity of Drosophila's P-transposon and the tissue specificity and expression enhancement of a K14 promoter. Gene therapy offers a new paradigm for curing human diseases. Rather than altering disease phenotypes by using agents that interact with gene products or are themselves gene products, gene therapy theoretically can modify specific genes, which results in a cure following a single administration. Initially, gene therapy was envisioned for the treatment of genetic disorders, but is currently studied for a broad

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spectrum of diseases, including cancer, peripheral vascular disease, arthritis, neurodegenerative disorders and other acquired diseases. Further, in combination with the Human Genome Project, gene therapy is expected to make a great progress in the treatment of far more diseases. With gene therapy, the delivery of genes into cells and their expression therein can be artificially regulated, so that the mutated genes of patients can be corrected by genetic recombination. There are disclosed patents regarding gene therapy. For instance, PCT publication No. 1997-27310 claims a retrovirus vector which can be used in gene therapy and PCT publication No. 199734009 discloses a recombinant adenovirus vector for gene therapy for human tumors. Virus vectors are, however, limited to only the treatment of hereditary diseases, owing to safety concerns and highly complex procedures. Also, the gene therapy utilizing virus vectors, as in such patents, suffers from the disadvantage of requiring much time and high expense. In prior arts, non-viral insulin vectors have been disclosed nowhere yet. Web site: http://www.delphion.com/details?pn=US06596515__ •

Temperature-sensitive polymer/nanoshell composites for photothermally modulated drug delivery Inventor(s): Averitt; Richard D. (Los Alamos, NM), Halas; Nancy J. (Houston, TX), Oldenburg; Steven J. (San Diego, CA), Sershen; Scott R. (Houston, TX), West; Jennifer L. (Pearland, TX) Assignee(s): William Rice Marsh Rice University (Houston, TX) Patent Number: 6,645,517 Date filed: June 5, 2002 Abstract: A thermally sensitive polymer-particle composite that absorbs electromagnetic radiation, and uses the absorbed energy to trigger the delivery of a chemical is disclosed. Metal nanoshells are nanoparticulate materials that are suitable for use in the present composites and can be made according to a process that includes optically tuning or tailoring their maximum optical absorption to any desired wavelength primarily by altering the ratio of the core diameter to the shell thickness. Preferred nanoshells are selected that strongly absorb light in the near-infrared and thus produce heat. These nanoshells are combined with a temperature-sensitive material to provide an implantable or injectable material for modulated drug delivery via external exposure to near-IR light. This invention provides a means to improve the quality of life for persons requiring multiple injections of a drug, such as diabetes mellitus patients. Excerpt(s): The present invention generally relates to chemical delivery by controlled release from an implanted device or medium. More particularly, the invention relates to composite materials containing a temperature-sensitive polymer, a drug, and lightabsorbing particles, and to methods of photothermally modulating drug release. Modulated drug delivery allows the release profiles of therapeutic agents to be manipulated to match the physiological requirements of the patient. This type of controlled delivery system is useful for treating diseases that affect the homeostatic functions of the body, such as diabetes mellitus. Insulin therapy for diabetes requires a low baseline release of the drug, with peaks after the ingestion of food (O. B. Crofford Ann. Rev. Med. 46:267-279 (1995); F. R. Kaufman Pediatr. Rev. 18:383-392 (1997); and F. Ginsberg-Fellner Pediatr. Rev. 11:239-247 (1990)). Various methods of accomplishing modulated in vivo drug delivery have been described in the literature and are currently in use or undergoing investigation. Mechanical pumps are one type of device that is commonly employed. Another method that has been examined is the use of ultrasound

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for "blasting off" a layer of material from a drug-containing polymer matrix to alter drug release. That method requires use of rigid, hydrophobic polymers that are generally incompatible with proteins and other hydrophilic macromolecular drugs. Other potential problems with the routine implementation of such ultrasound techniques may exist, as suggested by the widespread concern about the long term safety of repetitive exposure of body tissues to ultrasonic energy. Web site: http://www.delphion.com/details?pn=US06645517__ •

Treating NIDDM with RXR agonists Inventor(s): Cesario; Rosemary (San Diego, CA), Heyman; Richard A. (Encinitas, CA), Mukherjee; Ranjan (San Diego, CA) Assignee(s): Ligand Pharmaceuticals Incorporated (San Diego, CA) Patent Number: 6,521,633 Date filed: May 7, 2001 Abstract: This invention relates to methods and compositions for the treatment of noninsulin-dependent diabetes mellitus using an RXR agonist alone or in combination with a PPAR.gamma. agonist such as a thiazolidinedione compound. Excerpt(s): This invention relates to methods and pharmaceutical compounds for treating diabetes and related symptoms. Non-insulin-dependent diabetes mellitus (NIDDM, type II diabetes) is characterized by abnormalities in insulin secretion and insulin action. NIDDM constitutes 90-95% of the approximately 6 million diagnosed diabetics in the United States. NIDDM is characterized by hyperglycemia, the result of insulin resistance in peripheral tissues (skeletal muscle and adipose tissue), where insulin-stimulated uptake/utilization of glucose is blunted, and in liver, where insulin suppression of glucose output is insufficient. These impairments in insulin action play an important role in the development of elevated fasting blood glucose and glucose intolerance. Diet and exercise are first-line therapy for NIDDM patients. NIDDM patients also take oral hypoglycemic drugs to control blood glucose levels. The most widely used hypoglycemic agents are various formulations of insulin and sulfonylureas. A major drawback with these therapies is the occurrence of potentially life-threatening hypoglycemia due to hyperinsulinemia. Web site: http://www.delphion.com/details?pn=US06521633__

•

Treatment for diabetes Inventor(s): Brand; Stephen J. (Lincoln, MA), Lane; Anne (Westmount, CA), Nardi; Ronald V. (Mahwah, NJ), Parikh; Indu (Chapel Hill, NC) Assignee(s): The General Hospital Corporation (Boston, MA), Waratah Pharmaceuticals, Inc. (Quebec, CA) Patent Number: 6,558,952 Date filed: January 29, 1999 Abstract: Methods and compositions for treating diabetes mellitus in a patient in need thereof are provided. The methods include administering to a patient a composition providing a gastrin/CCK receptor ligand, e.g., a gastrin, and/or an epidermal growth factor (EGF) receptor ligand, e.g., TGF-.alpha., in an amount sufficient to effect

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differentiation of pancreatic islet precursor cells to mature insulin-secreting cells. The composition can be administered systemically or expressed in situ by cells transgenically supplemented with one or both of a gastrin/CCK receptor ligand gene, e.g., a preprogastrin peptide precursor gene and an EGF receptor ligand gene, e.g., a TGF-.alpha. gene. The methods also include transplanting into a patient cultured pancreatic islets in which mature insulin-secreting beta cells are proliferated by exposure to a gastrin/CCK receptor ligand and an EGF receptor ligand. Excerpt(s): This invention relates to a method for treating diabetes mellitus in an individual in need thereof by administering to the individual a composition comprising a gastrin/CCK receptor ligand and/or an EGF receptor ligand which effectively promotes differentiation of pancreatic islet precursor cells to mature insulin-secreting cells. The method is exemplified by administration of gastrin and transforming growth factor alpha (TGF-.alpha.) either alone or in combination to normal streptozotocin (STZ) induced diabetic and genetically predisposed diabetic Zucker rats. Diabetes is one of the most common endocrine diseases across all age groups and populations. In addition to the clinical morbidity and mortality, the economic cost of diabetes is huge, exceeding $90 billion per year in the US alone, and the prevalence of diabetes is expected to increase more than two-fold by the year 2010. There are two major forms of diabetes mellitus: insulin-dependent (Type 1) diabetes mellitus (IDDM) which accounts for 5 to 10% of all cases, and non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) which comprises roughly 90% of cases. Type 2 diabetes is associated with increasing age however there is a trend of increasing numbers of young people diagnosed with NIDDM, so-called maturity onset diabetes of the young (MODY). In both Type 1 and Type 2 cases, there is a loss of insulin secretion, either through destruction of the.beta.cells in the pancreas or defective secretion or production of insulin. In NIDDM, patients typically begin therapy by following a regimen of an optimal diet, weight reduction and exercise. Drug therapy is initiated when these measures no longer provide adequate metabolic control. Initial drug therapy includes sulfonylureas that stimulate.beta.-cell insulin secretion, but also can include biguanides,.alpha.-glucosidase inhibitors, thiazolidenediones and combination therapy. It is noteworthy however that the progressive nature of the disease mechanisms operating in type 2 diabetes are difficult to control. Over 50% of all drug-treated diabetics demonstrate poor glycemic control within six years, irrespective of the drug administered. Insulin therapy is regarded by many as the last resort in the treatment of Type 2 diabetes, and there is patient resistance to the use of insulin. Web site: http://www.delphion.com/details?pn=US06558952__ •

Treatment of diabetes and related pathologies Inventor(s): Haque; Wasimul (Winnipeg, CA), Sethi; Rajat (Winnipeg, CA) Assignee(s): Medicure, Inc. (CA) Patent Number: 6,489,345 Date filed: July 13, 2000 Abstract: Methods for treating diabetes mellitus and related conditions and symptoms are described. The methods are directed to administering a therapeutically effective amount of a compound. Compounds suitable for the invention include pyridoxal-5'phosphate, pyridoxal, pyridoxamine, pyridoxine, a 3-acylated pyridoxal analogue, a pharmaceutically acceptable acid addition salt thereof, or a mixture thereof. Also disclosed are methods directed to concurrently administering a therapeutically effective

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amount of a compound with other compounds known in the treatment of diabetes mellitus. In one embodiment, a therapeutically effective amount of a compound is administered concurrently with a therapeutically effective amount of insulin. In another embodiment, a therapeutically effective amount of a compound is administered concurrently with a therapeutically effective amount of a hypoglycemic compound. Excerpt(s): This invention relates to methods of treating insulin-dependent diabetes mellitus, noninsulin-dependent diabetes mellitus, and related conditions and symptoms. Diabetes mellitus is a condition in which blood glucose levels are abnormally high because the body is unable to produce enough insulin to maintain normal blood glucose levels or is unable to adequately respond to the insulin produced. Insulin-dependent diabetes mellitus (often referred to as type I diabetes) arises when the body produces little or no insulin. About 10% of all diabetics have type I diabetes. Noninsulin-dependent diabetes mellitus (often referred to as type II diabetes) arises when the body cannot adequately respond to the insulin that is produced in response to blood glucose levels. Type II diabetes is often associated with hyperglycemia (high plasma glucose levels due to decreased glucose utilization) and hyperinsulinemia (high plasma insulin levels due to decreased insulin receptors available), factors that contribute to insulin resistance. Available treatments include weight control, exercise, diet, and drug therapy. Drug therapy for type I diabetes mellitus requires the administration of insulin; however, drug therapy for type II diabetes mellitus usually involves the administration of insulin and/or oral hypoglycemic drugs to lower blood glucose levels. If the oral hypoglycemic drugs fail to control blood sugar, then insulin, either alone or in combination with the hypoglycemic drugs, will usually be administered. Web site: http://www.delphion.com/details?pn=US06489345__ •

Use of 4-amino pyridine for treatment of peripheral neuropathies Inventor(s): Meythaler; Jay M. (Birmingham, AL) Assignee(s): The UAB Research Foundation (Birmingham, AL) Patent Number: 6,503,931 Date filed: August 9, 2001 Abstract: The present invention provides methods of using aminopyridine compounds to treat peripheral nervous system demyelinating diseases including Guillain-Barre Syndrome, diabetes mellitus, and hereditary sensory-motor neuropathies. Excerpt(s): The subject invention relates to the treatment of peripheral neuropathies and, more specifically, to the treatment of demyelinating peripheral neuropathies. By way of background, demyelinating neuropathies or diseases can occur in both the central nervous system and peripheral nervous system. Multiple sclerosis (MS) is a degenerative and inflammatory neurological disease which affects the central nervous system and, more specifically, the myelin sheath. MS causes demyelination of nerve fibers which results in a short-circuiting of nerve impulses and thus a slowing or blocking of transmission along the nerve fibers with associated disabling symptoms including spasticity, loss of motor strength, and painful dysaesthesias (neurogenic pain). In contrast, with peripheral demyelinating neuropathy, spasticity does not occur; however, weakness and neurogenic pain are problematic. Peripheral neuropathies are associated with a number of diseases, syndromes, or conditions including but not limited to acquired diseases or conditions including Guillain-Barre Syndrome (GBS),

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chronic demyelinating polyradiculoneuropathy (CIDP), diabetic mellitus (prevalence of diabetic neuropathy alone is over one million in the United States), or the hereditary sensory-motor neuropathies (Charcopt-Marie-Tooth disease, Friedrich's ataxia, porphyria, lipoprotein neuropathies, and familial amyloid neuropathies). U.S. Pat. No. 5,540,938 to Masterson et al., issued Jul. 30, 1996, and assigned to Elan Corporation discloses a method for the treatment of neurological diseases characterized by central nervous system demyelination such as MS and Alzheimer's disease, by the administration of mono- or di-aminopyridine to a patient having the central nervous system demyelinating disease. The Masterson et al. patent only teaches the amelioration of symptoms associated with the central nervous system demyelating diseases and does not describe the use of aminopyridines for the treatment of peripheral nervous system demyelating diseases or their symptoms. Web site: http://www.delphion.com/details?pn=US06503931__ •

Use of exendins and agonists thereof for the treatment of gestational diabetes mellitus Inventor(s): Hiles; Richard A. (San Diego, CA), Prickett; Kathryn S. (San Diego, CA) Assignee(s): Amylin Pharmaceuticals, Inc. (San Diego, CA) Patent Number: 6,506,724 Date filed: June 1, 1999 Abstract: Methods for treating gestational diabetes which comprise administration of an effective amount of an exendin or an exendin agonist, alone or in conjunction with other compounds or compositions that lower blood glucose levels. Excerpt(s): The present invention relates to methods for treating gestational diabetes mellitus comprising administration of an effective amount of an exendin or an exendin agonist alone or in conjunction with other compounds or compositions that affect blood glucose control, such as an insulin or an amylin agonist. Pharmaceutical compositions for use in the methods of the invention are also disclosed. The following description summarizes information relevant to the present invention. It is not an admission that any of the information provided herein is prior art to the presently claimed invention, nor that any of the publications specifically or implicitly referenced are prior art to that invention. Gestational diabetes mellitus ("GDM") is a disorder associated with elevated circulating plasma glucose. Although the diagnostic criteria for GDM have been the subject of controversy for decades, it was defined by the Third Workshop Conference on Gestational Diabetes Mellitus as carbohydrate intolerance of varying severity with onset or first recognition during pregnancy, irrespective of the glycemic status after delivery. Metzger (ed.) Proceedings of the Third International Workshop Conference on Gestational Diabetes Mellitus, Diabetes 40(Suppl. 2), 1991. Despite advances in clinical management of GDM, there are problems associated with GDM which persist, including elevated rate of perinatal morbidity and elevated rate of malformations in newborns. Persson et al., Diabetes and Pregnancy, In International Textbook of Diabetes Mellitus, Second Edition, John Wiley & Sons 1997 (Alberti et al. Eds.). For example, it has been reported that, when the mean blood glucose level is greater than 105 mg/dl, there is a greater risk for the development of large-for-gestational age ("LGA") infants when compared with a control population. Id. Additional reported consequences of untreated GDM include an increased incidence of macrosomia, respiratory distress syndrome, and other abnormalities of fetal metabolism. Langer, Am. J. Obstet Gynecol. 176:S186, 1997; American Diabetes Association: Self-Monitoring of Blood Glucose Consensus Statement,

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Diabetes Care 17:81-82, 1994("ABA Consensus Statement"); Coetzee & Jackson, S. Afr. Med. J. 56:467-475, 1979. It has been clearly established by those in the field that tight glycemic control can serve as the primary prevention of fetal disease relating to GDM. Drexel et al., Diabetes Care 11:761-768, 1988; Roversi et al., Diabetes Care 3:489-494, 1980; Langer & Mazze, Am. J. Obstet Gynecol. 159:1478-1483, 1988; Langer et al., Am. J. Obstet Gynecol. 161:646-653, 1989). GDM results in a greater incidence of intrauterine death or neonatal mortality. Position Statement American Diabetes Association: Gestational Diabetes Mellitus, Diabetes Care 21 (Suppl. 1):S60-61, 1998. GDM pregnancies are at an increased risk for fetal macrosomia and neonatal morbidities including neural tube defects, hypoglycemia, hypocalcemiea, hypomagnsemia, polycythemia and hyperbilirubinemia and subsequent childhood and adolescent obesity. Siccardi, Gestational Diabetes. Other complications to the woman include increased rates of cesarean delivery, hypertensive disorders including preeclamsia and urinary tract infections. Web site: http://www.delphion.com/details?pn=US06506724__ •

Various thiol complexes, processes for their synthesis and clinical applications Inventor(s): Pearson; Don C. (Lakewood, WA), Richardson; Kenneth T. (Anchorage, AK) Assignee(s): Chronorx, LLC. (Anchorage, AK) Patent Number: 6,531,608 Date filed: June 11, 2002 Abstract: This invention relates to the synthesis of certain complexes of cysteine, Nacetylcysteine, N-(2-mercaptopropionyl)glycine, and L-2-oxothiazolidine-4-carboxylate and to the nutritional use of these and other related individual or complexed thiolcontributing glutathione predecessors. Clinical uses for these molecules and complexes in the beneficial modification of various physiological conditions and functions associated with aging, chronic glaucoma, diabetes mellitus, insulin resistance, macular degeneration, neurodegenerative diseases and vasoconstriction are described in particular. Excerpt(s): This invention is in the fields of pharmacology and biochemistry. It relates to the synthesis of certain complexes of L-cysteine, N-acetyl L-cysteine, N-(2-mercaptopropionyl)glycine, L-2-oxothiazolidine-4-carboxylate and the nutritional or clinical use of these and other related individual or complexed thiol contributing, glutathione predecessors. The use of these molecules and complexes in clinical presentations of chronic glaucoma, diabetes mellitus, macular degeneration, neurodegenerative diseases and vasoconstriction are described in particular. The eye is maintained in a homeostatic shape by a relatively stable intraocular pressure (IOP) that varies within a reasonably narrow range so long as the intraocular production of aqueous fluid remains equal to its exit from the eye. The optic nerve head can tolerate relatively high levels of IOP if the availability of oxygen from posterior ciliary arteries and optic nerve head arterioles remains adequate. However, if the global intraocular pressure is higher than the perfusion pressure driving oxygen through the arteriole into the surrounding tissues, decreasing amounts of oxygen will reach the optic nerve head and nerve disability will result. Web site: http://www.delphion.com/details?pn=US06531608__

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Patent Applications on Diabetes Mellitus 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 diabetes mellitus: •

ANTIDIABETIC AGENTS Inventor(s): Bigge, Christopher F.; (Ann Arbor, MI), Schaum, Robert P.; (Ann Arbor, MI) Correspondence: Heidi M. Berven; Warner-lambert Company, Llc; 2800 Plymouth Road; Ann Arbor; MI; 48105; US Patent Application Number: 20030220381 Date filed: March 17, 2003 Abstract: Compounds of formula I: 1wherein X, Y, B, E, J, K, L, Z, and R.sub.9-R.sub.12 have any of the meanings described herein, their pharmaceutically acceptable salts, lower blood glucose levels and are useful for treating diseases in mammals such as NonInsulin Dependent Diabetes Mellitus. Also disclosed are pharmaceutical compositions, processes for preparing compounds of formula (I) and intermediates useful for preparing compounds of formula I. Excerpt(s): This application claims benefit of priority from U.S. Provisional Application Serial No. 60/369,787 filed on Apr. 3, 2002. The present invention relates to compounds that are useful as antidiabetic agents. Type II diabetes, or non-insulin dependent diabetes (NIDDM) is a significant healthcare problem whose incidence is on the rise. Between 1990 and 1998, the prevalence of NIDDM in the United States increased by 33 percent, to about 13 million persons. An additional 5 million persons are presumed to have undiagnosed NIDDM, while another 14 million persons have impaired glucose tolerance. Direct medical costs associated with diabetes were $44 billion in 1997, due mainly to hyperglycemia-related diabetic complications, including diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation, and glaucoma. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Anti-interferon-alpha antibodies Inventor(s): Chuntharapai, Anan; (Colma, CA), Kim, Jin K.; (Cupertino, CA), Presta, Leonard G.; (San Francisco, CA), Stewart, Timothy; (San Francisco, CA) Correspondence: Merchant & Gould PC; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20030166228 Date filed: January 9, 2002 Abstract: The present invention relates generally to the generation and characterization of neutralizing anti-IFN-.alpha. monoclonal antibodies with broad reactivity against various IFN-.alpha. subtypes. The invention further relates to the use of such anti-IFN.alpha. antibodies in the diagnosis and treatment of disorders associated with increased

10

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

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expression of IFN-.alpha., in particular, autoimmune disorders such as insulindependent diabetes mellitus (IDDM) and systemic lupus erythematosus (SLE). Excerpt(s): This application claims the benefit under Title 35, United States Codes.sctn. 119(e) of the U.S. provisional Application No. 60/270,775, filed Feb. 22, 2001. Although interferons were initially discovered for their anti-viral activities, subsequent research has unraveled a plethora of regulatory activities associated with these powerful cytokines. Type I interferons form an ancient family of cytokines that includes IFN.alpha., IFN-.beta., IFN-.delta., IFN-.omega. and IFN-.tau. (Roberts et al., J. Interferon Cytokine Res. 18: 805-816 [1998]). They are coded by intronless genes and are widely distributed amongst vertebrates. Whereas IFN-.beta. is coded by a single gene in primates and rodents, more than 10 and 15 different subtypes of IFN-.alpha. have been found in mice and man respectively. Other interferons of type I are more restricted, e.g. IFN-.delta. in the pig, IFN-.tau. in cattle and sheep, and IFN-.omega. in cattle and humans. Thus, human type I interferons comprise multiple members of the IFN-.alpha. family, and single members of the IFN-.beta. and IFN-.omega. families. All type I IFNs appear to bind to a single receptor that is comprised of at least two membrane spanning proteins. Type II interferons on the other hand are represented by a single member, IFN.gamma., and bind to a distinct receptor. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Association of EDG5 polymorphism V286A with type II Diabetes mellitus and venous thrombosis/pulmonary embolism and the use thereof Inventor(s): Deleuze, Jean-Francois; (Combs La Ville, FR), Jacobs, Martina; (Mannheim, DE), Kostenis, Evi; (Grebenau, DE), Kozian, Detlef; (Hattersheim, DE), Mace, Sandrine; (Jouy-En-Josas, FR), Ricard, Sylvain; (Paris, FR), Siegler, Karl-Ernst; (Ludwigshafen, DE) Correspondence: Ross J. Oehler; Aventis Pharmaceuticals INC.; Route 202-206; Mail Code: D303a; Bridgewater; NJ; 08807; US Patent Application Number: 20030219808 Date filed: March 21, 2003 Abstract: The present invention relates to a method of identifying an increase in risk for type II Diabetes mellitus, venous thrombosis, or pulmonary embolism in a subject, wherein the presence of an amino acid exchange at position 286 from valine (Val) to alanine (Ala) in the EDG5 protein in a biological sample taken from the subject. Excerpt(s): This application claims priority under 35 U.S.C. 119 from U.S. Ser. No. 60/402,305 filed on Aug. 9, 2002 and European Patent Application No. 02007879.6 filed Apr. 9, 2002, wherein said applications are hereby incorporated by reference herein in their entireties. The present invention relates generally to a method of identifying an increase in risk for type II Diabetes mellitus venous thrombosis, pulmonary embolism, or a combination thereof. Endothelial differentiation gene (EDG) receptors are a new family of eight G protein-coupled receptors for the lysophospholipids lysophosphatitic acid and sphingosine-1-phosphate. The lysosphingolipid sphingosine 1-phosphate (S1P) regulates cell proliferation, apoptosis, motility, and neurite retraction (Pyne and Pyne, (2000) Biochem J 349: 385-402; MacLennan et al., (2001), J. of Neurosci. 14: 203-209). Its actions may be both intracellular as a second messenger and extracellular as a receptor ligand. S1P and the structurally related lysolipid mediator lysophosphatidic acid (LPA) signal through a set of G protein-coupled receptors known as EDG receptors. EDG5 (endothelial differentiation gene 5; also termed AGR16/H218) is a functional receptor

Patents 207

for S1P. The size of the EDG5 protein is 353 amino acids and the EDG5 gene is located on chromosome 19p13.2. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Carbohydrate Aborption Inhibitor and Method for Manufacturing the Same Inventor(s): Aitani, Michio; (Hyogo, JP), Arimuba, Tsutomi; (Osaka, JP), Konishi, Yotaro; (Osaka, JP), Murai, Hiromichi; (Aichi, JP), Okada, Tadashi; (Aichi, JP), Yamaguchi, Hiroshi; (Aichi, JP) Correspondence: Clark & Brody; Suite 600; 1750 K Street NW; Washington; DC; 20006; US Patent Application Number: 20030161903 Date filed: January 31, 2003 Abstract: This invention provides carbohydrate absorption inhibitor derived from evening primrose seed which is significantly effective to prevent and cure diabetes mellitus and prevent obesity, and the manufacturing method of the same.Carbohydrate absorption inhibitor in this invention is characterized that the effective component is an alcohol extract of evening primrose seed. The aforementioned evening primrose seed is preferably a defatted evening primrose seed. Extracting solvent of the aforementioned evening primrose seed is preferably ethanol, or preferably a 70 to 85% (v/v) aqueous ethanol. Also, this invention is characterized that the carbohydrate absorption inhibitor is an effective component of polyphenol derived from evening primrose seed. The polyphenol is preferably one or more substances selected from among gallic acid, ellagic acid, catechin, pentagalloylglucose, procyanidin, and proantocyanidin. The manufacturing method of the carbohydrate absorption inhibitor in this invention is characterized to be composed of the following processes A to C. Process A: evening primrose is compressed, oil is separated then the compressed cake is obtained. Process B: The aforementioned compressed cake is defatted in fat-soluble organic solvent, and defatted substance is obtained. Process C: The aforementioned defatted substance is extracted by alcohol, and then this extracted liquid is concentrated or evaporated. Excerpt(s): This invention relates to carbohydrate absorption inhibitor and method for manufacturing the same effective against e.g. diabetes prevention, diet, and so forth. Polysaccharide (starch, glycogen or the like) contained in food is hydrolyzed by.alpha.amylase in saliva and pancreas and converted into oligosaccharide such as maltose, isomaltose or the like, then decomposed to glucose by disaccharide degrading enzyme such as.alpha.-glucosidase or the like in the small intestine and absorbed. Thus,.alpha.amylase and.alpha.-glucosidase perform an important role as a digestive enzyme for carbohydrate in the body. These enzyme activities affect the blood glucose level. Therefore, it is important to control these enzyme activities for the preventions and medical treatments of diabetes mellitus and obesity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Cardioprotective phosphonates and malonates Inventor(s): Haque, Wasimul; (Edmonton, CA) Correspondence: Merchant & Gould P.C.; Attention: Anna M. Nelson; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20030181422 Date filed: February 28, 2003 Abstract: The present invention provides for pyridoxine phosphonate analogues such as, for example, ((2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)alkylphos- phonates, and (2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl)azaalkylphosph- onates) and to pyridoxine malonate analogues, such as, for example, ((2-methyl-3-hydroxy-4hydroxymethyl-5-pyridylmethyl)malonates), pharmaceutical compositions, and methods for treatment of cardiovascular and related diseases, and diabetes mellitus and related diseases. Excerpt(s): This application is a continuation of U.S. application Ser. No. 09/795,689 filed on Feb. 28, 2001, which claims priority of invention under 35 U.S.C.sctn.119(e) from U.S. provisional application No. 60/185,899, filed Feb. 29, 2000. This invention relates to pyridoxine phosphonate analogues, to pyridoxine malonate analogues, to their preparation, to pharmaceutical compositions thereof, and to treatments for cardiovascular and related diseases, for example, hypertrophy, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, heart failure subsequent to myocardial infarction, myocardial infarction, ischemia reperfusion injury, and diseases that arise from thrombotic and prothrombotic states in which the coagulation cascade is activated; and treatments for diabetes mellitus and related diseases, for example, hyperinsulinemia, diabetes-induced hypertension, obesity, insulin resistance, and damage to blood vessels, eyes, kidneys, nerves, autonomic nervous system, skin connective tissue, or immune system. Pyridoxal-5'-phosphate (PLP), an end product of vitamin B.sub.6 metabolism, plays a vital role in mammalian health. In previous patents (U.S. Pat. No. 6,051,587 and U.S. Pat. No. 6,043,259, herein incorporated by reference) the role of pyridoxal-5'-phosphate, and its precursors pyridoxal and pyridoxine (vitamin B.sub.6), in mediating cardiovascular health and in treating cardiovascular related diseases is disclosed. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Ceramide kinase and DNA encoding it Inventor(s): Kohama, Takafumi; (Tokyo, JP), Kono, Keita; (Kawasaki-shi, JP), Sugiura, Masako; (Tokyo, JP) Correspondence: Frishauf, Holtz, Goodman & Chick, PC; 767 Third Avenue; 25th Floor; New York; NY; 10017-2023; US Patent Application Number: 20030162206 Date filed: December 10, 2002 Abstract: A protein having ceramide kinase activity which can be a target for a prophylactic or therapeutic medicament against neuronal disease, inflammation, HIV infection, type 2 diabetes mellitus, obesity, septicemia, arteriosclerosis and cancer. Specifically, a protein which comprises an amino acid sequence shown in the amino acid numbers 1-537 of SEQ ID No. 2 of the Sequence Listing, a DNA which encodes the

Patents 209

protein, a recombinant vector comprising the DNA, a host cell transformed with the recombinant vector and a method for producing the protein. By using the method of the present invention, a compound is provided having a specifically activating or inhibiting activity to ceramide kinase and is useful as a medicament for treating a neuronal disorder, an anti-inflammatory medicament, a medicament for treating HIV infection, an anti-type 2 diabetes mellitus medicament, an anti-obesity medicament, an antisepticemia medicament, an anti-arteriosclerosis medicament and an anticancer medicament. Excerpt(s): This application is a continuation-in-part of International application PCT/JP01/04889 filed Jun. 11, 2001, the entire contents of which are hereby incorporated by reference herein. The present invention relates to a novel protein having ceramide kinase activity which may be a target of a medicament for preventing or treating neuronal disease, inflammation, HIV infection, type 2 diabetes mellitus, obesity, septicemia, arteriosclerosis and cancer; DNA which encodes the protein; a recombinant DNA vector comprising the DNA; a host transformed with the recombinant DNA vector; a method for producing the ceramide kinase; and use of the protein. Sphingolipids have been conventionally considered to be one of the major components of cell membrane as glycerophospholipids and cholesterol. It has been known that glycerophospholipids not only maintain cell membrane structure, but also let the cells produce many physiologically active substances as metabolites thereof. However, a physiological activity of sphingolipid metabolites has been hardly known until recently. In these years, physiological activities of some sphingolipid metabolites such as induction of apoptosis and cell proliferation-stimulating activity, have come to be known, and the possibility that enzymes metabolizing sphingolipid closely participate in physiological reactions or various diseases has been suggested. Especially, ceramide attracts attention as a regulator which controls many cell mechanisms (See Hannun, Y. A. and Obeid, L. M., (1995), TIBS, 20, 73-77). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

COMBINATIONS OD DIPEPTIDYL PEPTIDASE IV INHIBITORS AND OTHER ANTIDIABETIC AGENTS FOR THE TREATMENT OF DIABETES MELLITUS Inventor(s): Arch, Jonathan Robert Sanders; (Essex, GB), Lenhard, James Martin; (Durham, NC) Correspondence: Smithkline Beecham Corporation; Corporate Intellectual Property-us, Uw2220; P. O. Box 1539; King OF Prussia; PA; 19406-0939; US Patent Application Number: 20030166578 Date filed: February 20, 2003 Abstract: A method for the treatment of diabetes mellitus, especially Type 2 diabetes and conditions associated with diabetes mellitus in a mammal such as a human, which method comprises administering an effective, non-toxic and pharmaceutically acceptable amount of a dipeptidyl peptidase IV inhibitor and another antidiabetic agent, to a mammal in need thereof. Excerpt(s): This invention relates to a method of treatment, in particular to a method for the treatment of diabetes mellitus, especially non-insulin dependent diabetes (NIDDM) or Type 2 diabetes and conditions associated with diabetes mellitus and to compositions for use in such method. Dipeptidyl peptidase IV (DPP-IV) is a postproline/alanine cleaving serine protease found in various tissues of the body including

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kidney, liver, and intestine. It is known that DPP-IV inhibitorsare may be useful for the treatment of impaired glucose tolerance and diabetes mellitus (International Patent Application, Publication Number WO99/61431, Pederson R A et al,.Diabetes. August 1998;47(8):1253-8 and Pauly R P et al, Metabolism March 1999;48(3):385-9). In particular WO99/61431 discloses DPP-IV inhibitors comprising an amino acid and a thiazolidine or pyrrolidine group, and salts thereof, such as isoleucyl (or isoleucine) thiazolidide and salts thereof. 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

Patents 211

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Device for cell implantation Inventor(s): Fujisato, Toshia; (Osaka, JP), Rosenberg, Lawrence; (Montreal, CA) Correspondence: Ogilvy Renault; 1981 Mcgill College Avenue; Suite 1600; Montreal; QC; H3a2y3; CA Patent Application Number: 20030167054 Date filed: February 27, 2003 Abstract: A device for cell implantation has a housing containing a matrix which isolates the cells in the housing; the housing has a window which comprises a membrane which permits passage of nutrients for the cells into the matrix from a location externally of the housing; the housing has an injection port permitting injection of cells into the matrix in the housing. The device may be employed, for example, to facilitate islet implantation in the treatment of diabetes mellitus. Excerpt(s): The invention relates to the development of a device to facilitate cell implantation, for example, islet implantation in treatment for diabetes mellitus. Diabetes mellitus has been classified as type I, or insulin-dependent diabetes mellitus (IDDM) and type II, or non-insulin-dependent diabetes mellitus (NIDDM). NIDDM patients have been subdivided further into (a) nonobese (possibly IDDM in evolution), (b) obese, and (c) maturity onset (in young patients). Among the population with diabetes mellitus, about 20% suffer from IDDM. Diabetes develops either when a diminished insulin output occurs or when a diminished sensitivity to insulin cannot be compensated for by an augmented capacity for insulin secretion. In patients with IDDM, a decrease in insulin secretion is the principal factor in the pathogenesis, whereas in patients with NIDDM, a decrease in insulin sensitivity is the primary factor. The mainstay of diabetes treatment, especially for type I disease, has been the administration of exogenous insulin. Tight glucose control appears to be the key to the prevention of the secondary complications of diabetes. The results of the Diabetes Complications and Control Trial (DCCT), a multicenter randomized trial of 1441 patients with insulin dependent diabetes, indicated that the onset and progression of diabetic retinopathy, nephropathy, and neuropathy could be slowed by intensive insulin therapy (The Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and prgoression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993, 29:977-986). Strict glucose control, however, was associated with a three-fold increase in incidence of severe hypoglycemia, including episodes of seizure and coma. As well, although glycosylated hemoglobin levels decreased in the treatment group, only 5% maintained an average level below 6.05% despite the enormous amount of effort and resources allocated to the support of patients on the intensive regime (The Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and prgoression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993, 29:977-986). The results of the DCCT clearly indicated that intensive control of glucose can significantly reduce (but not completely protect against) the longterm microvascular complications of diabetes mellitus. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Diagnosis and treatment for immunoglobulin E ( IgE) implicated disorders Inventor(s): Lipps, Binie V.; (Bellaire, TX), Lipps, Frederick W.; (Bellaire, TX) Correspondence: John R. Casperson; PO Box 2174; Friendswood; TX; 77549; US Patent Application Number: 20030157555 Date filed: January 14, 2002 Abstract: Human saliva is used as a non-invasive source instead of invasive blood serum plasma for detection and assay of endogenously present proteins; nerve growth factor (NGF), myoglobin, Insulin, adenosine deaminase (ADA), including immunoglobulin E (IgE). It was discovered that people having high levels of IgE, show high levels in comparison to the normal controls of NGF, myoglobin, insulin and ADA, disrupting the homeostasis for these proteins. Oral administration of a synthetic peptide LT-10 disclosed in U.S. Pat. No. 5,576,297 having sequence L K A M D P T P P L reduces IgE level in humans and bring other proteins into homeostasis, for example, NGF, myoglobin, insulin and ADA and possibly other proteins and cytokines. Composition of synthetic LT-10 is advocated as a treatment for IgE implicated disorders such as asthma, depression and various types of autoimmune diseases, such as erythematosus (SLE); Rheumatoid arthritis Sjogren's syndrome; Reiter's syndrome; Diabetes mellitus (insulin-dependent); Graves' disease; Addison's disease; Hodgkin's disease, etc. Excerpt(s): In one aspect, this invention relates to the introduction of use of saliva as a non-invasive source for detection and assay of endogenously present proteins, for example, nerve growth factor (NGF), myoglobin, Insulin, adenosine deaminase (ADA), and most importantly immunoglobulin E (IgE). In another aspect, the invention relates to the treatment of human disorders characterized by elevated IgE levels by the administration of a peptide to reduce the level. A number of disorders and conditions are recognized by elevated levels of IgE. Human immunoglobulins are different types, such as IgG, IgA, IgM, IgD and IgE. IgG, IgA, and IgM are protective immunoglobulins. The role of IgD is not known. IgE is a minor component of total immunoglobulins and it is implicated in allergies, which in some cases manifests asthma. The presence of IgE in human serum was discovered in 1972 by Ishizaka K. and Ishizaka T. Normal adults have 0.2 to 1.0 mg % of IgE. Currently 20% of the US population has higher than the normal range of IgE and the percentage is increasing every year. Allergic diseases are caused by adverse immune response to allergens. Allergen-sensitized patients produce high levels of IgE, which manifest vasodilation, increased vascular permeability, edema, smooth muscle contraction and mucus secretion, resulting allergic reactions. IgE is implicated in asthma because asthma people show high levels of IgE. Allergic reaction causes inflammation and edema accumulating mast cells (MC) at the sites, which remain active for producing IgE under different conditions. Exercise-induced allergies producing IgE is a common phenomenon among athletes. During emotional stress MC are activated to produce IgE stress. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 213

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Enzyme inhibitors Inventor(s): Cascon, Mercedes Alonso; (Madrid, ES), Diaz, Isabel Dorronsoro; (Madrid, ES), Gil, Ana Martinez; (Madrid, ES), Jurado, Francisco Wandosell; (Madrid, ES), Morera, Ana Castro; (Madrid, ES), Munoz, Francisco Jose Moreno; (Madrid, ES), Perez, Maria Concepcion Martin; (Madrid, ES) Correspondence: Y. Rocky Tsao; Fish & Richardson P.C.; 225 Franklin Street; Boston; MA; 02110-2804; US Patent Application Number: 20030195238 Date filed: November 8, 2002 Abstract: Compounds of general formula (I): 1where A, E, G, X, Y and the bond - - - take various meanings are of use in the preparation of a pharmaceutical formulation, for example in the treatment of a disease in which GSK-3 is involved, including Alzheimer's disease or the non-dependent insulin diabetes mellitus, or hyperproliferative disease such as cancer, displasias or metaplasias of tissue, psoriasis, arteriosclerosis or restenosis. Excerpt(s): The present invention relates to enzyme inhibitors, and more particularly to heterocyclic inhibitors of glycogen synthase kinase 3.beta., GSK-3. Alzheimer's disease (AD) is a neurodegenerative process characterised by cognitive disorders associated with a progressive deterioration of the cholinergic function, and neuropathological lesions as senile plaques, formed by the fibrillary.beta.-amyloid, and neurofibrillary tangles, bundles of paired helical filaments. Generally speaking, AD is restricted to groups aged 60 years or more and is the most common cause of dementia in the elderly population. Today, AD affects 23 million people worldwide. As longevity increases, it is estimated that by the year 2050 the number of cases of AD will more than triplicate [Amaduci, L.; Fratiglioni, L. "Epidemiology of AD: Impact on the treatment", in Alzheimer Disease: Therapeutic Strategies, E. Giacobini and R. Becker, Eds., Birhauser, EEUU, 1994, pp. 8]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Fructose 1,6-bisphosphatase inhibitors Inventor(s): Bauer, Paul H.; (US), Schnur, Rodney C.; (US), Wright, Stephen W.; (US) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030144308 Date filed: September 20, 2002 Abstract: The present invention relates to certain quinazoline compounds which have utility in the treatment of diabetes mellitus, hypercholesterolemia, hyperlipidemia, diabetic complications and cancer. The invention also relates to pharmaceutical compositions and kits comprising such quinazoline compounds and to methods of using such compounds in the treatment of diabetes mellitus, hypercholesterolemia, hyperlipidemia, diabetic complications and cancer. Excerpt(s): This application claims priority from U.S. provisional application No. 60/324,751, filed Sep. 24, 2001. Diabetes mellitus is characterized by metabolic defects in production and utilization of carbohydrates, resulting in elevated blood glucose or hyperglycemia due to the failure to maintain appropriate blood sugar levels. Research in

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the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs and dietary and/or exercise therapies. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Heterocyclic compounds Inventor(s): Aoki, Tomiyoshi; (Harmadacho, JP), Kuwabara, Kenji; (Otsu-shi, JP) Correspondence: Greenberg Traurig, Llp; 885 3rd Avenue; New York; NY; 10022; US Patent Application Number: 20030166697 Date filed: November 18, 2002 Abstract: The present invention provides a preventive or therapeutic agent for hyperlipidemia, comprising as an active ingredient a heterocyclic compound of the formula [1], or a pharmaceutically acceptable salt thereof:R.sup.1-Het-D-E [1]wherein:R.sup.1 is optionally substituted aryl or aromatic heterocyclic group, Het is a divalent aromatic heterocyclic group, D is alkylene, alkenylene, alkynylene, or the like, and E is carboxy, or the like, and novel compounds among the heterocyclic compounds of the formula [1] above, which has blood triglyceride lowering effect, LDL-C lowering effect, and blood glucose lowering effect and blood insulin lowering effect, or HDL-C increasing effect or atherogenic index lowering effect all together, and hence is useful in the prevention or treatment of hyperlipidemia, arteriosclerosis, diabetes mellitus, hypertension, obesity, and the like. Excerpt(s): The present invention is related to novel heterocyclic compounds and pharmaceutically acceptable salts thereof. The compounds of the present invention have blood triglyceride lowering effect, low-density lipoprotein cholesterol (hereinafter, referred to as "LDL-C") lowering effect, and also blood glucose lowering effect, blood insulin lowering effect, or high-density lipoprotein cholesterol (hereinafter, referred to as "HDL-C") increasing effect, atherogenic index lowering effect, which index is the ratio of non-HDL-C to HDL-C calculated according to the formula: (total cholesterol--HDLC)/(HDL-C). Accordingly, the compounds of the present invention are useful in the prevention and treatment of coronary artery disease, cerebral infarction, hyperlipidemia, arteriosclerosis or diabetes mellitus. The insulin resistant syndrome complicated by disorder of carbohydrate and/or lipid metabolism and hypertension attracts attention as a multi-risk group of high incidence of ischemic heart disease. The insulin resistant syndrome is found in most of patients suffering from obesity and non insulin-dependent diabetes mellitus (NIDDM). The metabolic disorder of lipids herein recognized is the increase in blood triglycerides mainly due to the increase in chylomicron, very low density lipoproteins, and remnant lipoproteins which are the intermediary metabolites thereof, and the decrease in HDL-C (Diabetes, 37, 15951607(1988); Arch. Intern. Med., 149, 1514-1520(1989); Diabetes Care, 14, 173-194 (1991)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 215

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Insulin secretion promoter Inventor(s): Endo, Tetsuo; (Stanford, CA), Kamiya, Toshikazu; (Tsukuba-shi, JP), Koizumi, Satoshi; (Chiyoda-ku, JP), Takada, Miho; (Tsukuba-shi, JP) Correspondence: Fitzpatrick Cella Harper & Scinto; 30 Rockefeller Plaza; New York; NY; 10112; US Patent Application Number: 20030181401 Date filed: February 3, 2003 Abstract: Provided are a method for promoting insulin secretion, a method for suppressing the elevation of a blood glucose level, a method for ameliorating diabetes mellitus, a method for promoting growth of an animal, and a method for increasing an insulin level in breast milk. These methods comprising administering at least one member selected from the group consisting of a di- or a higher saccharide containing galactose, a derivative thereof, a saccharide containing N-acetylneuraminic acid, and a derivative thereof, to a patient in need thereof or an animal. Excerpt(s): The present invention relates to a method for promoting insulin secretion, a method for suppressing the elevation of a blood glucose level and a method for ameliorating diabetes mellitus, a method for promoting growth of an animal, and a method for increasing an insulin level in breast milk. Additionally, the present invention relates to an agent, food, drink, or feed, or an additive for foods, drinks or feeds, which has an activity to increase insulin secretion, to suppress the elevation of a blood glucose level, to ameliorate diabetes mellitus, or to increase an insulin level in breast milk. Further, the present invention relates to a nutritious composition, a feed, and an additive for a nutritious composition or for feeds, which has an activity to promote growth of an animal. It has been known that diabetes mellitus is a risk factor of brain stroke and cardiac diseases. Additionally, diabetes mellitus also causes complications such as retinopathy, neuropathy, renal disorders and cataract. A survey executed by the Ministry of Health and Welfare, Japan reported in 1998 showed that 6.9 million individuals are strongly suspected of having diabetes mellitus, and that the total number of individuals with the possibility of having diabetes mellitus is estimated to be 13.7 million. The survey of Japan Hospital Association reveals that 12.4% of persons in the hospital for a medical checkup in 1999 had abnormal glucose tolerance. The etiology of diabetes mellitus has not yet been elucidated completely. Diabetes mellitus is broadly classified as Type I diabetes mellitus with impairment of insulin secretion due to the damage of pancreatic beta-cells and Type II diabetes mellitus with reduced tissue sensitivity to insulin. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Islet cell antigen 1851 Inventor(s): Hagopian, William A.; (Seattle, WA), Jelinek, Laura J.; (Seattle, WA), Kindsvogel, Wayne; (Seattle, WA), LaGasse, James M.; (Seattle, WA), Sheppard, Paul O.; (Granite Falls, WA) Correspondence: Phillip B.C. Jones, J.D., PH.D.; Patent Department; Zymogenetics, INC.; 1201 Eastlake Avenue East; Seattle; WA; 98102; US Patent Application Number: 20030166067 Date filed: April 16, 2002

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Abstract: A mammalian islet cell antigen polypeptide involved in the development of insulin-dependent diabetes mellitus (IDDM) is disclosed. This islet cell antigen polypeptide, 1851, was found to contain regions of homology to the protein tyrosine phosphatase family. Methods for diagnosis and treatment, including use in immunoprecipitation assays and the induction of immune tolerance using the recombinant mammalian polypeptides and antibodies specific to mammalian islet cell antigen 1851 polypeptides are presented. Excerpt(s): Insulin-dependent diabetes mellitus (IDDM) is a disease resulting from the autoimmune destruction of the insulin-producing.beta.-cells of the pancreas. Studies directed at identifying the autoantigen(s) responsible for.beta.-cell destruction have generated several candidates, including poorly characterized islet cell antigens (ICA) (Bottazzo et al., Lancet 2: 1279-83, 1974), insulin (Palmer et al., Science 222: 1337-39, 1983), glutamic acid decarboxylase (GAD) (Baekkeskov et al., Nature 298: 167-69, 1982; Baekkeskov et al., Nature 347: 151-56, 1990), and a 64 kD islet cell antigen that is distinct from GAD and that which yields 37 kD and 40 kD fragments upon trypsin-digestion (Christie et al., Diabetes 41: 782-87, 1992). Detection of specific autoantigens in prediabetic individuals has been used as a predictive marker to identify, before clinical onset and significant.beta.-cell loss has occurred, those at greater risk of developing IDDM (Gorsuch et al., Lancet 2: 1363-65, 1981; Baekkeskov et al., J. Clin. Invest. 79: 92634, 1987; Johnstone et al., Diabetologia 32: 382-86, 1989; Ziegler et al., Diabetes 38: 132025, 1989; Baekkeskov et al., Nature (Lond) 347: 151-56, 1990; Bonifacio et al., Lancet 335: 147-49, 1990; and Bingley et al. Diabetes 43: 1304-10, 1994). Antibodies to the 40 kD, and more particularly the 37 kD, ICA fragments are detected when clinical onset of IDDM is imminent and are found to be closely associated with IDDM development (Christie et al., Diabetes 41: 782-87, 1992). Diabetic sera containing antibodies specific to the 40 kD fragment were recently found to bind to the intracellular domain of the protein tyrosine phosphatase, IA-2/ICA512 (Lu et al., Biochem. Biophys. Res. Comm. 204: 930-36, 1994; Lan et al., DNA Cell Biol. 13: 505-14, 1994; Rabin et al., J. Immunol. 152: 3183-88, 1994; Payton et al., J. Clinc. Invest. 96: 1506-11, 1995; and Passini et al., Proc. Natl. Acad. Sci. USA 92: 9412-16, 1995). Antibodies specific to the 37 kD fragment are thought to bind either to a posttranslational in vivo modification of IA-2/ICA512 or a different, but probably related, protein precursor (Passini et al., ibid.). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Isolated nucleic acids and polypeptides associated with glucose homeostasis disorders and method of detecting the same Inventor(s): Chen, Y.T.; (Chapel Hill, NC), McVie-Wylie, Alison J.; (Brookline, MA) Correspondence: Jenkins & Wilson, PA; 3100 Tower Blvd; Suite 1400; Durham; NC; 27707; US Patent Application Number: 20030157075 Date filed: December 23, 2002 Abstract: An isolated and substantially pure nucleic acid sequence located between D20S119 and D20S178 on human chromosome 20q13, the nucleic acid sequence including: a nucleic acid sequence coding for a glucose transporting protein and having the sequence shown in SEQ ID NO: 1; or a nucleic acid sequence having at least 70% sequence identity with the nucleic acid sequence shown in SEQ ID NO: 1. The disclosed nucleic acid sequences map to a locus associated with human Type II diabetes mellitus

Patents 217

and, therefore, therapeutic and diagnostic screening methods, which accommodate naturally and artificially occurring polymorphisms, are also disclosed. Excerpt(s): This application is based on and claims priority to U.S. Provisional Application Serial No. 60/215,477, filed Jun. 29, 2000, herein incorporated by reference in its entirety. The present invention relates generally to nucleic acid sequences coding for sugar transporters useful for screening against glucose homeostasis disorders, and particularly to nucleic acid sequences coding for the glucose transporter which map to the region between D20S119 and D20S178 on human chromosome 20q13. The publications and other materials used herein to illuminate the background of the invention, and in particular cases, to provide additional details respecting the practice, are incorporated herein by reference, and for convenience, are referenced by author and date in the text. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Ligand for peroxisome proliferator-activated receptor Inventor(s): Kishida, Hideyuki; (Kakogawa-shi, JP), Kitahara, Mikio; (Kobe-shi, JP), Kitano, Mitsuaki; (Takasago-shi, JP), Kuroda, Minpei; (Tokyo, JP), Mae, Tatsumasa; (Kakogawa-shi, JP), Mimaki, Yoshihiro; (Tokyo, JP), Nakagawa, Kaku; (Kyoto-shi, JP), Sashida, Yutaka; (Tokyo, JP), Tsukagawa, Misuzu; (Akashi-shi, JP) Correspondence: Kenyon & Kenyon; Suite 700; 1500 K Street, N.W.; Washington; DC; 20005; US Patent Application Number: 20030147979 Date filed: October 23, 2002 Abstract: The object of the present invention is to provide PPAR.gamma. ligand derived from naturally occurring sources and a composition for preventing and/or improving Insulin Resistance Syndrome, diabetes mellitus, obesity or visceral fat obesity comprising the PPAR.gamma. ligand as an active agent.The present invention relates to a ligand for peroxisome proliferator-activated receptorwhich comprises curcumin or its derivatives.The composition according to the present invention, which comprises the PPAR.gamma. ligand as an active agent is useful for preventing and/or improving Insulin Resistance Syndrome, diabetes mellitus, obesity or visceral fat obesity. Excerpt(s): The present invention relates to a ligand for peroxisome proliferatoractivated receptor, and a composition for preventing and/or improving Insulin Resistance Syndrome (e.g., type-II diabetes mellitus, hyperinsulinemia, dyslipidemia, obesity, hypertension and arteriosclerotic cardiovascular disease) comprising the ligand for peroxisome proliferator-activated receptor as an active agent. Peroxisome proliferator-activated receptor (PPAR) is a ligand-dependent transcriptional regulatory factor belonging to the nuclear receptor family, which has been identified as a transcriptional regulatory factor that regulates expression of a group of genes that maintain lipid metabolism. It is known that three subtypes of PPAR, i.e., PPAR.alpha., PPAR.delta. (PPAR.beta., NUC-1, FAAR) and PPAR.gamma., have been identified in mammals. PPAR.alpha. is mainly expressed in the liver while PPAR.delta. is ubiquitously expressed. PPAR.gamma. has two isoforms, PPAR.gamma.1 and PPAR65 2. PPAR.gamma.1 is expressed not only in adipose tissues but also in immune system organs, adrenals and small intestine. PPAR.gamma.2 is specifically expressed in adipose tissues, and is a master regulator which regulates differentiation/maturation of adipocytes (Teruo Kawada, Igaku no Ayumi (Journal of Clinical and Experimental

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Medicine) 184, 519-523, 1998). Examples of known PPAR.gamma. ligands include: arachidonic acid metabolites such as 15-deoxy-.DELTA.12, 14-prostaglandin J2 and.DELTA.12-prostaglandin J2; unsaturated fatty acids such as.omega.-3polyunsaturated fatty acid,.alpha.-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); and eicosanoids such as 9-hydroxy-octadecadienoic acid and 13-hydroxy-octadecadienoic acid (J. Auwerx, Diabetologia, 42, 1033-1049, 1999). It has been also disclosed that PPAR.gamma. ligands include C.sub.10-26 conjugatedunsaturated fatty acids having a conjugated-triene or tetraene structure (Japanese Patent Application 2000-355538). It is also known that examples of synthetic PPAR.gamma. ligands include thiazolidinediones such as troglitazone, pioglitazone and rosiglitazone. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Microorganisms for treatment or prevention of corpulence and diabetes mellitus, and pharmaceutical composition containing the same Inventor(s): Bang, Young Bae; (Choongcheongbuk-Do, KR), Joung, Hea Jung; (Choongcheongbuk-Do, KR), Kim, Bong Cheol; (Choongcheongbuk-Do, KR), Kim, Hang Rae; (Choongcheongbuk-Do, KR), Park, Han Oh; (Choongcheongbuk-Do, KR) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20030180271 Date filed: February 3, 2003 Abstract: The present invention relates to microorganisms for the treatment or the prevention of obesity or diabetes mellitus, which reduce the amount of monosaccharide or disaccharide which may be absorbed into human body by converting monosaccharides such as glucose, fructose, galactose et al. and disaccharides into polymeric materials which cannot be absorbed by the intestine, and relates to a pharmaceutical composition containing the said microorganisms. Excerpt(s): The present invention relates to microorganisms for preventing or treating obesity or diabetes mellitus, which are capable of reducing an amount of monosaccharides or disaccharides that can be absorbed into the intestine by converting those mono or disaccharides into polymeric materials that cannot be absorbed in the intestines. The present invention also relates to use of the microorganisms for preventing or treating obesity or diabetes mellitus and a pharmaceutical composition containing the microorganisms. Obesity is well known as a chronic disease caused by various factors whose origins have not yet been clearly discovered. It is understood that obesity induces hypertension, diabetes mellitus, coronary heart disease, gall bladder disease, osteoarthritis, sleep apnea, respiratory disorder, endomerial, prostate, breast and colon cancer and the like. According to the NIH Report (THE EVIDENCE REPORT: Clinical Guideline on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, 1999, NIH), about 97,000,000 Americans suffer from overweighting and obesesity, and the number of patients of type II diabetes mellitus associated with obesity, reaches about 15,700,000. Moreover, it is reported that about 200,000 people die of diseases associated with obesity each year (Dan Ferber, Science, 283,pp 1424, 1999). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Multiparticulate compositions for once-a-day administration Inventor(s): Bhagwatwar, Harshal Prabhakar; (Aurangabad, IN), Chaudhari, Sunil Sudhakar; (Aurangabad, IN), De Souza, Noel John; (Mumbai, IN), Malhotra, Manjusha; (New Delhi, IN), Saoji, Dilip Gopalkrishna; (Aurangabad, IN), Shukla, Milind C.; (Aurangabad, IN) Correspondence: Kenyon & Kenyon; One Broadway; New York; NY; 10004; US Patent Application Number: 20030219482 Date filed: March 20, 2003 Abstract: A pharmaceutical composition suitable for a once-a-day dosing regimen includes a combination of a biguanide and a sulfonylurea in the form of a multiparticulate, polyphasic system for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and for improving glycemic control. Excerpt(s): The present invention relates to a pharmaceutical composition suitable for a once-a-day dosing regimen comprising a combination of a biguanide and a sulfonylurea in the form of a multiparticulate, polyphasic system for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and for improving glycemic control. Diabetes mellitus of type II is a progressive metabolic disorder with diverse pathologic manifestations and is often associated with lipid metabolism and glycometabolic disorders. The long-term effects of diabetes result from its vascular complications: the microvascular complications of retinopathy, neuropathy and nephropathy and the macrovascular complications of cardiovascular, cerebrovascular and peripheral vascular diseases. Initially, diet and exercise is the mainstay of treatment of type II diabetes. However, these are followed by administration of oral hypoglycemic agents. Current drugs used for managing type II diabetes and its precursor syndromes such as insulin resistance, include classes of compounds such as for example, biguanides and sulfonylureas, among others. Biguanides, represented principally by metformin, phenformin and buformin, help in the control of blood glucose by decreasing hepatic glucose production and reducing intestinal absorption of glucose. Sulfonylureas, represented principally by glipizide, glimiperide, glyburide, glibomuride, glisoxepide, gliclazide acetohexamide, chlorpropamide, tolazamide, and tolbutamide, among others, help in controlling or managing NIDDM by stimulating the release of insulin from the pancreas. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Nitric oxide synthase gene diagnostic polymorphisms Inventor(s): Moskowitz, David W.; (St. Louis, MO) Correspondence: Senniger Powers Leavitt And Roedel; One Metropolitan Square; 16th Floor; ST Louis; MO; 63102; US Patent Application Number: 20030170674 Date filed: October 10, 2002 Abstract: Disclosed is a method for determining a genetic predisposition to hypertension, end stage renal disease due to hypertension, non-insulin dependent diabetes mellitus, end stage renal disease due to non-insulin dependent diabetes mellitus, breast cancer, lung cancer or prostate cancer by detecting the presence or absence of single nucleotide polymorphisms in the nitric oxide synthase gene. Also

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disclosed are kits for detecting the presence or absence of the single nucleotide polymorphisms, methods for the treatment and/or prophylaxis of diseases, conditions, or disorders associated with the single nucleotide polymorphisms. Excerpt(s): This application claims the benefit of U.S. provisional application serial No. 60/177,775, filed Jan. 24, 2000 and U.S. provisional application serial No. 60/220,662 filed Jul. 25, 2000 both of which are herein incorporated by reference in their entirety. This invention relates to detection of an individual's genetic predisposition for a disease, condition or disorder based on the presence or absence of single nucleotide polymorphisms (SNPs). During the course of evolution, spontaneous mutations appear in the genomes of organisms. It has been estimated that variations in genomic DNA sequences are created continuously at a rate of about 100 new single base changes per individual (Kondrashow, J. Theor. Biol., 175:583-594, 1995; Crow, Exp. Clin. Immunogenet., 12:121-128, 1995) These changes in the progenitor nucleotide sequences may confer an evolutionary advantage, in which case the frequency of the mutation will likely increase, an evolutionary disadvantage in which case the frequency of the mutation is likely to decrease, or the mutation will be neutral. In certain cases the mutation may be lethal in which case the mutation is not passed on to the next generation and so is quickly eliminated from the population. In many cases, an equilibrium is established between the progenitor and mutant sequences so that both are present in the population. The presence of both forms of the sequence results in genetic variation or polymorphism. Over time, a significant number of mutations can accumulate within a population such that considerable polymorphism can exist between individuals within the population. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel insulin/igf/relaxin family polypeptides and dnas thereof Inventor(s): Harada, Masataka; (Ibaraki, JP), Itoh, Yasuaki; (Ibaraki, JP), Kizawa, Hideki; (Ibaraki, JP), Nishi, Kazunori; (London, GB), Ogi, Kazuhiro; (Ibaraki, JP), Suzuki, Nobuhiro; (Osaka, JP) Correspondence: Takeda Pharmaceuticals North America, Inc; Intellectual Property Department; 475 Half Day Road; Suite 500; Lincolnshire; IL; 60069; US Patent Application Number: 20030158381 Date filed: October 17, 2002 Abstract: The present invention relates to (1) a polypeptide containing the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:7 (A chain), (2) a polypeptide containing the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:8 (B chain), (3) a polypeptide wherein the A and B chains are bonded to each other via disulfide bonds (2 chains) or its salt, (4) DNAs encoding the same, etc.These polypeptides and DNAs encoding the same can be used for the diagnosis, treatment, prevention, etc. for diseases, including abnormalities (e.g., diabetes mellitus, etc.) in metabolic regulation (sugar metabolism, lipid metabolism, etc.) of energy sources such as carbohydrates. Excerpt(s): The present invention relates to a novel secretory biological function regulatory protein and its DNA, etc., and more particularly, to a novel protein of the insulin/IGF/relaxin family and its DNA, etc. Organisms are engaged in signal transduction mutually between cells or tissues, thus maintaining well-balanced regulation of development, differentiation, proliferation, maintenance of homeostasis,

Patents 221

etc. In many cases, proteinous factors mediate them. For example, many secretory factors (humoral factors) that participate in the immune system or the erythropoietic system were found and these factors are called cytokines. Lymphokines, monokines, interferons, colony-stimulating factors, tumor necrosis factors, etc. are included in cytokines. These cytokines have been actively studied on their involvement in diseases or applications to pharmaceuticals. Humoral factors produced in endocrine tissues such as peptide hormones, growth factors, etc. also play some crucial roles for sustained homeostasis or growth and their application to medicaments have been extensively studied. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel LDL-receptor Inventor(s): Caskey, Charles T.; (Houston, TX), Cox, Roger D.; (Oxon, GB), Gerhold, David; (Lansdale, PA), Hammond, Holly; (Telford, PA), Hess, John W.; (Lansdale, PA), Hey, Patricia; (Lansdale, PA), Kawaguchi, Yoshihiko; (Osaka, JP), Merriman, Tony R.; (Dunedin, NZ), Metzker, Michael L.; (Ft. Washington, PA), Nakagawa, Yusuke; (Osaka, JP), Phillips, Michael S.; (Lansdale, PA), Todd, John A.; (Cambridge, GB), Twells, Rebecca C.J.; (Cambridge, GB) Correspondence: Nixon & Vanderhye, PC; 1100 N Glebe Road; 8th Floor; Arlington; VA; 22201-4714; US Patent Application Number: 20030181660 Date filed: December 31, 2002 Abstract: A novel receptor, "LDL-receptor-related protein-3" ("LRP-3"), is provided, along with encoding nucleic acid. The gene is associated with type 1 diabetes (insulin dependent diabetes mellitus), and experimental evidence provides indication that it is the IDDM susceptibility gene IDDM4. In various aspects the invention provides nucleic acid, including coding sequences, oligonucleotide primers and probes, polypeptides, pharmaceutical compositions, methods of diagnosis or prognosis, and other methods relating to and based on the gene, including methods of treatment of diseases in which the gene may be implicated, including autoimmune diseases, such as glomerulonephritis, diseases and disorders involving disruption of endocytosis and/or antigen presentation, diseases and disorders involving cytokine clearance and/or inflammation, viral infection, elevation of free fatty acids or hypercholesterolemia, osteoporosis, Alzheimer's disease, and diabetes. Excerpt(s): The present invention relates to nucleic acids, polypeptides, oligonucleotide probes and primers, methods of diagnosis or prognosis, and other methods relating to and based on the identification of a gene, which is characterised as a member of the LDL-receptor family and for which there are indications that some alleles are associated with susceptibility to insulin-dependent diabetes mellitus ("IDDM"), also known as type 1 diabetes. More particularly, the present invention is based on cloning and characterisation of a gene which the present inventors have termed "LDL-receptor related protein-5 (LRP5)" (previously "LRP-3"), based on characteristics of the encoded polypeptide which are revealed herein for the first time and which identify it as a member of the LDL receptor family. Furthermore, experimental evidence is included herein which provides indication that LRP5 is the IDDM susceptibility gene IDDM4. Diabetes, the dysregulation of glucose homeostasis, affects about 6% of the general population. The most serious form, type 1 diabetes, which affects up to 0.4% of European-derived population, is caused by autoimmune destruction of the insulin

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producing.beta.-cells of the pancreas, with a peak age of onset of 12 years. The.beta.-cell destruction is irreversible, and despite insulin replacement by injection patients suffer early mortality, kidney failure and blindness (Bach, 1994; Tisch and McDevitt, 1996). The major aim, therefore, of genetic research is to identify the genes predisposing to type 1 diabetes and to use this information to understand disease mechanisms and to predict and prevent the total destruction of.beta.-cells and the disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel polypeptide of protein p140 and DNAs encoding it Inventor(s): Kitagawa, Koichiro; (Osaka, JP), Ohno, Hiroyuki; (Osaka, JP), Tajima, Hisao; (Osaka, JP) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, NW; Washington; DC; 20037-3213; US Patent Application Number: 20030170865 Date filed: July 3, 2002 Abstract: The present invention is related to a novel protein p140 polypeptide which is a key protein involved in the signal transmission system of insulin; method for preparation of it; DNA encoding the said polypeptide; vector derived the said DNA; host cells transformed the said vector; antibody of the said polypeptide; pharmaceutical composition containing the said peptide or antibody; method for the prevention and/or treatment of diabetes, which is characterized by tyrosine phosphorylation of the said protein p140; agent for the prevention and/or treatment for the currently said the prevention and/or treatment method; agent for the prevention and/or treatment of diabetes, which is characterized by containing a compound which can tyrosine phosphorylation of protein p140, as active ingredient and the screening methods of the said prevention and/or treatment agent.Tyrosine phosphorylation of protein p140 is an essential step in the induction of hypoglycemia by glucose uptake. Method and agent of prevention and/or treatment based on tyrosine phosphorylation of protein p140 in the present invention is not only improve the diabetes-derived hyperglycemic conditions but are also useful for the treatment and/or prevention of diabetes, especially noninsulin dependent diabetes mellitus (NIDDM). Excerpt(s): Diabetes, an abnormal metabolic disease, is induced by a defect in the mechanism of glucose metabolism. Under normal conditions, glucose metabolism occurs as follows: Carbohydrates, consumed in the form of food, are digested to glucose in the intestines prior to absorption into the circulatory system. Pancreatic.beta. cells respond to an increase in the blood glucose level by secreting insulin, which in turn stimulates the target peripheral tissues (muscles and liver) to decrease the blood glucose level by enhancing tissue absorption of the blood glucose followed by conversion to glycogen for storage. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 223

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Novel transcription factor regulating TNF-alpha Inventor(s): Amar, Salomon; (Brookline, MA) Correspondence: Kevin M. Farrell; Pierce Atwood; Suite 350; One New Hampshire Avenue; Portsmouth; NH; 03801; US Patent Application Number: 20030166159 Date filed: April 2, 2003 Abstract: Disclosed herein is an isolated polypeptide which binds to the DNA binding domain located from -550 to -487 in the promoter of the human TNF-.alpha. gene. This isolated polypeptide is referred to herein as the LITAF protein. Polypeptides of human origin are specifically provided. Also disclosed is a nucleic acid sequence which encodes the LITAF protein. Such nucleic acids may be incorporated into an expression vector, which may be inserted into a cell. LITAF dependent induction of TNF-.alpha. gene expression in a cell can be inhibited by delivering an inhibitor of expression of the LITAF gene to the cell. Such an inhibitor is for example an antisense construct which encodes an antisense RNA molecule which is complementary to a portion of the LITAF mRNA which is greater than 200 nucleotides in length. Preferably, the antisense RNA molecule is complementary to the start site of translation, upstream adjacent 5' untranslated sequence, and downstream adjacent coding sequence of the LITAF mRNA. Optimal lengths and specific nucleotides for complementary are discussed. Inhibition of LITAF dependent induction of TNF-.alpha. gene expression in a cell can also be achieved by contacting an inhibitor of LITAF protein function to the LITAF protein within a cell. Such an inhibitor may be an antibody which binds the LITAF protein, or alternatively a small molecule which inhibits the function of the LITAF protein. One example of such an inhibitor is a recombinant mutant LITAF protein. Administration of a LITAF inhibitor can be performed as a therapeutic method for treating a patient with a disease associated with chronic inflammation. Such diseases include rheumatoid arthritis, gum disease Crohn's disease, and graft-versus-host disease. Therapeutic methods for treating a patient with a disease in which TNF-.alpha. plays a role in pathology are also provided. Examples of such diseases are diabetes mellitus, cancer, cachexia, breast cancer, HIV, sepsis, malaria, trypanomiasis and asthma. Other methods provided include a method for identifying genes which are regulated by the LITAF protein, a method for identifying a molecule which inhibits LITAF binding to the TNF.alpha. promoter, and a method for identifying molecules which bind LITAF from a protein array. Excerpt(s): The innate host response to bacterial pathogens is characterized by an immediate release of biologically active compounds, including monokines and cytokines. These proinflammatory molecules, which are intended to enable the host to eliminate the pathogen, may also adversely affect the host. In acute situations, the pathogen is often eliminated, with resolution of inflammation and minimal tissue damage. However, failure to control the pathogen often leads to a state of metabolic anarchy in which the inflammatory response is not controlled and significant tissue damage results. Endotoxins, produced from the outer membrane of Gram-negative bacteria, and exotoxins, released from the cell wall of Gram-positive bacteria, are known to be potent inducers of the inflammatory response. Lipopolysaccharide (LPS), extracted from the outer membrane of Gram-negative bacteria, has been identified as a principal endotoxic component. Although the inflammatory response is mediated by a variety of secreted factors, the cytotoxic effects of LPS have been ascribed to TNF-.alpha. activity (Beutler et al., Science 229: 869-871 (1985); Tracey et al., Science 234: 470-474 (1986); Miethke et al., J. Exp. Med. 175: 91-98 (1992)). TNF-.alpha. is a pleiotropic cytokine

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which serves to either benefit the host or in some situations exert detrimental effects on the host (Beutler and Cerami, Nature 320: 584-588 (1986); Beutler et al., Science 232: 977980 (1986); Beutler and Cerami, N. Engl. J. Med. 316: 379-385 (1987)). TNF-.alpha. benefits the host by helping to prevent cancer, protecting against infection, promoting tissue remodeling, and activating inflammatory responses. Conversely, in host responses which have gone awry, TNF-.alpha. mediates septic shock in chronic infections, is responsible for cachexia in cancer patients, causes inflammation in rheumatoid arthritis patients, and activates the human immunodeficiency virus. The pleiotropic effects of TNF-.alpha. are dose-dependent. Hence, the perceived need to control TNF-.alpha. production has raised interest into the understanding of the mechanisms that modulate TNF-.alpha. gene expression. It is well known that gene transcription is controlled by DNA-binding proteins. Recently, several groups have examined the transcriptional regulation of TNF-.alpha. by various inducers, such as virus, LPS, and PMA. The human TNF-.alpha. promoter contains motifs that resemble nuclear factor kappa B (NF-.kappa.B) binding sites; however, controversy exists as to the involvement of NF-.kappa.B in TNF-.alpha. gene regulation. The nature of the nuclear factor(s) involved in the regulation of LPS-induced TNF-.alpha. gene expression in humans remains unknown. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Oxyiminoalkanoic acid derivatives Inventor(s): Imoto, Hiroshi; (Shiga, JP), Kimura, Hiroyuki; (Osaka, JP), Momose, Yu; (Hyogo, JP), Odaka, Hiroyuki; (Hyogo, JP), Sakamoto, Junichi; (Osaka, JP) Correspondence: Takeda Pharmaceuticals North America, Inc; Intellectual Property Department; 475 Half Day Road; Suite 500; Lincolnshire; IL; 60069; US Patent Application Number: 20030186985 Date filed: December 27, 2002 Abstract: To provide a novel oxyiminoalkanoic acid derivative which has excellent hypoglycemic and hypolipidemic actions and which is used for the prevention or treatment of diabetes mellitus, hyperlipemia, insulin insensitivity, insulin resistance and impaired glucose tolerance.A compound represented by the formula: 1wherein R.sup.1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, --CO--, --CH(OH)-- or a group represented by -NR.sup.6-- wherein R.sup.6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, --SO--, --SO.sub.2-- or a group represented by --NR.sup.7-- wherein R.sup.7 is a hydrogen atom or an optionally alkyl group; ring A is a benzene ring optionally having additional one to three substituents; p is an integer of 1 to 8; R.sup.2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R.sup.3 is a hydroxy group, OR.sup.8 (R.sup.8 is an optionally substituted hydrocarbon group.) or NR.sup.9R.sup.10 (R.sup.9 and R.sup.10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group or R.sup.9 and R.sup.10 combine together to form a ring); R.sup.4 and R.sup.5 are the same or different groups which are selected from a hydrogen atom or an optionally substituted hydrocarbon group wherein R.sup.4 may form a ring with R.sup.2; provided that when R.sup.1 is a ethoxymethyl, a C.sub.1-3 alkyl, phenyl or p-methoxyphenyl and q=m=0, R.sup.3 is NR.sup.9R.sup.10; and

Patents 225

provided that O-[2-chloro-4-(2-quinolylmethoxy)phenylmethyl]oxime and a methylpyruvate of [2-chloro-4-(2-quinolylmethoxy)phenylmethyl]-2-iminox- ypropionic acid are excluded; or a salt thereof. Excerpt(s): The present invention relates to novel oxyiminoalkanoic acid derivatives having hypoglycemic effect and hypolipidemic effect, a novel pharmaceutical composition and retinoid-related receptor function adjuster comprising an oxyiminoalkanoic acid. Such novel oxyiminoalkanoic acid derivatives, pharmaceutical compositions and retinoid-related receptor function adjusters are useful as an agent for prevention and/or treatment of diabetes mellitus, hyperlipemia, impaired glucose tolerance, an inflammatory disease, an arteriosclerosis and the like. Examples of known oxyiminoalkanoic acid derivatives are the intermediates used in the production of.beta.lactam compounds (Japanese Patent Application KOKAI No.49382/1983, 167576/1984, 77391/1987, 192387/1987, 47186/1991) and a compound having a leukotriene biosynthesis inhibiting effect (e.g., WO96/02507). However, these compounds have not been reported to have hypoglycemic, hypolipidemic effects and retinoid-related receptor function adjuster activity yet. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Peptides derived from the superantigen (SAg) ENV protein of HERV-K18 and their use in obtaining SAG-inhibitory antibodies and in vaccination against SAG Inventor(s): Dupuis, Marc; (Geneva, CH) Correspondence: Mintz, Levin, Cohn, Ferris, Glovsky; And Popeo, P.C.; One Financial Center; Boston; MA; 02111; US Patent Application Number: 20030162263 Date filed: September 6, 2002 Abstract: The present invention relates to peptides derived from the superantigen (SAg) ENV protein of the human endogenous retrovirus HERV-K18, and to the use of the peptides in obtaining antibodies which inhibit the superantigen activity of HERV-K18 ENV. The invention also relates to vaccine compositions for treating and preventing disorders associated with the ENV gene product of HERV-K18, for example autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM). A preferred peptide consists of a portion of an N- or C-terminal segment of the HERV-K18.1 ENV protein, as illustrated in FIG. 1A, said N-terminal segment extending from amino acids 22 to 62 of HERV-K18.1 ENV, and said C-terminal segment extending from amino acids 110 to 153 of HERV-K18.1 ENV, wherein the peptide has a length of 6 to 40 amino acids and is capable of giving rise to antibodies which inhibit superantigen activity associated with HERV-K18 envelope proteins. Excerpt(s): This application claims the benefit of priority under 35 U.S.C. 119(e) to copending U.S. Provisional Application No. 60/317,703, filed on Sep. 6, 2001, and No. 60/317,704, filed on Sep. 6, 2001; the entire contents of which are incorporated herein by reference. This application is also related to U.S. application Ser. No. 09/490,700, filed Jan. 24, 2000, the entire contents of which are incorporated herein by reference. The human endogenous retrovirus HERV-K18 is a member of the HERV-K family. Its defective provirus has been found to be integrated in a reverse orientation in Intron I of the CD48 gene. A number of allelic variants of HERV-K18 have been identified, including the previously named IDDMK.sub.1.222 (Conrad 1997; International patent application WO 99/05527). The expression product of the env gene of HERV-K18 has

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been shown to have superantigen (SAg) activity. This SAg activity has been linked to a number of pathological states, including autoimmune diseases such as InsulinDependent Diabetes Mellitus (IDDM). Indeed, previous experiments have identified the HERV-K18 env gene as a candidate associated with aberrant activation of a subset of T cells found in the pancreas of individuals that succumbed to acute insulinitis [Conrad, 1997; Conrad 1994]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Peptidyl ketones as inhibitors of DPIV Inventor(s): Demuth, Hans-Ulrich; (Halle/Saale, DE), Heiser, Ulrich; (Halle/Saale, DE), Hoffmann, Torsten; (Halle/Saale, DE), Niestroj, Andre; (Halle/Saale, DE) Correspondence: Brown, Rudnick, Berlack & Israels, LLP.; Box Ip, 18th Floor; One Financial Center; Boston; MA; 02111; US Patent Application Number: 20030148961 Date filed: August 9, 2002 Abstract: The present invention relates to compounds of the general formula 1 1and pharmaceutically acceptable salts thereof, to the use of the compounds for the treatment of impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy and of sequelae caused by diabetes mellitus in mammals. Excerpt(s): This application claims the benefit of priority to U.S. Provisional Patent Application No. 06/340,151 filed Dec. 14, 2001 and to German Patent Application DE 101 50 203 filed Dec. 10, 2001. The present invention relates to peptidyl ketones and salts thereof, hereinafter referred to as peptidyl ketones, and to the use of the compounds for the preparation of a medicament for the in vivo inhibition of DPIV or/and DPIV-like enzymes. The invention relates especially to the use of the compounds for the preparation of a medicament for the treatment of impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy and of sequelae caused by diabetes mellitus in mammals, for the treatment of metabolism-related hypertension and of cardiovascular sequelae caused by hypertension in mammals, for the prophylaxis or treatment of skin diseases and diseases of the mucosae, autoimmune diseases and inflammatory conditions, and for the treatment of psychosomatic, neuropsychiatric and depressive illnesses, such as anxiety, depression, sleep disorders, chronic fatigue, schizophrenia, epilepsy, nutritional disorders, spasm and chronic pain. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Photodynamic diagnosis and therapy for insulin-dependent diabetes mellitus Inventor(s): Aizawa, Katsuo; (Tokyo, JP), Imai, Satoshi; (Kawasaki-shi, JP), Kanazawa, Masao; (Tokyo, JP), Saito, Keiji; (Kawasaki-shi, JP) Correspondence: Varndell & Varndell, Pllc; 106-a S. Columbus ST.; Alexandria; VA; 22314; US Patent Application Number: 20030157026 Date filed: March 25, 2003

Patents 227

Abstract: This invention relates to a method for diagnosing insulin-dependent diabetes mellitus, which comprises administering to a mammal such a photosensitizer or an Xray absorbing substance that has a property capable of accumulating specifically in the macrophages having infiltrated the inflammatory sites of Langerhans islets in the pancreas and also has a property capable of being activated upon absorption of a light ray or an X-ray of a specific wavelength, then irradiating the pancreas with the light ray or X-ray of the specific wavelength, and detecting or judging whether the fluorescence of the photo-excited photosensitizer or the X-ray absorption image occurs in the inflammatory sites of Langerhans islets or not.This invention also relates to a method for treating therapeutically insulin-dependent diabetes mellitus, which comprises administering to a mammal with the diabetes mellitus such a photosensitizer or an Xray absorbing substance that has a property capable of accumulating specifically in the macrophages having infiltrated the inflammatory sites of Langerhans islets in the pancreas and also has a property capable of being activated upon absorption of a light ray or an X-ray of a specific wavelength so as to damage or destroy the macrophages, and then irradiating the inflammatory sites of Langerhans islets with the light ray or Xray of the specific wavelength at an intensity and for a time sufficient to damage or destroy the macrophages having infiltrated the Langerhans islets. Excerpt(s): This application is a continuation-in-part application of International PCT application No. PCT/JP02/06510, filed on Jun. 27, 2002; and is the non-provisional application of prior provisional application Serial No. 60/367,487, filed on Mar. 27, 2002. This invention relates to a photodynamic diagnostic method and a photodynamic therapeutic method for insulin-dependent diabetes mellitus (IDDM). Diabetes mellitus is a disease of which major characteristic is a chronic hyperglycemia attributable to a deficiency of the action of insulin in the body of a patient and which is accompanied by a variety of characteristic metabolic disorders. Diabetes mellitus is classified into insulin-dependent diabetes mellitus and insulin-independent diabetes mellitus. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Preparations and methods for the treatment of T cell mediated diseases Inventor(s): Cohen, Irun R.; (Rehovot, IL), Elias, Dana; (Gedera, IL), Shinitzky, Meir; (Kfar Shmaryahu, IL) Correspondence: Winston & Strawn; Patent Department; 1400 L Street, N.W.; Washington; DC; 20005-3502; US Patent Application Number: 20030190323 Date filed: December 2, 2002 Abstract: The present invention provides pharmaceutical compositions and methods for reducing the incidence or severity of insulin dependent diabetes mellitus, insulitis,.beta.-cell destruction, or latent autoimmune diabetes in adults by administering to a patient a pharmaceutical composition comprising an antigen and a carrier, wherein the antigen is recognized by inflammatory T cells associated with the pathogenesis of the disease and the carrier is a metabolizable lipid emulsion. The composition induces a TH1.fwdarw.TH2 shift in the cytokines produced by said T cells and it is administered in an amount, which is therapeutically effective to reduce the symptoms of the disease. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 08/981,861, filed Apr. 19, 1998, which is a 371 national stage application of

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PCT/US96/11373, filed Jul. 2, 1996. The present invention relates to compositions and methods of reducing the severity of insulin-dependent diabetes mellitus or insulitis. The invention further relates to compositions and methods of reducing or inhibiting.beta.-cell destruction. The invention further relates to compositions and methods of reducing the severity of latent diabetes. More generally, the invention relates to vaccine therapy for T-cell mediated diseases, and in particular to therapeutic preparations comprising peptides recognized by T cells involved in the pathogenesis of T cell mediated diseases, such as autoimmune diseases, and a metabolizable lipid emulsion as a biologically active carrier. Autoimmune disorders, e.g., insulin-dependent diabetes mellitus (IDDM or type I diabetes), multiple sclerosis, rheumatoid arthritis and thyroiditis, are characterized by reactivity of the immune system to an endogenous antigen, with consequent injury to tissues. These immune responses to self-antigens are maintained by the persistent activation of self-reactive T lymphocytes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Process and product extracted from herbal composition useful in controlling diabetes mellitus type II Inventor(s): Leko, Vladimir; (Pozega, HR) Correspondence: ST. Onge Steward Johnston & Reens, Llc; 986 Bedford Street; Stamford; CT; 06905-5619; US Patent Application Number: 20030206976 Date filed: April 30, 2003 Abstract: An active substance is extracted from an herbal composition which comprises: Centaurii umbellatum, Gentianaceae (centaury plant), Teraxacum officinale, Asteraceae (dandelion root), Juniperi communis L, Cupresaceae (juniper berry), Urticae dioica L, Urticeae (nettle plant), Urticae dioica L, Urticaceae (nettle root), Cichorium intybus L, Cichoriaceae (chicory root), Morus nigra L, Moraceae, (mulberry leaf), Achilleae millefolium L, Asteraceae (yarrow flower), Vaccinium myrtillus L, Ericaceae (bilberry leaf), Phaseolus vulgaris L, Fabaceae (bean pods), Valeriana officinalis L, Valerlanaceae (Valerian root). The active substance is used in the manufacture of pharmaceutical compositions used in connection with control of diabetes mellitus type II. Excerpt(s): This application is a continuation in part of Applicant's U.S. patent application Ser. No. 09/952,055 filed Sep. 11, 2001 and entitled <>., which is a continuation of International Patent Application No. PCT/HR/00008 filed Apr. 22, 1999, with a foreign priority claim to Croatia Application No. P990080A filed Mar. 12, 1999. The present invention relates to processes for preparation of products using active ingredients extracted from herbal compositions. A technical problem, the solution of which is disclosed in this patent application, consists in finding a treatment for diabetes mellitus type II which will have the following characteristics: (1) that it is suitable for peroral application; (2) that even very high values of glucose concentration in blood can be reduced to or near its normal value; (3) no evident harmful side effects occur even in case of large daily doses, and even in case of a long-time use; and (4) that its effectivess is not caused by a strict diet. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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p-thienylbenzylamides as agonists of angiotensin-(1-7) receptors, and methods of their preparation and use Inventor(s): Heitsch, Holger; (Mainz-Kastel, DE) Correspondence: Finnegan, Henderson, Farabow, Garrett &; Dunner Llp; 1300 I Street, NW; Washington; DC; 20006; US Patent Application Number: 20030144343 Date filed: December 5, 2002 Abstract: The invention relates to p-thienylbenzylamides of formula (I) 1in whichR(1), R(2), R(3), R(4), R(5), R(6) and X have the meanings given in the description. The compounds of formula (I) are potent agonists of angiotensin-(1-7) receptors and are useful as pharmaceutically active compounds to treat and/or prevent hypertension; cardiac hypertrophy; cardiac insufficiency; coronary heart diseases, such as angina pectoris; and endothelial dysfunction or endothelial damage as a consequence, for example, of atherosclerotic processes or in association with diabetes mellitus. Excerpt(s): in which R(1), R(2), R(3), R(4), R(5), R(6) and X have the meanings given below. The compounds of formula (I) are potent agonists of angiotensin-(1-7) receptors. As a result of the stimulation of these receptors, which is elicited by the compounds of formula (I), and the production and release of the vasorelaxing and cardioprotective messengers cyclic guanosine monophosphate (cGMP) and nitrogen monoxide (NO) associated with endothelial cells, the compounds of formula (I) are suitable as pharmaceutically active compounds for treating and preventing hypertension; cardiac hypertrophy; cardiac insufficiency; coronary heart diseases, such as angina pectoris; and endothelial dysfunction or endothelial damage, for example, as a consequence of atherosclerotic processes or in association with diabetes mellitus. PCT application WO0068226 describes 1-(p-thienylbenzyl)imidazoles as agonists of angiotensin-(1-7) receptors for the treatment and/or prophylaxis of hypertension, cardiac hypertrophy, cardiac insufficiency and endothelial dysfunction or endothelial damage. In view of the multifarious possibilities for using angiotensin (ANG)-(1-7) receptor agonists as pharmaceuticals, and the demands for such properties, there is a need for further ANG(1-7) receptor agonists which exhibit favorable activity and selectivity (i.e., a good pharmacodynamic or pharmacokinetic profile). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Pyrido [2,1-a] isoquinoline derivatives Inventor(s): Gobbi, Luca Claudio; (Oberwil, CH), Luebbers, Thomas; (Loerrach, DE), Mattei, Patrizio; (Riehen, CH), Narquizian, Robert; (Bartenheim, FR), Wyss, Pierre Charles; (Therwil, CH) Correspondence: Hoffmann-la Roche INC.; Patent Law Department; 340 Kingsland Street; Nutley; NJ; 07110 Patent Application Number: 20030149071 Date filed: December 17, 2002 Abstract: The present invention provides compounds of formula (I) 1wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined in the specification, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment

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and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, particularly non-insulin dependent diabetes mellitus, and impaired glucose tolerance. Excerpt(s): The enzyme dipeptidyl peptidase IV (EC.3.4.14.5, abbreviated in the following as DPP-IV) is involved in the regulation of the activities of several hormones. In particular DPP-IV is degrading efficiently and rapidly glucagon like peptide 1 (GLP1), which is one of the most potent stimulator of insulin production and secretion. Inhibiting DPP-IV would potentiate the effect of endogenous GLP-1, and lead to higher plasma insulin concentrations. In patients suffering from impaired glucose tolerance and type 2 diabetes mellitus, higher plasma insulin concentration would moderate the dangerous hyperglycaemia and accordingly reduce the risk of tissue damage. Consequently, DPP-IV inhibitors have been suggested as drug candidates for the treatment of impaired glucose tolerance and type 2 diabetes mellitus (e.g. Vilhauer, WO98/19998). Without disclosing any medical use, Buzas et al., Lab. Chim. Org. V, Fac. Sci., Orleans, Fr. Chim. Ther. (1992), 7(5), 404-7 describe synthesis of the compounds of Examples 41 and 42 below. The compounds of the present invention are useful for the treatment and/or prophylaxis of diabetes or non-insulin dependent diabetes. with the exception of rac-3.beta.-Isobutyl-9,10-dimethoxy-1,3,4,6,7- ,11b.beta.-hexahydro-2Hpyrido[2,1-a]isoquinolin-2.beta.-ylamine dihydrochloride and rac-3.beta.-Isobutyl-9,10dimethoxy-1,3,4,6,7,11b.bet- a.-hexahydro-2H-pyrido[2,1-a]isoquinolin-2.alpha.-ylamine dihydrochloride. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Renin-angiotensin system in diabetes mellitus Inventor(s): Agerholm-Larsen, Birgit; (Birkerod, DK), Pedersen-Bjergaard, Ulrik; (Hillerod, DK), Pramming, Stig; (Copenhagen K, DK), Thorsteinsson, Birger; (Hellerup, DK) Correspondence: Jacobson Holman Pllc; 400 Seventh Street N.W.; Suite 600; Washington; DC; 20004; US Patent Application Number: 20030158090 Date filed: October 4, 2002 Abstract: The present invention provides novel methods of treatment of diabetes mellitus as well as methods of diagnosing the susceptibility of hypoglycaemia in an individual. The method of treatment includes administering to an individual a sufficient amount of at least one inhibitor of the renin-angiotensin II system and at least one antidiabetic, for example insulin. Another objective of the present invention is to provide methods of preventing hypoglycaemia in an individual in need thereof comprising administering to said individual a pharmaceutical effective amount of an inhibitor of the renin-angiotensin II system. In particular, such an individual may be an individual suffering from diabetes mellitus. A further objective of the present invention is to provide methods to diagnose the susceptibility to hypoglycaemia of an individual comprising detecting within a predetermined tissue sample the genotype of the angiotensin-converting enzyme (ACE) gene; or detecting within a predetermined tissue sample the activity of ACE; and correlating said genotype or activity to the susceptibility of hypoglycaemia. Excerpt(s): This application is a non-provisional of U.S. provisional application Serial No. 60/306,859 filed on Jul. 23, 2001, which is hereby incorporated by reference in its entirety. All patent and non-patent references cited in the application, or in the present

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application, are also hereby incorporated by reference in their entirety. The present invention provides novel pharmaceutical compositions for the treatment of diabetes mellitus. Furthermore, the invention provides novel methods of treatment of diabetes mellitus as well as methods of diagnosing the susceptibility of hypoglycaemia in an individual. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Substituted phenyl compounds for the treatment of non-insulin dependent diabetes mellitus Inventor(s): Caufield, Craig E.; (New York, NY), Greenfield, Alexander A.; (Princeton Junction, NJ), Morris, Koi M.; (Plainsboro, NJ), Morrison, Eamonn P.; (Yardley, PA), Sabatucci, Joseph P.; (Collegeville, PA) Correspondence: Wyeth; Patent Law Group; Five Giralda Farms; Madison; NJ; 07940; US Patent Application Number: 20030203941 Date filed: April 8, 2003 Abstract: This invention provides compounds of formula I, having the structure 1wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, A, and B are as defined in the specification, or a pharmaceutically acceptable salt thereof, that are useful in treating metabolic disorders mediated by insulin resistance or hyperglycemia. Excerpt(s): This application claims the benefit under 35 U.S.C.sctn.119(e) to U.S. provisional application Serial No. 60/371,540 filed Apr. 10, 2002, which is hereby incorporated by reference in its entirety. This invention relates to novel compounds of general formula I or pharmaceutically acceptable salts thereof, which lower plasma glucose levels and/or insulin levels in vivo and/or inhibit the production of PEPCK enzyme and/or lower glucose and/or insulin levels in cultured cells and are therefore useful in the treatment of non-insulin dependent diabetes mellitus (NIDDM). Diabetes mellitus is a syndrome characterized by abnormal insulin production, increased urinary output and elevated blood glucose levels. There are two major subclasses of diabetes mellitus. One is the insulin-dependent diabetes mellitus (IDDM or Type 1), formerly referred to as juvenile onset diabetes since it was evident early in life, and non-insulin dependent diabetes mellitus (NIDDM or Type 2), often referred to as maturity-onset diabetes. Exogenous insulin by injection is used clinically to control diabetes but suffers from several drawbacks. Insulin is a protein and thus cannot be taken orally due to digestion and degradation but must be injected. It is not always possible to attain good control of blood sugar levels by insulin administration. Insulin resistance sometimes occurs requiring much higher doses of insulin than normal. Another shortcoming of insulin is that while it may control hormonal abnormalities, it does not always prevent the occurrence of complications such as neuropathy, retinopathy, glomerulosclerosis, or cardiovascular disorders. Insulin regulates glucose homeostasis mainly by acting on two targets tissues: liver and muscle. Liver is the only site of glucose production and skeletal muscle the main site of insulin mediated glucose uptake. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Synergistic effect of a sulfonylurea and/or non-sulfonylurea Kchannel blocker, and a phosphodiesterase 3 type inhibitor Inventor(s): Fryburg, David A.; (East Lyme, CT), Parker, Janice C.; (Ledyard, CT) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030216294 Date filed: June 5, 2003 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): This application is filed claiming priority to U.S. Ser. No. 09/829,874, filed Apr. 10, 2001, now allowed, which claims priority to U.S. Provisional Application Serial No. 60/196,728, filed Apr. 13, 2000. 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,

Patents 233

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

Therapeutic uses of PAF-AH products in diabetes Inventor(s): Dietsch, Gregory N.; (Snohomish, WA), Peterman, Gary M.; (Seattle, WA), Yu, Albert S.; (Bothell, WA) Correspondence: Marshall, Gerstein & Borun Llp; 6300 Sears Tower; 233 S. Wacker Drive; Chicago; IL; 60606; US Patent Application Number: 20030215439 Date filed: February 24, 2003 Abstract: The present invention relates to uses of PAF-AH products to prevent or slow the progression of diabetes, particularly insulin dependent diabetes mellitus. Excerpt(s): The present invention relates generally to novel therapeutic methods for preventing the progression of diabetes mellitus by administration of platelet activating factor acetylhydrolase (PAF-AH) products. Insulin-dependent diabetes mellitus, or IDDM, is a disease of metabolic dysregulation, particularly glucose metabolism dysregulation, with severe and long-term health consequences for sufferers, including vascular and neurologic complications. The predominant abnormality in patients with IDDM is a deficiency in insulin, the major anabolic hormone in humans. IDDM, also known as "Type I" or juvenile onset diabetes, affects 1 in 250 Americans, with 10,00015,000 new cases every year. Its prevalence is greatest in Caucasians, its frequency in that population being twice that among people of African and Asian ancestry. Typically, clinical onset is during childhood. The majority of sufferers are diagnosed before the age of 20, with peak onset around puberty; fewer than 10% of cases first appear in patients over the age of 50. The survival of patients suffering from IDDM depends entirely on the intake of exogenous insulin. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Thiazolidinedione salt for treatment of diabetes mellitus Inventor(s): Craig, Andrew Simon; (Kent, GB), Ho, Tim Chien Ting; (Kent, GB) Correspondence: Smithkline Beecham Corporation; Corporate Intellectual Property-us, Uw2220; P. O. Box 1539; King OF Prussia; PA; 19406-0939; US Patent Application Number: 20030162815 Date filed: April 25, 2003 Abstract: A novel pharmaceutical compound 5-[4-[2-(N-methyl-N-(2pyridyl)amino)ethox- y]benzyl]thiazolidine-2,4-dione hydrobromide or a solvate thereof, a process for preparing such a compound, a pharmaceutical composition comprising such a compound and the use of such a compound in medicine.

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Excerpt(s): This invention relates to a novel pharmaceutical, to a process for the preparation of the pharmaceutical and to the use of the pharmaceutical in medicine. European Patent Application, Publication Number 0,306,228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycaemic and hypolipidaemic activity. The compound of example 30 of EP 0,306,228 is 5-[4-[2-(N-methyl-N-(2pyridyl)amino)ethoxy]benzyl]thiazo- lidine-2,4-dione (hereinafter also referred to as "Compound (I)"). International Patent Application, Publication Number WO94/05659 discloses certain salts of the compounds of EP 0,306,228 including salts formed from mineral acids such as hydrobromic, hydrochloric and sulphuric acids, and organic acids, such as methanesulphonic, tartaric and, in-particular, maleic acid salts. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Transgenic fatty acid transport one (FATP1) non-human knockout mammals uses thereof Inventor(s): Gimeno, Ruth E.; (Wellesley, MA), Hirsch, David J.; (Somerset, NJ), Kim, Jason K.; (Hamden, CT), Lodish, Harvey F.; (Brookline, MA), Shulman, Gerald I.; (East Haven, CT), Stahl, Andreas; (Mountain View, CA) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20030165430 Date filed: December 12, 2002 Abstract: The present invention provides a transgenic Fatty Acid Transport One (FATP1), non-human knockout mammal, e.g., mammal, useful for elucidating the function of FATP in intact animals whose genomes comprise a wild-type FATP gene. Further aspects of the invention provide a method for the identification of agents, e.g., therapeutic agents, that inhibit FATP1 activity, and methods of treating diseases or conditions associated with FATP1 function, e.g., insulin resistance, non-insulin dependent diabetes mellitus, and cellular triglyceride accumulation. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/341,163 filed Dec. 13, 2001. The entire teachings of the above application are incorporated herein by reference. Non-insulin dependent diabetes (NIDDM) or Type 2 diabetes is the form of diabetes characterized by insulin resistance combined with a relative, rather than an absolute, deficiency of insulin. Insulin resistance can be defined as a diminished ability of insulin to exhibit effective biological activity over a range of concentrations. Individuals suffering from Type 2 diabetes manifest considerable variation in the degree of each of the two defects, from demonstrating predominantly insulin resistance with minimal insulin deficiency to demonstrating predominantly insulin deficiency with minimal insulin resistance. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Treatment involving Dkk-1 or antagonists thereof Inventor(s): DeAlmeida, Venita I.; (San Carlos, CA), Stewart, Timothy A.; (San Francisco, CA) Correspondence: Genentech, INC.; 1 Dna Way; South San Francisco; CA; 94080; US Patent Application Number: 20030165501 Date filed: February 15, 2002 Abstract: Antagonists to Dickkopf-1 (Dkk-1) protein are administered in effective amounts to treat disorders involving insulin resistance, such as non-insulin-dependent diabetes mellitus (NIDDM), hypoinsulinemia, and disorders involving muscle atrophy, trauma, or degeneration. Preferably, the antagonists are composed of compositions comprising antibodies directed to Dkk-1 in a pharmaceutically acceptable carrier for use in blocking the effects of Dkk-1. Additionally provided is a method of treating obesity or hyperinsulinemia in a mammal by administering an effective amount of Dkk-1 to a mammal. Also provided are methods of diagnosing insulin resistance, hyper- and hypoinsulinemia, obesity, and related disorders using Dkk-1 as a target and non-human transgenic animals that overexpress dkk-1 nucleic acid. Excerpt(s): This application is a non-provisional application filed under 37 CFR 1.53(b)(1), claiming priority under 35 USC 119(e) to provisional application number 60.backslash.269,435 filed Feb. 16, 2001, the contents of which are incorporated herein by reference. The present invention provides for the diagnosis and treatment of disorders involving obesity, insulin resistance, hypoinsulinemia, and hyperinsulinemia and for repairing and regenerating muscle in mammals. More particularly, the present invention relates to the use of Dickkopf-1 (Dkk-1) protein to treat obesity and hyperinsulinemia and to the use of antagonists that bind to Dkk-1 and/or neutralize its activity in the treatment of insulin resistance and hypoinsulinemia, and in muscle repair. The Dickkopf (dkk) proteins are a group of secreted proteins that modulate Wnt activity (Krupnik et al., Gene, 238: 301-313 (1999); Monaghan et al., Mech. Dev., 87: 45-56 (1999); Roessler et al., Cell Genet., 89: 220-224 (2000)). This family is composed of four members, which are highly related and contain two conserved cysteine-rich domains (WO 00/52047 published Sep. 8, 2000). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Treatment of the insulin resistance syndrome Inventor(s): Fryburg, David Albert; (Groton, CT), Gibbs, Earl Michael; (Groton, CT), Koppiker, Nandan Parmanand; (Sandwich, GB) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030166662 Date filed: February 19, 2003 Abstract: Use of a selective cGMP PDE5 inhibitor or a pharmaceutical composition thereof in the preparation of a medicament for the curative, palliative or prophylactic treatment of the insulin resistance syndrome wherein the insulin resistance syndrome means the concomitant existence in a subject of two or more of dyslipidemia; hypertension; type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes; hyperuricaemia and/or gout; a pro-coagulant state; atherosclerosis;

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or truncal obesity wherein said use can occur alone or in combination with other agents to treat the insulin resistance syndrome or individual aspects of the insulin resistance syndrome. Excerpt(s): This invention relates to the use of selective cGMP PDE5 inhibitors and in particular to selective cGMP PDE5 inhibitor compounds such as the compound sildenafil for the treatment of the Insulin Resistance Syndrome. The Insulin Resistance Syndrome as defined herein means the concomitant existence in a subject of two or more of: dyslipidemia, hypertension, type 2 diabetes mellitus or impaired glucose tolerance (IGT) or a family history of type 2 diabetes mellitus, hyperuricaemia and/or gout, a pro-coagulant state, atherosclerosis, truncal obesity. A family history of type 2 diabetes mellitus as defined herein means having a first degree relation, sibling, parent or grandparent with type 2 diabetes mellitus. At the centre of the Insulin Resistance Syndrome, also known as "Syndrome X" and "Metabolic Syndrome" in the biomedical literature is the common feature of tissue resistance to the action of insulin. This impaired biological response to insulin can be manifested in both the metabolic and vascular effects of insulin. Although there are monogenic syndromes of insulin resistance (IR), in which a definite gene has been identified as the cause of insulin resistance (such as leprechaunism), these are relatively rare. By contrast, the more common presentation of the IRS is associated with obesity (particularly abdominal) and appears to be polygenic. 6. Atherosclerosis. 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 diabetes mellitus, 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 “diabetes mellitus” (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 diabetes mellitus. You can also use this procedure to view pending patent applications concerning diabetes mellitus. 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 7. BOOKS ON DIABETES MELLITUS Overview This chapter provides bibliographic book references relating to diabetes mellitus. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on diabetes mellitus 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 “diabetes mellitus” (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 diabetes mellitus: •

Diabetes Mellitus: Diagnosis and Treatment. 4th ed Source: Philadelphia, PA: W.B. Saunders Company. 1998. 461 p. 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: $68.00. ISBN: 0721664032. Summary: This book, which has been updated to reflect the changes that have occurred in diabetes care since the last edition was published, presents the latest information on all basic aspects of diabetes. Chapter one describes the new classification and diagnostic criteria recently adopted by the American Diabetes Association and the World Health Organization. Chapter two differentiates the clinical and pathogenetic features of type 1 and type 2 diabetes and provides evidence to demonstrate the relationship between diabetes control and complications. Chapter three explains how to apply the recent

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American Diabetes Association changes in nutritional therapy involving sucrose, other carbohydrates, and fat content in the diet. Chapter four presents general considerations for using insulin, offers guidelines on initiating insulin therapy in hospitalized and nonhospitalized patients, describes various regimens, and discusses the side effects of insulin therapy. Chapter five examines the use of oral antidiabetes agents, focusing on sulfonylurea agents, metformin, and acarbose. Information includes mechanism of action, pharmacology, clinical use, and side effects. Chapter six provides information on the pathophysiology, etiology, symptoms, diagnosis, and treatment of diabetic ketoacidosis and hyperosmolar nonketotic syndrome. Chapter seven presents new evidence based guidelines on diabetes care, discusses the monitoring of diabetic control, and provides information on various aspects of self care. Chapter eight examines the features and treatment of complications, focusing on macrovascular, microvascular, and neuropathic complications. Chapter nine explores the impact of pregestational and gestational diabetes on pregnancy. The final chapter provides an overview of the material that a diabetes educator can use to teach and treat people who have diabetes. 2 appendixes. Numerous figures. Numerous tables. Numerous references. •

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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Manual for Management of Diabetes Mellitus: A Hong Kong Chinese Perspective Source: Hong Kong: Chinese University Press. 1998. 144 p. Contact: Available from Chinese University Press. Chinese University of Hong Kong, Sha Tin, N.T., Hong Kong. (852) 2609 6508. Fax (852) 2603 6692. E-mail: cup @cuhk.hk. PRICE: $19.00 plus shipping and handling. ISBN: 9622017576. Summary: This manual, which combines the latest international and Chinese information on diabetes, serves as a quick reference to all health care personnel involved in the management of diabetes. The manual begins with a chapter on the classification and pathogenesis of diabetes, focusing on intermediary metabolism, insulin, and counterregulatory hormones; the classification, presentation, and pathogenesis of diabetes; the overlap between type 1 and type 2 diabetes; and diabetes in Chinese people. This is followed by a chapter on the diagnosis of diabetes. Topics include the American Diabetes Association and World Health Organization diagnostic criteria and the oral glucose tolerance test. The third chapter recommends standards of medical care for patients who have diabetes, focusing on the initial visit, continuing care, the annual assessment, target values, hospital admission criteria, and referral for specialist assessment. The next chapter addresses the issue of patient education. Topics include health beliefs and affective responses, knowledge and skills, patient rights and roles, obstacles to glycemic control, self monitoring of blood glucose, insulin administration, sick day management, hypoglycemia, diabetic complications, treatment noncompliance, psychosociological problems, and finances. The fifth chapter focuses on the dietary management of diabetes and exercise in diabetes. Diet-related topics include the goals of dietary management, diet composition, healthy eating and dining out guidelines, food choices, weight control, and sweeteners. This is followed by a chapter on oral drugs for treating diabetes, including sulfonylureas, biguanides, antiabsorptive drugs, antiobesity drugs, and insulin and oral agent combinations. The next chapter discusses insulin use in terms of indications for use, actions and duration, types, regimen, dosage, adjustment of dosage, and use while travelling. The eighth chapter describes diabetic complications, including ophthalmic complications, diabetic foot, diabetic neuropathy, and microalbuminuria and renal involvement. This is followed by chapters on the treatment of hypertension and dyslipidemia. Perioperative management of people who have poorly and well controlled type 1 or type 2 diabetes is the topic of the next chapter. This is followed by a chapter on diabetic emergencies such as diabetic ketoacidosis, hyperosmolar nonketotic coma, and lactic acidosis. Remaining chapters discusses the diagnosis and management of gestational diabetes and the primary, secondary, and tertiary prevention of diabetes. 2 appendices. 9 figures. 1 table.

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Diabetes Mellitus in the Elderly Source: Binghamton, NY: Pharmaceutical Products Press. 1999. 84 p. Contact: Available from Pharmaceutical Products Press. 10 Alice Stret, Binghamton, NY 13904-1580. (800)429-6784. E-mail: [email protected]. Website: www.haworthpressinc.com. PRICE: $49.95 plus shipping and handling. ISBN: 0789006820. Summary: This volume is devoted to the diagnosis and treatment of diabetes mellitus in the elderly. The first chapter in the monograph addresses the frustration and futility health care providers and ministers sometimes experience in attempting to help patients with diabetes care for themselves. The monograph then includes four articles: the pathophysiology of diabetes in aging; the management of type 2 diabetes in the elderly patient; the use of acarbose in Europe; and insulin use in the elderly. The first article

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stresses that the recently revised American Diabetes Association (ADA) guidelines that include impaired glucose tolerance (IGT) and a lower level of fasting plasma glucose for the diagnosis of diabetes underscore the need for earlier detection of diabetes in the older adult and the relationship of diabetes with obesity. The articles on drug therapy offer practical insight to using the four new oral agents (acarbose, metformin, repaglinide and troglitazone) for type 2 diabetes, particularly in light of the ADA revised guidelines that suggest the trial of all oral agents before resorting to insulin. The last article discusses the comorbidities (other illnesses present at the same time as the diabetes), nutritional issues, pharmacodynamics, and physiologic effects of various insulin preparations and regimens. Each chapter concludes with a list of references and a subject index concludes the volume. This monograph has been copublished simultaneously as Journal of Geriatric Drug Therapy, Volume 12, Number 2, 1999.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print®). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “diabetes mellitus” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “diabetes mellitus” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “diabetes mellitus” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

A Slide Atlas of Diabetes Mellitus on CD-ROM by Ian N. Scobie; ISBN: 184214183X; http://www.amazon.com/exec/obidos/ASIN/184214183X/icongroupinterna

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An Atlas of Diabetes Mellitus by I. N. Scobie (Editor); ISBN: 1850704899; http://www.amazon.com/exec/obidos/ASIN/1850704899/icongroupinterna

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Bones and Joints in Diabetes Mellitus (Series in Radiology, V. 4) by S. Forgacs (1983); ISBN: 9024723957; http://www.amazon.com/exec/obidos/ASIN/9024723957/icongroupinterna

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Cardiovascular Risk in Type 2 Diabetes Mellitus by Howard Bloom (Author), N. Hancu (Author); ISBN: 3540438033; http://www.amazon.com/exec/obidos/ASIN/3540438033/icongroupinterna

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Chronic Diseases in the Year 2005: Scenarios on Diabetes Mellitus, 1990-2005 by H. Verkleij (Editor), et al (1993); ISBN: 0792313771; http://www.amazon.com/exec/obidos/ASIN/0792313771/icongroupinterna

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Clinical Diabetes Mellitus: A Problem Oriented Approach by John K. Davidson (Editor); ISBN: 086577370X; http://www.amazon.com/exec/obidos/ASIN/086577370X/icongroupinterna

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Davidson's Diabetes Mellitus: Diagnosis and Treatment by Anne Peteres Harmel (Editor), et al (2004); ISBN: 0721695965; http://www.amazon.com/exec/obidos/ASIN/0721695965/icongroupinterna

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Diabetes Mellitus by Bernoville (2003); ISBN: 817021985X; http://www.amazon.com/exec/obidos/ASIN/817021985X/icongroupinterna

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Diabetes Mellitus (Pathophysiology for Nurses Series) by Blanchard, et al (2000); ISBN: 1930138040; http://www.amazon.com/exec/obidos/ASIN/1930138040/icongroupinterna

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Diabetes Mellitus and Hypertension by Laura Ninger, et al (1999); ISBN: 0815120400; http://www.amazon.com/exec/obidos/ASIN/0815120400/icongroupinterna

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Diabetes Mellitus in Children and Adolescents (Major Problems in Clinical Pediatrics, Vol 29) by Luther B. Travis, et al (1998); ISBN: 0721688993; http://www.amazon.com/exec/obidos/ASIN/0721688993/icongroupinterna

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Diabetes Mellitus: A Fundamental and Clinical Text by Derek Leroith (Editor), et al; ISBN: 0781720583; http://www.amazon.com/exec/obidos/ASIN/0781720583/icongroupinterna

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Diabetes Mellitus: A Practical Handbook by Suellyn K. Milchovich, et al; ISBN: 0923521313; http://www.amazon.com/exec/obidos/ASIN/0923521313/icongroupinterna

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Diabetes Mellitus: An Incredibly Easy! Miniguide by Springhouse Corporation, et al; ISBN: 1582550123; http://www.amazon.com/exec/obidos/ASIN/1582550123/icongroupinterna

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Diabetes Mellitus: Diagnosis and Treatment by Rifkin (1980); ISBN: 0876197470; http://www.amazon.com/exec/obidos/ASIN/0876197470/icongroupinterna

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Diabetes Mellitus: Methods and Protocols (Methods in Molecular Medicine, 83) by Sabire Ozcan (Editor) (2003); ISBN: 1588291480; http://www.amazon.com/exec/obidos/ASIN/1588291480/icongroupinterna

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Diabetes Mellitus: Pathophysiology, Etiologies, Complications, Management, and Laboratory Evaluation: Special Topics in Diagnostic Testing by William E., Md. Winter, Maria Rita, Md. Signorino; ISBN: 189088362X; http://www.amazon.com/exec/obidos/ASIN/189088362X/icongroupinterna

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Diabetes Mellitus: Theory and Practice by Max Ellenberg, Harold Rifkin (Editor); ISBN: 0874888417; http://www.amazon.com/exec/obidos/ASIN/0874888417/icongroupinterna

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Diabetes Sourcebook: Basic Information About Insulin-Dependent and NoninsulinDependent Diabetes Mellitus, Gestational Diabetes, and Diabetic Complications Symptoms (Health Reference, Vol 3) by Karen Bellenir (Editor), Peter D. Dresser (Editor) (1995); ISBN: 1558887512; http://www.amazon.com/exec/obidos/ASIN/1558887512/icongroupinterna

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Dogs, Diet, & Disease: An Owner's Guide to Diabetes Mellitus, Pancreatitis, Cushing's Disease, & More by Caroline D. Levin; ISBN: 0967225329; http://www.amazon.com/exec/obidos/ASIN/0967225329/icongroupinterna

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Early Vascular Complications in Children With Diabetes Mellitus: Proceedings (Pediatric and Adolescent Endocrinology, Vol 17) by B. Weber (Editor) (1988); ISBN: 3805544855; http://www.amazon.com/exec/obidos/ASIN/3805544855/icongroupinterna

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Ellenberg and Rifkin's Diabetes Mellitus by Daniel Porte (Editor), et al; ISBN: 0838521789; http://www.amazon.com/exec/obidos/ASIN/0838521789/icongroupinterna

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How to Control and Manage Diabetes Mellitus by American Diabetes Association (2004); ISBN: 1878049089; http://www.amazon.com/exec/obidos/ASIN/1878049089/icongroupinterna

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How to Control and Manage Diabetes Mellitus by American Diabetes Association, et al; ISBN: 1580401279; http://www.amazon.com/exec/obidos/ASIN/1580401279/icongroupinterna

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Instructional Aid on Insulin Dependent Diabetes Mellitus by Luther B. Md. Travis; ISBN: 0963618806; http://www.amazon.com/exec/obidos/ASIN/0963618806/icongroupinterna

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International Textbook of Diabetes Mellitus (2 Volume Set) by K. G. M. M. Alberti (Editor), et al (1997); ISBN: 0471939307; http://www.amazon.com/exec/obidos/ASIN/0471939307/icongroupinterna

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Joslin's Diabetes Mellitus by Ronald C. Kahn (Editor), et al; ISBN: 0781727960; http://www.amazon.com/exec/obidos/ASIN/0781727960/icongroupinterna

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Joslin's Diabetes Mellitus; ISBN: 0812107632; http://www.amazon.com/exec/obidos/ASIN/0812107632/icongroupinterna

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Management of Diabetes Mellitus by Sherwyn L. Schwartz (1994); ISBN: 092924060X; http://www.amazon.com/exec/obidos/ASIN/092924060X/icongroupinterna

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Management of Diabetes Mellitus: Perspectives of Care Across the Life Span by Debra Haire-Joshu (Editor); ISBN: 0815142234; http://www.amazon.com/exec/obidos/ASIN/0815142234/icongroupinterna

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Management of Type 2 Diabetes Mellitus in Primary Care: A Practical Guide by Louis Steven Levene (2003); ISBN: 0750687800; http://www.amazon.com/exec/obidos/ASIN/0750687800/icongroupinterna

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Medical Management of Diabetes Mellitus by Jack L. Leahy (Editor), et al; ISBN: 0824788575; http://www.amazon.com/exec/obidos/ASIN/0824788575/icongroupinterna

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Molecular Pathology of Type 1 Diabetes Mellitus (Current Directions in Autoimmunity, Vol 4) by Matthias G. Von Herrath (Editor), Matthias G. Von Herrath (Editor) (2001); ISBN: 3805572409; http://www.amazon.com/exec/obidos/ASIN/3805572409/icongroupinterna

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Nursing Management of Diabetes Mellitus: A Guide to the Pattern Approach by Diana W. Guthrie, Richard A. Guthrie; ISBN: 082617261X; http://www.amazon.com/exec/obidos/ASIN/082617261X/icongroupinterna

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Nutrition Care of People With Diabetes Mellitus: A Nutrition Reference for Health Professionals by Catherine Higgins, et al (1996); ISBN: 1560220074; http://www.amazon.com/exec/obidos/ASIN/1560220074/icongroupinterna

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The Global Epidemiology of Noncommunicable Diseases: The Epidemiology and Burdens of Cancers, Cardiovascular Diseases, Diabetes Mellitus, Respiratory Disorders, and Other Major Conditions (Global Burden of Disease and Injury, No 5) by Christopher J. L. Murray (Editor), Alan D. Lopez (Editor) (2004); ISBN: 0674354478; http://www.amazon.com/exec/obidos/ASIN/0674354478/icongroupinterna

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The Handbook of Diabetes Mellitus and Cardiovascular Disease by Steven Marso (Editor), et al (2003); ISBN: 1901346595; http://www.amazon.com/exec/obidos/ASIN/1901346595/icongroupinterna

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Therapy for Diabetes Mellitus and Related Disorders by Harold E. Lebovitz (Editor); ISBN: 0945448945; http://www.amazon.com/exec/obidos/ASIN/0945448945/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 “diabetes mellitus” (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 •

Abnormal vascular reactions in diabetes mellitus; a clinical physiological study. [Tr. from the Swedish]. Author: Bárány, Franz R.; Year: 2003; Lund, Ohlsson, 1955

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Aetiology of diabetes mellitus and its complications, ed. by Margaret P. Cameron and Maeve O'Connor. Author: Ciba Foundation.; Year: 1964; Boston, Little, Brown, 1964

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Cardiovascular-renal disease in diabetes mellitus; a clinical study. Author: Aarseth, Sverre.; Year: 2003; Oslo, Bøhler; Larsen, 1953

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Clinical studies on adrenocortical function in diabetes mellitus. Author: Jakobson, Theodor.; Year: 1953; Helsinki, 1958

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Diabetes mellitus in Bergen, 1925-1941; a study of morbidity, mortality, causes of death and complications. Author: Hanssen, Per.; Year: 1958; Helsingfors, 1946

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Diabetes mellitus in Sweden; statistical data on the number of diabetics, their state of health, working capacity, diet and treatment, by Gunnar Dahlberg [and others]. Author: Dahlberg, Gunnar,; Year: 2002; Lund, H. Ohlssons boktr., 1947

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Diabetes mellitus. Author: Magyar, Imre.; Year: 1965; Budapest, Medicina Könyvkiadó, 1963

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Incidence and coincidence of diabetes mellitus and pulmonary tuberculosis in a Swedish county, by Hans Silwer and Per Nanne Oscarsson. [Tr. from Swedish]. Author: Silwer, Hans,; Year: 1964; Kristianstad, 1958

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Management of juvenile diabetes mellitus [by] Howard S. Traisman [and Alvah L. Newcomb]. Author: Traisman, Howard S. (Howard Senn),; Year: 1960; St. Louis, Mosby, 1965

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On diabetes mellitus; selected topics for students and clinicians. Author: Jackson, W. P. U. (William Peter Uprichard); Year: 1947; Springfield, Ill., Thomas [c1964]

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Pregnancy and diabetes mellitus; a clinical study. [Tr. from the Swedish.]. Author: Hagbard, Lars.; Year: 1938; Göteborg, Elander, 1956

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Studies in diabetes mellitus. [Tr. from Swedish]. Author: Engleson, Gunnar.; Year: 1945; Lund, 1954

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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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Treatment of diabetes mellitus; guest editor: Thomas F. Frawley. Emergency treatment of trauma; guest editor: Henry C. Cleveland. Author: Frawley, Thomas F.,; Year: 2003; [New York] Harper; Row, 1965

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

Type 1 Diabetes Mellitus Source: in Molitch, M.E. Challenging Cases in Endocrinology. Totowa, NJ: The Humana Press, Inc. 2002. p.287-301. Contact: Humana Press, Inc. 999 Riverview Dr., Suite 208 Totowa, NJ 07512. (973) 2561699. Fax (973) 256-8341. E-mail: [email protected] PRICE: $145.00, plus shipping and handling. ISBN:0896039145. Summary: In medicine, the difficult cases can yield valuable insights because they force physicians to think a little harder when making a diagnosis and to be creative when treating the patient. In this textbook, distinguished clinician-scientists describe in concise studies their most difficult cases and reveal what they did, how they did it, and why. The cases cover a wide range of medical problems in endocrinology. In this chapter, the authors present four cases of type 1 diabetes mellitus: with coronary artery disease; latent autoimmune diabetes in adults; changing an insulin regimen; and progressive diabetic nephropathy (kidney disease related to diabetes). Each case study reviews how the patient was managed, details the reasons why various tests and treatments (many only recently available) were carried out, and provides references to ensure that these novel methodologies can be easily translated into the endocrine specialist's daily practice. 2 tables. 47 references.

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Preoperative Assessment and Perioperative Management of the Surgical Patient with Diabetes Mellitus Source: in Johnstone, M.T. and Veves, A. Diabetes and Cardiovascular Disease. Totowa, NJ: The Humana Press, Inc. 2001. p. 299-326. Contact: Humana Press, Inc. 999 Riverview Dr., Suite 208 Totowa, NJ 07512. (973) 2561699. Fax (973) 256-8341. E-mail: [email protected] PRICE: $125.00, plus shipping and handling. ISBN: 089603755X. Summary: Patients with diabetes mellitus are more likely than patients without diabetes to undergo surgery and may be at a higher than average risk of perioperative complications, usually because of frequent concomitant (present at the same time) cardiovascular disease. The manifestations of cardiovascular disease in patients with diabetes are often atypical, making identification and management more difficult. This chapter on preoperative assessment and perioperative management of the surgical

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patients with diabetes mellitus is from a textbook that offers physicians practical knowledge about cardiovascular disease and diabetes. The authors stress that the role of the physician asked to provide preoperative consultation is to work with the surgical team in assessing and reducing the risk of complications in the perioperative period and also to identify opportunities to make a favorable impact on long term health. The authors discuss epidemiology, pathophysiology, risk assessment, risk reduction, metabolic management, and the role of the consultant. A patient care algorithm is also provided. After one determines the magnitude of perioperative risk, the nest task of the consultant is to make recommendations aimed at lowering that risk. This may be by medical management, preoperative revascularization, and perioperative surveillance. A critical role of the consultant is to communicate the severity and stability of the patient's cardiovascular condition and to determine whether the patient is in a reasonable medical condition in the context of the surgical illness. Follow up increases compliance with recommendations and allows for modifications in the original management plan as the clinical context changes. 2 figures. 2 tables. 174 references. •

Peripheral Vascular Disease in Patients with Diabetes Mellitus Source: in Johnstone, M.T. and Veves, A. Diabetes and Cardiovascular Disease. Totowa, NJ: The Humana Press, Inc. 2001. p. 375-382. Contact: Humana Press, Inc. 999 Riverview Dr., Suite 208 Totowa, NJ 07512. (973) 2561699. Fax (973) 256-8341. E-mail: [email protected] PRICE: $125.00, plus shipping and handling. ISBN: 089603755X. Summary: The pattern of atherosclerotic occlusion (blockage in the arteries) commonly found in diabetes involves the tibial and peroneal arteries but spares both the superficial femoral artery as well as the arteries of the foot. Noninvasive vascular evaluation of diabetic and nondiabetic patients presenting with foot ulceration confirmed that there was no evidence of higher vascular resistance. This chapter on peripheral vascular disease in patients with diabetes mellitus is from a textbook that offers practicing physicians information about managing patients with diabetes and cardiovascular disease. The authors note that in general, after vascular reconstruction, the foot is more resistant to recurrent ulceration, and can withstand and recover from infections better. The authors discuss pathogenesis, principles of therapy, patient selection, technical considerations, special situations, and the results of revascularization. The principles of therapy include drainage and debridement, evaluation for ischemia (lack of blood flow), proper arteriographic technique, arterial reconstruction, and secondary revisions. The authors conclude that improvements in both angiography and results of distal reconstruction have established extreme distal autogenous vein reconstruction to the foot vessels is a safe and effective treatment for limb-threatening ischemia. This has proved especially important for patients with diabetes mellitus. The authors note that their increased use of bypass grafts to the dorsalis pedis artery has correlated almost precisely with a decline in the incidence of all levels of amputations. A carefully planned approach (including prompt control of infection, complete arteriography, and arterial reconstruction to maximize foot perfusion) affords a likelihood of successful limb salvage in people with diabetes. 1 figure. 20 references.

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Intestinal and Liver Complications of Diabetes Mellitus Source: in Stollerman, G.H., et al., eds. Advances in Internal Medicine. Vol 38. St. Louis, MO: Mosby-Year Book, Inc. 1993. p. 269-286.

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Contact: Available from Mosby Year-Book, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 426-4545. Fax (800) 535-9935. E-mail: [email protected]. PRICE: $72.95. ISBN: 0815183089. ISSN: 00652822. Summary: This chapter, from a yearbook on advances in internal medicine, reviews the intestinal and liver complications of diabetes mellitus. The authors review the problems most likely to be encountered in practice, based on their experiences as gastroenterologists at a diabetes referral center. Diabetes mellitus appears to influence primarily the motor functions of the gastrointestinal tract and gallbladder, resulting mainly in delayed transit and emptying. The clinical consequences are delayed esophageal transit, slowed gastric emptying, and gallbladder stasis with gallstones. Diarrhea in some people with diabetes can be attributed to delayed small bowel transit resulting in bacterial overgrowth. Other topics include gastroparesis, constipation, fecal incontinence, hepatic steatosis, and fibrosis. The authors focus on the pathophysiology and treatment of the individual disorders. The most common hepatobiliary lesions found in patients with diabetes include excessive glycogen deposition, fatty liver, and gallstones. Cirrhosis of the liver can develop in people with diabetes as a result of progressive fatty steatosis, pericentral hepatic fibrosis, and, at times, central hyaline sclerosis. 3 figures. 1 table. 84 references. (AA-M). •

Nitric Oxide and Its Role in Diabetes Mellitus Source: in Johnstone, M.T. and Veves, A. Diabetes and Cardiovascular Disease. Totowa, NJ: The Humana Press, Inc. 2001. p. 213-236. Contact: Humana Press, Inc. 999 Riverview Dr., Suite 208 Totowa, NJ 07512. (973) 2561699. Fax (973) 256-8341. E-mail: [email protected] PRICE: $125.00, plus shipping and handling. ISBN: 089603755X. Summary: With over ten million diagnosed patients and another five million undiagnosed, diabetes mellitus and its complications is a major public health problem that will assume epidemic proportions as the population grows older. This chapter on nitric oxide and its role in diabetes mellitus and atherosclerosis (hardening and narrowing of the arteries) is from a textbook that offers physicians practical knowledge about cardiovascular disease and diabetes. This chapter is in Part I, which focuses on pathophysiology, including the mechanisms and risk factors for diabetic cardiovascular disease. The authors note atherosclerosis occurs earlier in diabetics than nondiabetics, its severity is often greater, and its distribution is more diffuse. Vascular (blood vessel) disease in people with diabetes also affects not only large vessels but microvasculature as well, resulting in diabetic retinopathy (eye disease) and nephropathy (kidney disease). The authors discuss endothelium-derived relaxing factor (EDRF), the physiologic effects of nitric oxide (NO) on the vascular system, NO and the development of atherosclerosis, endothelial (the cells that line the body cavity and cardiovascular system) dysfunction and diabetes mellitus, endothelium-dependent vasodilation in animal models, human studies of endothelium-dependent vasodilation, the possible mechanisms of impaired endothelium-dependent vasodilation, other risk factors in diabetic endothelial dysfunction, and potential therapeutic options. The authors conclude that improved glucose control, supplementation with either tetrahydrobiopterin, L-arginine, or vitamin C, or the addition of ACE inhibitors have been shown to improve endothelial function. 6 figures. 1 table. 202 references.

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CHAPTER 8. MULTIMEDIA ON DIABETES MELLITUS Overview In this chapter, we show you how to keep current on multimedia sources of information on diabetes mellitus. 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 diabetes mellitus is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “diabetes mellitus” 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 “diabetes mellitus” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on diabetes mellitus: •

Life is What You Make It Source: Princeton, NJ: Novo Nordisk Pharmaceuticals Inc. 199x. Contact: Available from Novo Nordisk Pharmaceuticals Inc. 100 Overlook Center, Suite 200, Princeton, NJ 08540-7810. (800) 727-6500. PRICE: Single copy free. Summary: In this videotape, five patients and their doctor, all of whom have insulindependent diabetes mellitus (IDDM), share their stories. The patients focus on when and how their diabetes was diagnosed, how they adapted to insulin injections, and how diabetes has changed their lives. Patients include a 7-year old child (diagnosed at age 4); an African-American man, diagnosed as an adult; a 61-year old white woman (diagnosed at age 29); a white teenager; and an older white male who ignored his diabetes for many years. The physician, who has had diabetes for over 22 years, stresses the importance of early diagnosis and treatment.

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Type I Diabetes: One Man's Story as Student, Husband, Father Source: Chapel Hill, NC: Health Sciences Consortium. 1990. Contact: Available from Health Sciences Consortium (HSC). 201 Silver Cedar Court, Chapel Hill, NC 27514. (919) 942-8731. PRICE: $195 ($136.50 for HSC members). Order Number N900-V1-059. Summary: In this videotape, Mike, a man with insulin-dependent diabetes mellitus, describes his experiences as a child, teenager, college student, and parent. Topics in his discussion include family and peer relations, motivation factors, and relations with health care professionals. (AA-M).

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Healthy Ways, Healthy Days: An Easy Walking Program for People with Type II Diabetes Source: Chambalee, GA: Upjohn Company. 1993. Contact: Available from Upjohn Company. 5251 Peachtree Industrial Boulevard, Chambalee, GA 30341. (800) 241-7117. PRICE: Single copy free. Distribution may be limited to health professionals. Summary: This patient education videocassette program describes the benefits of exercise, specifically walking, for people with noninsulin-dependent diabetes mellitus (NIDDM). The author, a physical therapist, emphasizes the role of exercise or activity as part of a total diabetes management program. The videotape is directed primarily at patients taking Glynase PresTab (glyburide) oral hypoglycemic agents. The program describes an easy walking program for people with NIDDM and depicts how the program can work for a variety of ages and health levels.

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Living Well With Your Diabetes Source: Kalamazoo, MI: The Upjohn Company. March 1990. Contact: Available from Upjohn Company. 7000 Portage Road, Kalamazoo, MI 49001. (616) 323-4000. PRICE: Single copy free. Summary: This patient education videotape is designed to increase patient adherence to the treatment regimen for noninsulin-dependent diabetes mellitus (NIDDM), emphasizing the diet and exercise components of treatment. The program presents two individuals who are successfully following a treatment plan. The program emphasizes positive reinforcement rather than frightening the viewer with a list of potentially serious consequences of nontreatment. The two health care providers portrayed in the video do not specify a particular treatment regimen, but reiterate the importance of adhering to the treatment plan prescribed by the individual's own physician. (AA-M).

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Taking Charge: Living with Diabetes Source: Santa Monica, CA: Oracle Film and Video. 1990. (videocassette series). Contact: Available from Oracle Film and Video. 1820 14th Street, Suite 202, Santa Monica, CA 90404. (800) 262-4550 or (310) 450-6637. PRICE: $229 for 8 programs (as of 1995); rentals available. Summary: This series of eight audiovisual programs is designed to help people with diabetes understand and control their condition. The eight programs cover an overview of diabetes, meal planning, exercise, insulin, monitoring, noninsulin-dependent diabetes mellitus (NIDDM), pregnancy, and complications. The videos provide information to

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help people with diabetes become self-sufficient, while avoiding medical details and terminology. The series is available in Spanish and English. (AA-M). •

Pancreas Transplant: A Cure for Diabetes Source: Minneapolis, MN: University of Minnesota Hospitals and Clinics. 1991. Contact: Available from University of Minnesota Hospitals and Clinics. The Transplant Center, Box 482 UMHC, Minneapolis, MN 55455. (800) 328-5465. PRICE: $25 minimum donation. Written orders only for tape. Summary: This video, produced especially for people with diabetes, presents insights into the world of pancreas transplantation. Led by pancreas transplant pioneer Dr. David Sutherland and the transplant team at the University of Minnesota Hospitals, the program discusses who is eligible and describes transplant advances. Topics include: an overview of insulin-dependent diabetes mellitus and its complications; a history of pancreas transplantation; interviews with donors, recipients, and people with diabetes; the benefits and risks of pancreas transplantation; patient evaluation for transplantation; transplant surgery; potential complications; a summary of immunosuppressive drugs; what life is like after transplantation; how a donor is selected; and financial considerations. (AA-M).

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Diabetes at Time of Diagnosis Source: New York, NY: Patient Education Media, Inc. Time Life Medical. 1996. (videocassette). Contact: Available from Milner-Fenwick, Inc. 2125 Greenspring Drive, Timonium, MD 21093. (800) 432-8433. Fax (410) 252-6316. Website: www.milner-fenwick.com. Summary: This videocassette program provides information for patients newly diagnosed with diabetes mellitus (DM). The half-hour, newsmagazine style educational program features four sections or 'reports'. The first report examines what is going on inside the body and how the diagnosis was made; computer animation is used to aid viewer understanding. The second report covers what happens after the diagnosis and introduces the viewer to practical issues, including the types of health professionals they may encounter and what lifestyle changes may need to occur. The third report explores options for treatment and management of the condition. The final report addresses issues and answers common questions through the use of an in-studio question-andanswer session. The videotape comes with a personal workbook that includes the program highlights, a glossary, a resource guide, and blank space for readers to record their personal medical journal. (AA-M).

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Management of Type II Diabetes Source: Camp Hill, PA: Chek-Med Systems, Inc. 1993. Contact: Available from Chek-Med Systems, Inc. 200 Grandview Avenue, Camp Hill, PA 17011. (800) 451-5797. Fax (717) 761-0216. PRICE: $89 (as of 1995); bulk prices available. Item Number CV-25. Summary: This videotape discusses noninsulin-dependent diabetes mellitus (NIDDM) self-management and its elements. The tape explains the importance of diet, exercise, and medication as interactive and individual components of self-management. The program explains insulin injections may not be necessary for all cases of NIDDM. The program stresses that proper management of these three elements help people with

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diabetes lead active, healthy, and productive lives. The program depicts real patients and medical situations and is one of a 10-part series on diabetes. (AA-M). •

Management of Insulin-Dependent Diabetes Source: Camp Hill, PA: Chek-Med Systems, Inc. 1993. Contact: Available from Chek-Med Systems, Inc. 200 Grandview Avenue, Camp Hill, PA 17011. (800) 451-5797. Fax (717) 761-0216. PRICE: $89 (as of 1995); bulk prices available. Item Number CV-23. Summary: This videotape for patients describes the three elements that comprise management of insulin-dependent diabetes mellitus (IDDM). The tape describes the importance of diet, exercise, and insulin administration, individually and collectively. The program stresses that proper management of these three elements help people with diabetes lead active, healthy, and productive lives. The program depicts real patients and real medical situations and is one of a 10-part series on diabetes. (AA-M).

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Diabetes Management for the Hmong Patient Source: Ringle, WI: RRR Productions, Ltd. 1995. (videocassette). Contact: Available from RRR Productions, Ltd. E1817 EauClaire River Road, Ringle, WI 54471. (715) 446-2809. PRICE: $995.00; $500.00 for each additional set; $2985.00 for master copy. Summary: This videotape is designed to introduce Hmong immigrants to western health care theory, diabetes symptom recognition, and diabetes management principles. The narrator, who is a Hmong immigrant, shares his personal experience with insulindependent diabetes mellitus (IDDM). Topics include heredity, insulin, the patient care team, a treatment plan, IDDM, noninsulin-dependent diabetes mellitus (NIDDM), diabetes pills, blood glucose, complications, foot care, record keeping, meal planning, exchanges, hypertension, and exercise. The narrator advises viewers with diabetes to conscientiously monitor their blood glucose levels and take insulin if it is prescribed, eat nutritious foods, exercise daily, and communicate regularly with the members of their health care team. The videotape is presented in four parts, each of which is about 14 minutes long. (AA-M).

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Diabetes and Glaucoma Source: Alexandria, VA: PBS Video. 1992. Contact: Available from PBS Video. Public Broadcasting Service, 1320 Braddock Place, Alexandria, VA 22314-1598. (800) 344-3337. PRICE: $59.95 VHS, $79.95 U-matic, plus $8.50 shipping and handling. Order No. LIFM-704L. ISBN: 1559519924. Summary: This videotape is from a series that takes an in-depth look at the internal strength and convictions of people who live active and productive lives in spite of illnesses that can cause disabilities or become fatal. This video discusses diabetes mellitus and glaucoma. In the first half of the video, viewers meet Gerald Brennecke, who has been maintaining daily control of his diabetes for more than 30 years. Faced with the possibility of vision loss, losing a limb, or experiencing an early death, Brennecke lives as normal a lifestyle as possible, looking forward to a promising future. The second half of the video discusses glaucoma. (AA-M).

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Colonic and Anorectal Disorders Source: in Schwartz, R.S., ed. Aging and the Elderly: A Review Course of Geriatric Medicine. Seattle, WA: University of Washington School of Medicine. 1992. Tape Number 9, Section 33. Contact: Available from CME Conference Video, Inc. 2000 Crawford Place, Suite 100, Mount Laurel, NJ 08054. (800) 284-8433. PRICE: $549; plus $18.25 shipping and handling; Group Practice Package $150 plus $5.25 shipping and handling. Program Number 053. Summary: This videotape is part of the 16th Annual Symposium on Aging and the Elderly, a continuing medical education (CME) program offered through the University of Washington School of Medicine. This program covers colonic and anorectal disorders, including colorectal neoplasms and benign polyps; diverticular disease; vascular extasia, angiodysplasia, and arteriovenous malformations; infectious colitis; antibioticassociated diarrhea or colitis; ischemic colitis; idiopathic inflammatory bowel disease; drug-induced colitis; radiation-induced colitis; diversion colitis; appendicitis; adhesions; megacolon; volvulus; abdominal; functional bowel syndrome; anorectal disorders, including anal neoplasms, hemorrhoids; anorectal abscess and fistula; and rectal prolapse; and systemic disorders, including diabetes mellitus, Parkinson's disease, myxedema, and amyloidosis. The proceedings include the author's outline of his presentation. The videotape includes the question-and-answer period conducted after the section.

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Living with Diabetes Source: Andover, MA: Xenejenex, Inc. 1990. Contact: Available from Xenejenex, Inc. 300 Brickstone Square, Andover, MA 01810. (800) 228-2495 or (508) 475-3000. PRICE: $24.95 plus $3 shipping and handling. Summary: This videotape presents a positive approach to healthy living with diabetes mellitus. The videotape presents the best techniques for self-monitoring and suggests ways to avoid common complications. Experts from the Joslin Clinic of Boston discuss alternatives to insulin therapy and how to achieve healthy weight loss. The film also gives recipes to fit this healthier lifestyle.

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Type II Diabetes: A Stranger in Your Midst Source: Chapel Hill, NC: Health Sciences Consortium. 1990. Contact: Available from Health Sciences Consortium (HSC). 201 Silver Cedar Court, Chapel Hill, NC 27514. (919) 942-8731. PRICE: $195 ($97.50 for HSC members). Order Number C900-VI-042. Summary: This videotape presents case histories of a man and woman with noninsulindependent diabetes mellitus (NIDDM) who discuss how the disease has affected their lives. Topics in their discussion include symptoms, treatment, diet, and family support, as well as how they solved problems and made decisions about the various aspects of their condition. The authors note that how a patient perceives his or her diagnosis and whether or not the patient accepts and complies with the diabetes treatment plan can be influenced by a number of factors: past experiences, the severity of the symptoms, how the management plan is presented, and the significance of the changes required in the patient's lifestyle. (AA-M).

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Complications of Diabetes Source: Camp Hill, PA: Chek-Med Systems, Inc. 1993. Contact: Available from Chek-Med Systems, Inc. 200 Grandview Avenue, Camp Hill, PA 17011. (800) 451-5797. Fax (717) 761-0216. PRICE: $89 (as of 1995); bulk prices available. Item Number CV-27. Summary: This videotape presents in documentary style the risks for artery, verve, and kidney disease that may result from diabetes mellitus. The tape depicts real patients and medical situations to describe how and why the diseases develop and the early warning signs that should lead a person to seek medical care. This is one of a 10-part series on diabetes and emphasizes the importance of regular blood glucose monitoring to prevent the development of complications. (AA-M).

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Blood and Urine Monitoring Source: Camp Hill, PA: Chek-Med Systems, Inc. 1993. Contact: Available from Chek-Med Systems, Inc. 200 Grandview Avenue, Camp Hill, PA 17011. (800) 451-5797. Fax (717) 761-0216. PRICE: $89 (as of 1995); bulk prices available. Item Number CV-29. Summary: This videotape presents the importance of blood and urine monitoring as an important part of the proper management of diabetes mellitus. The tape describes various forms of blood and urine monitoring that give patients the information they need to maintain a proper balance of insulin, diet, and exercise. The program explains how the tests work, demonstrates how to perform them properly, and stresses the importance of regular testing and accurate record keeping. The program depicts real patients and medical situations and is one of a 10-part series on diabetes. (AA-M).

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Controlling My Diabetes from Head-To-Toe Source: Evanston, IL: Altschul Group Corporation. 1994. Contact: Available from Altschul Group Corporation. 1560 Sherman Avenue, Suite 100, Evanston, IL 60201. (800) 421-2363 or (708) 328-6700. Fax (708) 328-6706. PRICE: $295 (as of 1995). Order no. 7841. Summary: This videotape program is one of a series of six videotapes that present a common sense approach for living with and controlling diabetes mellitus. This program highlights an easy routine of head-to-toe care for people with diabetes. Important hints are given for the care of feet, skin, and eyes; also provided is basic information on healthy eating, the need for exercise, and the importance of regular medical checkups. Sound advice is presented by people with diabetes to lessen the risk of complications. (AA-M).

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Close Watch: Intensified Management of Type II Diabetes Source: Cypress, CA: Medcom, Inc. 1995. Contact: Available from Medcom, Inc. P.O. Box 6003, Cypress, CA 90630. (800) 320-1444. Fax (714) 898-4852. PRICE: $39.95 plus shipping (as of 1995). Summary: This videotape program provides information on the use of intensive management to control noninsulin dependent diabetes mellitus (NIDDM). The program emphasizes how intensive management can be integrated into an active, fulfilling lifestyle. In the program, diabetes experts describe new tools and techniques

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used to maintain tight control of blood glucose levels, and people with NIDDM show how they have made intensive management part of their lives. Topics include the use of meal planning, exercise, stress reduction, medication, and daily home blood glucose monitoring in a comprehensive program of diabetes management; the impact of exercise on reducing stress; tips for creating and staying on a realistic meal plan; the technique of blood glucose monitoring and the importance of keeping a daily diabetes control record; and the use of medication for controlling diabetes. (AA-M). •

What is Diabetes? (Non-Insulin Dependent) 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. PRICE: List price $175; discounts available. Item number DB-33. Summary: This videotape, one of a series of patient education videos, provides an overview of noninsulin-dependent diabetes mellitus (NIDDM, or Type 2). The program delivers a concise picture of how diabetes affects the way blood sugar and insulin work, and summarizes diabetes treatment and self-care skills. The program summarizes symptoms, reviews healthy eating, exercise, medication, foot care, eye care, and the association between diabetes and heart disease. 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 closedcaptioned 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 “diabetes mellitus” (or synonyms) into the “For these words:” box. The following is a typical result when searching for sound recordings on diabetes mellitus: •

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

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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 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. •

Therapeutic Dilemmas In Type II Diabetes Mellitus: Premixed Human Insulin Regimens Source: Princeton, NJ: Novo Nordisk Pharmaceuticals Inc. 199x. (audiotape). Contact: Available from Novo Nordisk Pharmaceuticals Inc. 100 Overlook Center, Suite 200, Princeton, NJ 08540-7810. (800) 727-6500. PRICE: Single copy free. Order number 000-11A. Summary: This audiotape is the first in a series of three accredited continuing education audio programs and monographs that explore controversial issues of interest to the primary care physician who treats patients with diabetes. Dr. Alan O. Marcus and Dr. Mark Mengel discuss the decision to use premixed human insulin in the patient with noninsulin-dependent diabetes mellitus (NIDDM). Their discussion includes an analysis of the daily insulin needs of the patient and the glycemic control that may be achieved by providing a balanced mixture of intermediate-acting and short-acting insulin. Clinical experience with various regimens is discussed and evaluated along with the metabolic and pharmacokinetic factors that influence clinician prescribing preferences. Common pitfalls that can be avoided by using premixed human insulin are described. The study guide includes a post-test quiz for earning Continuing Medical Education (CME) credit. 4 references. (AA-M).

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Therapeutic Dilemmas In Type II Diabetes Mellitus: Guidelines for Managing the Resistant NIDDM Patient Source: Princeton, NJ: Novo Nordisk Pharmaceuticals Inc. 199x. (audiotape). Contact: Available from Novo Nordisk Pharmaceuticals Inc. 100 Overlook Center, Suite 200, Princeton, NJ 08540-7810. (800) 727-6500. PRICE: Single copy free. Order number 000-11B. Summary: This audiotape is the second in a series of three accredited continuing education audio programs and monographs that explore controversial issues of interest to the primary care physician who treats patients with diabetes. Dr. Alan O. Marcus and Dr. Barbara Ross-Lee discuss methods of initiating insulin therapy, guidelines for use of various insulin combinations, and monitoring results to achieve optimal therapeutic benefits. Other topics include the onset and duration of action of regular and NPH

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insulins and the complications of insulin therapy. The study guide includes a post-test quiz for earning Continuing Medical Education (CME) credit. 5 references. (AA-M). •

Therapeutic Dilemmas In Type II Diabetes Mellitus: Specialized Combination Regimens for the NIDDM Patient Source: Princeton, NJ: Novo Nordisk Pharmaceuticals Inc. 199x. (audiotape). Contact: Available from Novo Nordisk Pharmaceuticals Inc. 100 Overlook Center, Suite 200, Princeton, NJ 08540-7810. (800) 727-6500. PRICE: Single copy free. Order number 000-11C. Summary: This audiotape is the third in a series of three accredited continuing education audio programs and monographs that explore controversial issues of interest to the primary care physician who treats patients with diabetes. Dr. Alan O. Marcus and Dr. Mary Elizabeth Roth discuss approaches to pharmaceutical intervention in noninsulin-dependent diabetes mellitus (NIDDM). The authors consider the use of oral hypoglycemic agents, insulin, or a combination of the two. Various aspects of combination therapy are discussed with a focus on indications, efficacy, and other implications. The study guide includes a post-test quiz for earning Continuing Medical Education (CME) credit. 20 references. (AA-M).

Bibliography: Multimedia on Diabetes Mellitus The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in diabetes mellitus (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on diabetes mellitus: •

Care of the patient with diabetes mellitus [filmstrip] Source: Trainex Corporation; Year: 1970; Format: Filmstrip; Garden Grove, Calif.: Trainex, c1970

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Diabetes mellitus: pathophysiology [filmstrip] Source: Trainex Corporation; Year: 1970; Format: Filmstrip; Garden Grove, Calif.: Trainex, c1970

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Diabetes mellitus and the kidney: part one, fluid and electrolyte loss [slide] Source: McMaster University Health Sciences; Year: 1974; Format: Slide; [Hamilton, Ont.: Health Sciences McMaster Univ.], 1974

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Diabetes mellitus and the kidney: part two, acidosis [slide] Source: McMaster University Health Sciences; Year: 1974; Format: Slide; [Hamilton, Ont.: Health Sciences McMaster Univ., 1974]

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Heart disease and diabetes mellitus [slide] Source: Herman L.Falsetti; Year: 1973; Format: Slide; [New York]: Medcom, c1973

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The I.V. GTT and other approaches to diagnosing diabetes mellitus [motion picture] Source: National Medical Audiovisual Center, in cooperation with New Jersey College of Medicine and Dentistry; Year: 1972; Format: Motion picture; [Atlanta]: The Center, 1972

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CHAPTER 9. PERIODICALS AND NEWS ON DIABETES MELLITUS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover diabetes mellitus.

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

Diabetes mellitus may increase the risk of idiopathic pulmonary fibrosis Source: Reuters Medical News Date: July 01, 2003

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Protease inhibitor use increases risk of diabetes mellitus in women Source: Reuters Industry Breifing Date: March 25, 2003

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Retinopathy in type 2 diabetes mellitus may have genetic basis Source: Reuters Medical News Date: November 22, 2002

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Low-dose ER niacin safe and effective for dyslipidemia in diabetes mellitus Source: Reuters Medical News Date: July 22, 2002

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Mother's birthweight linked to gestational diabetes mellitus risk Source: Reuters Medical News Date: May 15, 2002

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Atypical neuroleptics seen to increase the risk of diabetes mellitus somewhat Source: Reuters Medical News Date: April 30, 2002

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Taller children may be at increased risk of type 1 diabetes mellitus Source: Reuters Medical News Date: March 27, 2002

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Treatment of insulin-dependent diabetes mellitus costly in India Source: Reuters Industry Breifing Date: February 01, 2002

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Undiagnosed diabetes mellitus common in men with erectile dysfunction Source: Reuters Medical News Date: August 16, 2001

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Inflammation may have a pathogenic role in diabetes mellitus Source: Reuters Medical News Date: July 18, 2001 The NIH

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

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

Newsletters on Diabetes Mellitus Find newsletters on diabetes mellitus using the Combined Health Information Database (CHID). You will need to use the “Detailed Search” option. To access CHID, go to the following hyperlink: http://chid.nih.gov/detail/detail.html. Limit your search to “Newsletter” and “diabetes mellitus.” 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.” Type “diabetes mellitus” (or synonyms) into the “For these words:” box. The following list was generated using the options described above: •

Kidney Disease? Know Your Options Source: Lexington, MA: Kidney Options. 2002. 2 p. Contact: Available from Kidney Options. 95 Hayden Avenue, Lexington, MA 124209192. (866) 543-6391. Website: www.kidneyoptions.com. PRICE: Full-text available online at no charge. Summary: Kidney disease happens when there is damage to the filters in the kidneys. These filters remove waste products and excess fluid from the blood. There are many causes of kidney disease, including high blood pressure (hypertension) and diabetes mellitus. This newsletter briefly outlines the treatment options for people with kidney

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disease. Topics include hemodialysis, peritoneal dialysis, kidney transplants, the role of pre-dialysis education, social services, the importance of appropriate diet therapy, and commonly asked questions about transplants. The newsletter includes a brief profile of a transplant patient. Readers are referred to a web site (www.kidneyoptions.com) for more information.

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 “diabetes mellitus” (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 diabetes mellitus: •

Rheumatic Manifestations of Diabetes Mellitus Source: Bulletin on the Rheumatic Diseases. 49(5): 1-4. 2000. Contact: Available from Arthritis Foundation. 1330 West Peachtree Street, Atlanta, GA 30309. (404) 872-7100. Fax (404) 872-9559. Summary: This newsletter article provides health professionals with information on the rheumatic manifestations of diabetes mellitus. There are several musculoskeletal disorders that occur either exclusively or predominantly in people who have diabetes, so the presence of this disease must be recognized when evaluating and treating patients who have musculoskeletal complaints. Syndromes related to increased collagen deposition include cheiroarthropathy, frozen shoulder, flexor tenosynovitis, and Dupuytren's contracture. Syndromes related to neuropathy, a frequent complication of diabetes, include Charcot's arthropathy and reflex sympathetic dystrophy. Other syndromes and conditions that people who have diabetes may be more prone to are osteoarthritis, osteopenia, diffuse idiopathic skeletal hyperostosis, infections, gout, pseudogout, carpal tunnel syndrome, and rheumatoid arthritis. The effect of various treatment modalities on musculoskeletal complaints in people who have diabetes must also be considered. Drugs commonly used for musculoskeletal conditions include nonsteroidal antiinflammatory drugs and glucocorticoids; however, these drugs may have an adverse impact on patients who also have diabetes. 1 table and 20 references.

Academic Periodicals covering Diabetes Mellitus Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to diabetes mellitus. In addition to these sources, you can search for articles covering diabetes mellitus 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.”

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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 10. 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 diabetes mellitus. 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 diabetes mellitus. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.).

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The following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to diabetes mellitus: Acarbose •

Systemic - U.S. Brands: Precose http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203498.html

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

Becaplermin •

Topical - U.S. Brands: Regranex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203460.html

Gabapentin •

Systemic - U.S. Brands: Neurontin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202732.html

Glucagon •

Systemic - U.S. Brands: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202732.html

Glyburide and Metformin •

Systemic - U.S. Brands: Glucovance http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500237.html

Insulin •

Systemic - U.S. Brands: Humulin 50/50; Humulin 70/30; Humulin 70/30 Pen; Humulin L; Humulin N; Humulin N Pen; Humulin R; Humulin R, Regular U500 (Concentrated); Humulin U; Lente; Lente Iletin II; Novolin 70/30; Novolin 70/30 PenFill; Novolin 70/30 Prefilled; Novolin L; Novoli http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203298.html

Insulin Aspart •

Systemic - U.S. Brands: NovoLog http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500253.html

Insulin Glargine •

Systemic - U.S. Brands: Lantus http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500147.html

Insulin Lispro •

Systemic - U.S. Brands: Humalog http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203622.html

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Isoxsuprine •

Systemic - U.S. Brands: Vasodilan http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202310.html

Metformin •

Systemic - U.S. Brands: Glucophage http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202756.html

Miglitol •

Systemic - U.S. Brands: Glyset http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500231.html

Nateglinide •

Systemic - U.S. Brands: Starlix http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500277.html

Niacin (Vitamin B 3 ) •

Systemic - U.S. Brands: Endur-Acin; Nia-Bid; Niac; Niacels; Niacor; Nico-400; Nicobid Tempules; Nicolar; Nicotinex Elixir; Slo-Niacin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202405.html

Pioglitazone •

Systemic - U.S. Brands: Actos http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500036.html

Repaglinide •

Systemic - U.S. Brands: Prandin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203463.html

Rosiglitazone •

Systemic - U.S. Brands: Avandia http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500022.html

Zinc Supplements •

Systemic - U.S. Brands: Orazinc; Verazinc; Zinc 15; Zinc-220; Zinca-Pak; Zincate http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202622.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

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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

269

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

•

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

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

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

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

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

•

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

•

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

•

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

•

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

•

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

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.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/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

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

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

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

•

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 Combined Health Information Database

A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “diabetes mellitus” using the “Detailed Search” option. Go directly to the following hyperlink: 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 the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “diabetes mellitus” (or synonyms) into the “For these words:” box. The following is a sample result: •

Is Diabetes Mellitus a Risk Factor for Ovarian Cancer? A Case-Control Study in Utah and Washington (United States) Source: Cancer Causes and Control. 7(4): 475-478. July 1996. Contact: Available from Rapid Science Publishers. 400 Market Street, Suite 750, Philadelphia, PA 19106. (215) 574-2210. Fax (215) 574-3533. Summary: This article is based on a study which examined diabetes as a risk factor for the various types of ovarian cancer. According to the authors, insulin resistance may coexist in clinical syndromes with hyperestrogenism and hyperandrogenism, suggesting that the ovary may be sensitive to effects of insulin. Further, insulin-like growth factor-I receptors, which are capable of binding inulin, have been identified in ovarian cancer tissue and are proposed to regulate cell growth. In a 1975 to 1987 case-control study in seven counties in Washington and Utah, researchers evaluated the association between a history of diabetes mellitus and ovarian cancer. Women recently diagnosed with ovarian cancer were identified for cases through population-based cancer reporting. Controls similar to these women with regard to age and county of residence were identified via household surveys or random digit dialing. While the study consisted of 595 cases and 1,587 controls, 27 cases (4.5 percent) and 72 controls (4.5 percent) reported a history of diabetes. An odds ratio of 0.9 resulted from the logistic regression analysis of the association between diabetes and ovarian cancer. Controlling for prior oral contraceptive use or prior pregnancy did not alter the odds ratio. In addition, none of the 20 women with nonepithelial tumors had a history of diabetes. The results of this study, as well as two cohort studies, do not support the hypothesis that diabetes is a risk factor for epithelial ovarian cancer. 1 table. 33 references. (AA-M).

•

Prevention of Diabetes Mellitus: Report of a WHO Study Group Source: Geneva, Switzerland: World Health Organization (WHO). 1994. 100 p. Contact: Available from WHO Publications Center USA. 49 Sheridan Avenue, Albany, NY 12210. (518) 436-9686. Fax (518) 436-7433. PRICE: $13.50. ISBN: 9241208449. Order Number 1100844.

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Summary: This report by an international group of experts outlines the epidemiological situation, presents the current classification and diagnostic criteria, and reviews the possibilities for the prevention of the main types of diabetes and its complications. The authors also discuss the introduction of prevention and control programs and their costeffectiveness. The report emphasizes the potential for preventing complications of diabetes and for interventions in groups at high risk of developing the disease, and urges the implementation of appropriate prevention and control strategies. 188 references. 4 appendices. (AA-M). •

Diabetes Mellitus and the Kidneys Source: in Exceptional Parent. End Stage Renal Disease: A Practical Guide for Physicians, Dietitians, Nurses, Patients, Families, and Caregivers. Englewood Cliffs, NJ: Exceptional Parent. 1999. p. 39-40. Contact: Available from Exceptional Parent. P.O. Box 1807, Englewood Cliffs, NJ 07632. (800) 535-1910. Fax (201) 947-9376. E-mail: [email protected]. Website: www.eparent.com. PRICE: $5.95. Summary: This report discusses the impact of diabetes on the kidneys. Diabetes is an endocrine disease that results from an abnormality in either the production of insulin or the way in which the body uses insulin. Type 1 generally begins in childhood and is caused by a deficiency in the amount of insulin secreted by the pancreas, whereas type 2 diabetes generally begins in adulthood and is caused by a decline in the capability of the pancreas to secrete insulin. Diabetes is the leading cause of kidney failure in the United States. The initial stage of kidney disease, which is mild, involves leakage of protein into the urine. Macroproteinuria is the next stage of kidney damage associated with diabetes. Once this stage is reached, progressive loss of kidney function is expected. With the loss of function, the concentration of toxic waste products in the blood rises. End stage renal disease occurs when kidney function reaches less than 10 to 15 percent. Risk factors for diabetic renal disease include genetic susceptibility, poor blood sugar control, and high blood pressure. Treatment, which depends on the patient's stage of disease, may include pharmacologic measures, diet therapy, dialysis, and transplantation.

•

Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Source: Diabetes Care. 23(Supplement 1): S4-S19. January 2000. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus aims to define and describe diabetes as it is currently understood, present a classification scheme that reflects the etiology or pathogenesis of the disease, provide diagnostic criteria for diabetes mellitus, and develop recommendations for testing that can help reduce the morbidity and mortality associated with diabetes. Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia that results from defects in insulin secretion, insulin action, or both. The pathogenic processes involved in the development of diabetes range from autoimmune destruction of the beta cells of the pancreas to abnormalities that result in resistance to insulin action. The classification of diabetes published in 1979 divided diabetes into insulin dependent diabetes mellitus (IDDM), noninsulin dependent diabetes mellitus (NIDDM), gestational diabetes mellitus, malnutrition-related diabetes, and other types. The Expert Committee is proposing changes to this classification scheme. One of the major changes

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is the elimination of the terms IDDM and NIDDM and the retention of the terms type 1 diabetes and type 2 diabetes. The report presents the features of immune mediated and idiopathic type 1 diabetes; type 2 diabetes; gestational diabetes; and other specific types of diabetes caused by genetic defects of the beta cell, genetic defects in insulin action, endocrinopathies, drugs, infections, and other genetic syndromes. The report also presents the rationale for revising the diagnostic criteria for diabetes and discusses the new criteria for diagnosing diabetes. The report concludes with criteria for testing for diabetes in asymptomatic, undiagnosed people. 2 figures. 6 tables. 143 references. •

Patient Education for Persons with Noninsulin Dependent Diabetes Mellitus by Primary Care Physicians: A Survey Report Source: Columbia, SC: South Carolina Department of Health and Environmental Control. 1998. 42 p. Contact: Available from South Carolina Department of Health and Environmental Control. Diabetes Control Program, Mills/Jarrett Complex, Box 101106, Columbia, SC 29211-0106. (803) 737-4129. Fax (803) 253-4001. PRICE: Single copy free. Summary: This survey report examines patient education for people with type 2 diabetes by primary care physicians in South Carolina. Because physicians provide information, guidance, and psychological reinforcement, they are central to effective patient management of diabetes. Despite the importance of physician involvement, barriers limit physician delivery of effective diabetes education. The report points out that educational efforts must be directed at both health care professionals and patients if diabetes care is to be improved. To determine the extent of physician education of patients with diabetes, a mail-back survey was distributed to a random sample of primary care physicians. Based on the results of the survey, rural physicians in South Carolina are more likely to encounter barriers when caring for people with diabetes. Among all physicians, patient noncompliance was the most commonly cited barrier. The report recommends that each of the following should be increased: patient education during doctor appointments, continuing education for physicians, and availability of certified diabetes educators and dietitians in rural areas. In addition, appropriate reimbursement for health care professionals should be supported. Three appendices include the survey that was administered, answer frequencies, and physician comments. 13 tables. 22 references. (AA-M).

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 “diabetes mellitus” (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.

15 16

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

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).

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Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 186182 3789 1111 501 161 191744

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 “diabetes mellitus” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

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/.

17

Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html.

18

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

19

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. 20 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 21

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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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/.

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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 diabetes mellitus 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 diabetes mellitus. 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 diabetes mellitus. 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 “diabetes mellitus”:

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•

Guides on diabetes mellitus Diabetes http://www.nlm.nih.gov/medlineplus/diabetes.html

•

Other guides Diabetes and Pregnancy http://www.nlm.nih.gov/medlineplus/diabetesandpregnancy.html Diabetic Diet http://www.nlm.nih.gov/medlineplus/diabeticdiet.html Diabetic Eye Problems http://www.nlm.nih.gov/medlineplus/diabeticeyeproblems.html Juvenile Diabetes http://www.nlm.nih.gov/medlineplus/juvenilediabetes.html

Within the health topic page dedicated to diabetes mellitus, the following was listed: •

General/Overviews Diabetes http://www.fda.gov/opacom/lowlit/diabetes.html Diabetes http://www.nlm.nih.gov/medlineplus/tutorials/diabetesintroductionloader.html Diabetes: A Growing Public Health Concern Source: Food and Drug Administration http://www.fda.gov/fdac/features/2002/102_diab.html What is Diabetes? http://www.ncfh.org/pateduc/en-diabetes.htm

•

Diagnosis/Symptoms A1C Test Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/a1c/test.html Diabetes: Assessing Your Risk Source: American Academy of Family Physicians http://familydoctor.org/handouts/347.html Diagnosis of Diabetes Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/diagnosis/index.htm Glucose Tests Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/glucose/test.html Microalbumin Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/microalbumin/test.html

Patient Resources

Oral Glucose Tolerance Test Source: National Institutes of Health, Clinical Center http://www.cc.nih.gov/ccc/patient_education/procdiag/oralglu.pdf Serum Creatinine Test Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=SA00007 •

Treatment Diabetes Pills Source: Food and Drug Administration http://www.fda.gov/diabetes/pills.html Diabetes: New Treatments Source: American Academy of Family Physicians http://familydoctor.org/handouts/388.html Giving a Subcutaneous Injection Source: National Institutes of Health, Clinical Center http://www.cc.nih.gov/ccc/patient_education/pepubs/subq.pdf Medicines for People with Diabetes Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/medicines_ez/index.htm Oral Diabetes Medications Source: American Diabetes Association http://www.diabetes.org/type2/medical/oralmeds.jsp

•

Alternative Therapy Alternative Therapies for Diabetes Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/alternativetherapies/index.htm

•

Coping Coping with Diabetes Complications Source: American Diabetes Association http://www.diabetes.org/info/complications/other/default.jsp Diabetes: Helping a Family Member Who Has Diabetes Source: American Academy of Family Physicians http://familydoctor.org/handouts/353.html Q&A: Lifestyle Adjustments When You Have Diabetes Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DA00018 Tips for Helping a Person with Diabetes Source: National Diabetes Education Program http://www.ndep.nih.gov/diabetes/pubs/TipsHelping_Eng.pdf

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Specific Conditions/Aspects Alcohol Source: American Diabetes Association http://www.diabetes.org/health/nutrition/alcohol/alcohol.jsp Aspirin Therapy for People with Diabetes Source: American Diabetes Association http://www.diabetes.org/main/info/aspirin.jsp Blood Pressure Control in People with Type 2 Diabetes Recommendations from the American College of Physicians Source: American College of Physicians http://www.annals.org/cgi/content/full/138/7/I-70

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Cholesterol, Triglycerides, and Diabetes http://www.diabetes.org/main/uedocuments/ADACholesterolPatient.pdf Depression and Diabetes Source: National Institute of Mental Health http://www.nimh.nih.gov/publicat/depdiabetes.cfm Diabetes and Common Mouth Problems Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DA00013 Diabetes and Vaccines Source: Centers for Disease Control and Prevention http://www.cdc.gov/nip/vacsafe/concerns/Diabetes/default.htm Diabetes in African Americans Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/africanamerican/index.htm Diabetes in Hispanic Americans Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/hispanicamerican/index.htm Diabetic Arthritis Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AN00526 Diabetic Coma: A Serious but Controllable Condition Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DA00022 Financial Help for Diabetes Care Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/financialhelp/index.htm Frequently Asked Questions about Importing Beef Insulin for Personal Use Source: Center for Drug Evaluation and Research http://www.fda.gov/cder/drug/beefinsulin/default.htm Gastroparesis and Diabetes Source: National Digestive Diseases Information Clearinghouse http://digestive.niddk.nih.gov/ddiseases/pubs/gastroparesis/index.htm

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High Blood Pressure and Diabetes Source: American Diabetes Association http://www.diabetes.org/main/uedocuments/HighBloodPressure-English.pdf Hyperglycemia (High Blood Sugar) Source: American Diabetes Association http://www.diabetes.org/type2/medical/hyperglycemia/default.jsp Hyperinsulinemia Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HQ00896 Hyperosmolar Hyperglycemic Nonketotic Syndrome (HHNS) Source: American Diabetes Association http://www.diabetes.org/type2/medical/HHNS.jsp If You Have Diabetes, Talk to Your Doctor about Your Increased Risk for Heart Disease and Stroke http://www.diabetes.org/main/uedocuments/ADALinkQA.pdf Insulin Resistance and Pre-Diabetes Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/insulinresistance/index.htm JAMA Patient Page: Safe Driving for People with Diabetes Source: American Medical Association http://www.medem.com/MedLB/article_detaillb.cfm?article_ID=ZZZRHSKYMA C&sub_cat=268 Liver Disease and Diabetes Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AN00193 Medicare Coverage of Diabetes Related Supplies and Services Source: Centers for Medicare & Medicaid Services http://www.medicare.gov/Health/Diabetes.asp Pima Indians: Pathfinders for Health Source: National Institute of Diabetes and Digestive and Kidney Diseases http://diabetes.niddk.nih.gov/dm/pubs/pima/index.htm Prevent Diabetes Problems: Keep Your Heart and Blood Vessels Healthy Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/complications_heart/index.htm Prevent Diabetes Problems: Keep Your Teeth and Gums Healthy Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/complications_teeth/index.htm Skin Care Source: American Diabetes Association http://www.diabetes.org/main/health/body_care/skin/default.jsp Stress Source: American Diabetes Association http://www.diabetes.org/health/stress/stress.jsp

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Take Care of Your Heart. Manage Your Diabetes Source: National Diabetes Education Program http://www.ndep.nih.gov/diabetes/pubs/TCH_AsAm_flyer_Eng.pdf What Is Hypoglycemia? (Low Blood Sugar) Source: American Diabetes Association http://www.diabetes.org/type2/medical/hypoglycemia/default.jsp When You're Sick Source: American Diabetes Association http://www.diabetes.org/type2/living/sick/default.jsp •

Children Diabetes in Children and Adolescents Source: National Diabetes Education Program http://ndep.nih.gov/diabetes/youth/youth_FS.htm MEDLINEplus: Juvenile Diabetes Source: National Library of Medicine http://www.nlm.nih.gov/medlineplus/juvenilediabetes.html Tips for Kids with Type 2 Diabetes: Be Active Source: National Diabetes Education Program http://ndep.nih.gov/diabetes/pubs/Youth_Tips_Active.pdf Tips for Kids with Type 2 Diabetes: What Is Diabetes? Source: National Diabetes Education Program http://ndep.nih.gov/diabetes/pubs/Youth_Tips_Diabetes.pdf

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From the National Institutes of Health 7 Principles for Controlling Your Diabetes for Life Source: National Diabetes Education Program http://ndep.nih.gov/diabetes/control/principles.htm Diabetes Overview Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm Your Guide to Diabetes: Type 1 and Type 2 Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/type1and2/index.htm

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Journals/Newsletter Diabetes Dateline Source: National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/health/diabetes/dateline/index.htm

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Latest News Buckwheat Holds Promise for Diabetes Source: 11/25/2003, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_14836 .html

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Cinnamon May Cut Blood Sugar Levels Source: 11/25/2003, United Press International http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_14842 .html Fiber Does Not Explain Rye Bread's Insulin Effect Source: 11/24/2003, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_14816 .html HHS Releases 2003 National Diabetes Estimates Source: 11/13/2003, Dept. of Health and Human Services http://www.hhs.gov/news/press/2003pres/20031113.html High Risk of Narrowed Blood Vessels in Legs for People with Diabetes Source: 11/21/2003, American Diabetes Association http://ada.yellowbrix.com/pages/ada/Story.nsp?story_id=43948162&ID=ada More News on Diabetes http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/alphanews_d.html#D iabetes Prevalence of Self-Reported Heart Disease and Stroke among U.S. Adults with and without Diabetes Source: 11/06/2003, Centers for Disease Control and Prevention http://www.cdc.gov/od/oc/media/pressrel/fs031106.htm •

Law and Policy Fighting Discrimination Based on Diabetes Source: American Diabetes Association http://www.diabetes.org/main/community/advocacy/discrimination.jsp Traveling with Diabetes Supplies Source: American Diabetes Association http://www.diabetes.org/main/community/advocacy/travel.jsp

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Men Diabetes Can Affect Men's Sexual Health http://www.diabetes.org/main/uedocuments/Channel16-Men.pdf Diabetes Facts & Figures among Men Source: American Diabetes Association http://www.diabetes.org/info/facts/facts_men.jsp Erectile Dysfunction in Diabetes: Keys to Prevention Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DA00045

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Organizations American Diabetes Association http://www.diabetes.org/

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CDC's Diabetes Public Health Resource Source: National Center for Chronic Disease Prevention and Health Promotion http://www.cdc.gov/diabetes/ National Diabetes Education Program http://ndep.nih.gov/ National Diabetes Information Clearinghouse Source: National Institute of Diabetes and Digestive and Kidney Diseases http://diabetes.niddk.nih.gov/ National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/ •

Prevention/Screening Am I at Risk for Type 2 Diabetes? Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/riskfortype2/index.htm Lipid Panel Test: Gauging Your Heart Disease Risk Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=SA00006 Task Force Issues Two Recommendations on Screening for Diabetes in Adults and Pregnant Women Source: Agency for Healthcare Research and Quality http://www.ahrq.gov/news/press/pr2003/diabscpr.htm Your Game Plan for Preventing Type 2 Diabetes Source: National Diabetes Education Program http://ndep.nih.gov/diabetes/pubs/GP_Booklet.pdf

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Research Blood Pressure Drug Losartan Appears to Benefit the Kidneys of People with Type 2 Diabetes Who Do Not Have High Blood Pressure Source: American College of Physicians http://www.annals.org/cgi/content/full/139/2/I-24 Comparison of Three Insulin Regimens.for Treating Type 2 Diabetes Source: American College of Physicians http://www.annals.org/cgi/content/full/138/12/I-33 Diabetes and Hypertension Combo Invite Silent Stroke Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3015383 Diabetes Control and Complications Trial (DCCT) Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/control/index.htm Diabetes Prevention Program Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/preventionprogram/index.htm

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Diabetes Prevention Program: Questions and Answers Source: National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/patient/dpp/dpp-q&a.htm Diabetic Women Gain Significant Health Benefits from Eating Fish Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3010518 Eating Breakfast May Reduce Risk of Obesity, Diabetes, Heart Disease Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3009715 Heart Health Should Be the Front Line of Diabetes Care Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3002623 Less Fit Teens More Likely to Have Precursor to Diabetes Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3009762 Lower Blood Pressure Decreases Heart Attack Risk in Diabetics with Clogged Leg Arteries Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3007755 Many Obese Youth Have Condition That Precedes Type 2 Diabetes Source: National Institute of Child Health and Human Development http://www.nih.gov/news/pr/mar2002/nichd-13.htm Men with 3 of 5 Metabolic Abnormalities Risk Diabetes, Heart Disease Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3013637 NIH Reports Progress in Diabetes Research Source: National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/welcome/releases/10-23-02.htm Postmenopausal Hormone Therapy and Blood Sugar Source: American College of Physicians http://www.annals.org/cgi/content/full/138/1/I-10 Short Thighs Linked to Greater Likelihood of Diabetes Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3009764 Study Examines Cost-Effectiveness of Treatment Interventions for Type 2 Diabetes Source: Centers for Disease Control and Prevention http://www.cdc.gov/od/oc/media/pressrel/r020514.htm Use of Common Laboratory Tests to Identify People with Insulin Resistance Source: American College of Physicians http://www.annals.org/cgi/content/full/139/10/I-16

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Statistics Diabetes and Women's Health Across the Life Stages: A Public Health Perspective Source: National Center for Chronic Disease Prevention and Health Promotion http://www.cdc.gov/diabetes/pubs/women/index.htm Diabetes Statistics Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm Diabetes: Disabling, Deadly, and on the Rise http://www.cdc.gov/nccdphp/aag/aag_ddt.htm Eliminate Disparities in Diabetes Source: Centers for Disease Control and Prevention, Office of Minority Health http://www.cdc.gov/omh/AMH/factsheets/diabetes.htm FASTATS: Diabetes Source: National Center for Health Statistics http://www.cdc.gov/nchs/fastats/diabetes.htm HHS Issues Report Charting Steady Gains in Americans' Health, Though Diabetes Remains Growing Concern Source: Centers for Disease Control and Prevention http://www.cdc.gov/od/oc/media/pressrel/r031003.htm New State Data Show Obesity and Diabetes Still On the Rise Source: Centers for Disease Control and Prevention http://www.cdc.gov/od/oc/media/pressrel/r021231.htm Pre-Diabetes in the United States in 2000 Source: National Center for Chronic Disease Prevention and Health Promotion http://www.cdc.gov/diabetes/pubs/factsheets/prediabetes.htm Prevalence of Self-Reported Heart Disease and Stroke among U.S. Adults with and without Diabetes Source: Centers for Disease Control and Prevention http://www.cdc.gov/od/oc/media/pressrel/fs031106.htm Preventing Diabetes and Its Complications Source: National Center for Chronic Disease Prevention and Health Promotion http://www.cdc.gov/nccdphp/pe_factsheets/pe_ddt.htm Study Shows Sharp Rise in the Cost of Diabetes Nationwide Source: Dept. of Health and Human Services http://www.os.dhhs.gov/news/press/2003pres/20030227a.html

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Teenagers Diabetes in Children and Adolescents Source: National Diabetes Education Program http://ndep.nih.gov/diabetes/youth/youth_FS.htm

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Women Diabetes Can Affect Women's Sexual Health http://www.diabetes.org/main/uedocuments/Channel15-Women.pdf

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Diabetes Facts & Figures among Women Source: American Diabetes Association http://www.diabetes.org/info/facts/facts_women.jsp Menopause and Diabetes Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DA00038 Overcoming the Challenges of Blood Sugar Control during Menstruation Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DA00041 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 diabetes mellitus. 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: •

Diabetes Mellitus Source: in Kerestes-Smith, J.; Chua, G.; Sullivan, K. Guidelines for Nutritional Care. Ann Arbor, MI: Food and Nutrition Services, University of Michigan Medical Center. 1995. Chapter 49, p. 49.1-49.16. Contact: Available from Guidelines for Nutritional Care. Food and Nutrition Services, 2C227-0056, University of Michigan Hospitals, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0056. (313) 936-5199. Fax (313) 936-5195. PRICE: $79.00 including shipping and handling (as of 1996). ISBN: 0964799405. Summary: This chapter on dietary recommendations for individuals with diabetes mellitus is from a manual on the impact nutrition has on promoting health and in preventing and treating disease. The diet differentiates between insulin-dependent diabetes (IDDM), noninsulin-dependent diabetes (NIDDM), gestational diabetes, and impaired glucose tolerance. Included are sections detailing indications for use, contraindications, a description of the diet including a brief physiological and/or biochemical rationale, guidelines for nutritional management, nutrient adequacy, ordering procedures, and references for both the health care providers and the layperson. 11 tables. 41 references.

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Non-Insulin Dependent Diabetes Mellitus (NIDDM) Source: West Hills, CA: Nutrition Prescriptives. 1996. 2 p.

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Contact: Available from Nutrition Prescriptives. P.O. Box 4417, West Hills, CA 91308. (818) 347-4760. Fax (818) 992-4319. PRICE: $10.00 for reproducible master copy. Order number: P10. Summary: This copier-ready, interactive counseling tool is designed to help health care professionals educate patients about type 2 diabetes. It provides an assessment and screening guide that allows health care professionals to check the patient's nutrition problems and record the date each problem was discussed. The tool is designed to facilitate discussion with the patient of possible eating behavior problems in the areas of quality, quantity, and frequency of intake. It points out that nutrition education goals include facilitating the patient's ability to both understand and apply type 2 diabetes nutrition and diet principles. The importance of involving the patient as an active participant in the counseling process is stressed. •

Guidelines for Optometric Care of Patients with Diabetes Mellitus Source: St. Louis, MO: American Optometric Association. 1994. 2 p. Contact: Available from American Optometric Association. Order Department, 243 North Lindbergh Boulevard, St. Louis, MO 63141-7881. (800) 262-2210. Fax (314) 9914101. PRICE: Single copy free. Summary: This fact sheet for optometrists presents eye care guidelines for patients with diabetes mellitus. The fact sheet stresses that optometrists, as primary health care providers, have an opportunity to reduce the complications of diabetes through early detection, management, and appropriate referral of diabetes-related eye disease and related systemic conditions. Topics by the guidelines include patient education; the initial eye exam after the patient is diagnosed with diabetes; classification of diabetic retinopathy; scheduling of patient followup; managing pregnant patients with diabetes; consulting with other health care providers, including ophthalmologists; and managing visually impaired patients with diabetes. Two tables summarize the types of vision loss related to diabetes mellitus and the nonretinal ocular complications of diabetes.

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Diabetes Mellitus, Insulin-Dependent (Type I Diabetes; IDDM) Source: in Griffith, H.W. Instructions for Patients. 5th ed. Philadelphia, PA: W.B. Saunders Company. 1994. p. 121. Contact: Available from W.B. Saunders Company. Book Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887-4430. (800) 545-2522. Fax (800) 874-6418. PRICE: $49.95. ISBN: 0721649300 (English); 0721669972 (Spanish). Summary: This fact sheet on insulin-dependent diabetes mellitus is from a compilation of instructions for patients, published in book format. The fact sheet provides information in three sections: basic information, including a description of the condition, frequent signs and symptoms, causes, risk factors, preventive measures, expected outcome, and possible complications; treatment, including general measures, medication, activity guidelines, and diet; and when to contact one's health care provider. The fact sheet can be photocopied and distributed to patients as a reinforcement of oral instructions and as a teaching tool. The book in which the fact sheet appears is available in English or Spanish.

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Diabetes Mellitus, Non-Insulin-Dependent (Type II Diabetes; NIDDM) Source: in Griffith, H.W. Instructions for Patients. 5th ed. Philadelphia, PA: W.B. Saunders Company. 1994. p. 122.

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Contact: Available from W.B. Saunders Company. Book Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887-4430. (800) 545-2522. Fax (800) 874-6418. PRICE: $49.95. ISBN: 0721649300 (English); 0721669972 (Spanish). Summary: This fact sheet on noninsulin-dependent diabetes mellitus is from a compilation of instructions for patients, published in book format. The fact sheet provides information in three sections: basic information, including a description of the condition, frequent signs and symptoms, causes, risk factors, preventive measures, expected outcome, and possible complications; treatment, including general measures, medication, activity guidelines, and diet; and when to contact one's health care provider. The fact sheet can be photocopied and distributed to patients as a reinforcement of verbal instructions and as a teaching tool. The book in which the fact sheet appears is available in English or Spanish. •

Ayurvedic Interventions for Diabetes Mellitus: A Systematic Review Source: Rockville, MD: Agency for Healthcare Research and Quality. June 2001. 5 p. Contact: Available from National Center for Complementary and Alternative Medicine Clearinghouse. P.O. Box 7923, Gaithersburg, MD 20898. (888) 644-6226; INTERNATIONAL PHONE: (301) 519-3153; TTY: (866) 464-3615; FAX: (866) 464-3616; EMAIL: [email protected]. PRICE: Free. Publication Number: D154. Summary: This fact sheet, produced by the Agency for Healthcare Research and Quality, summarizes the Evidence Report/Technology Assessment titled 'Ayurvedic Interventions for Diabetes Mellitus: A Systematic Review.' It provides an overview of the Ayurvedic medicine/therapies for diabetes report, including its purpose and the search methods used, specific questions addressed in the project, evidence reporting, methodology, findings, and future research. The fact sheet offers instructions on how to download the full evidence report. 1 reference.

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Making a Difference in Diabetes Mellitus: Diabetic Nephropathy Source: Indianapolis, IN: Indiana University Diabetes Research and Training Center. 1995. (instructional package). Contact: Available from David Marrero, Indiana University Diabetes Research and Training Center. 250 University Boulevard, Room 122, Indianapolis, IN 46202. (317) 2780900. PRICE: Free to participating physicians; contact producer for more information. Summary: This instructional package informs physicians of the recent significant advances in diabetic nephropathy detection and treatment and, ultimately, to improve care. The package includes a booklet that focuses on American Diabetes Association guidelines for nephropathy screening, methods of albumin screening, and use of ACE inhibitor therapy. Also included are sample tablets of MicroBumintest tablets; implementation aids, including a pull-out wallchart, patient handout, and samples of patient chart stickers; and a reply card for physicians to request additional information on urine albumin screening, ACE inhibitor therapy, and other topics. 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

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located at http://www.guideline.gov/ by using the keyword “diabetes mellitus” (or synonyms). The following was recently posted: •

ACR Appropriateness Criteriaâ„¢ for imaging diagnosis of osteomyelitis in patients with diabetes mellitus Source: American College of Radiology - Medical Specialty Society; 1995 (revised 1999); 8 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2424&nbr=1650&a mp;string=diabetes+AND+mellitus

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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=diabetes+AND+mellitus

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Care of the patient with diabetes mellitus. 2nd edition Source: American Optometric Association - Professional Association; 1998 (Second Edition); 69 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1986&nbr=1212&a mp;string=diabetes+AND+mellitus

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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=diabetes+AND+mellitus

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Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus Source: National Academy of Clinical Biochemistry - Professional Association; 2002; 37 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3521&nbr=2747&a mp;string=diabetes+AND+mellitus

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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=diabetes+AND+mellitus

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Management of diabetes mellitus Source: University of Michigan Health System - Academic Institution; 1996 May (revised 1998 Apr) http://www.guideline.gov/summary/summary.aspx?doc_id=1783&nbr=1009&a mp;string=diabetes+AND+mellitus

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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=diabetes+AND+mellitus

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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=diabetes+AND+mellitus

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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=diabetes+AND+mellitus

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Physical activity/exercise and diabetes mellitus Source: American College of Sports Medicine - Medical Specialty Society; 1990 February (revised 1999; republished 2003 Jan); 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3571&nbr=2797&a mp;string=diabetes+AND+mellitus

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Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Source: American Diabetes Association - Professional Association; 1997 (revised 1999; republished 2003 Jan); 16 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3565&nbr=2791&a mp;string=diabetes+AND+mellitus

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Screening for gestational diabetes mellitus: recommendations and rationale Source: United States Preventive Services Task Force - Independent Expert Panel; 1996 (revised 2003 Feb); 3 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3493&nbr=2719&a mp;string=diabetes+AND+mellitus

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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=diabetes+AND+mellitus

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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=diabetes+AND+mellitus

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The American Association of Clinical Endocrinologists medical guidelines for the management of diabetes mellitus: the AACE system of intensive diabetes selfmanagement--2002 update Source: American Association of Clinical Endocrinologists - Medical Specialty Society; 2000 January (revised 2002 Jan); 43 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3172&nbr=2398&a mp;string=diabetes+AND+mellitus

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The evidence base for tight blood pressure control in the management of type 2 diabetes mellitus Source: American College of Physicians - Medical Specialty Society; 2003 April 1; 6 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3739&nbr=2965&a mp;string=diabetes+AND+mellitus

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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=diabetes+AND+mellitus

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Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

Ayurvedic Interventions for Diabetes Mellitus: A Systematic Review (Summary) Summary: The objective of this evidence report was to conduct a search of the published literature on the use of Ayurvedic medicine/therapies for the treatment of health conditions and, on the basis of that Source: Agency for Healthcare Research and Quality http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6475

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Diabetes in American Indians and Alaska Natives Summary: Facts, statistics and a general overview of diabetes mellitus as it affects American Indians and Alaska Natives. The focus here is on type 2 diabetes, the type most commonly found in this group. Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6126

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Diabetes in Asian and Pacific Islander Americans Summary: Facts, statistics and a general overview of diabetes mellitus as it affects Asian and Pacific Islander Americans. The focus here is on type 2 diabetes, the type most commonly found in this group. Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6125

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Diabetes Insipidus Summary: Describes diabetes insipidus and the types of diabetes insipidus, including central, nephrogenic, dipsogenic, and gestational. Differentiates diabetes insipidus and diabetes mellitus. Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6498

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Lower Extremity Amputation Prevention Program (LEAP) Summary: A comprehensive prevention program developed at the Bureau of Primary Health Care that can dramatically reduce lower extremity amputations in individuals with diabetes mellitus, Hansen's disease, or Source: Bureau of Primary Health Care, Health Resources and Services Administration http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=3549 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 diabetes mellitus. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

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

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

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

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

•

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

•

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 diabetes mellitus. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with diabetes mellitus. 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 diabetes mellitus. For more information,

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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 “diabetes mellitus” (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 “diabetes mellitus”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “diabetes mellitus” (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 “diabetes mellitus” (or a synonym) into the search box, and click “Submit Query.”

297

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.

298 Diabetes Mellitus

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

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

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

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

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/

•

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.

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•

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

•

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

•

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

•

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

•

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

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

300 Diabetes Mellitus

•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

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/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

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

•

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/

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•

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

•

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/

302 Diabetes Mellitus

•

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

303

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

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

•

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

•

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

•

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

•

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

•

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

•

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

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

Basic Guidelines for Diabetes Mellitus Diabetes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001214.htm Diabetes mellitus Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001214.htm Iddm Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000305.htm Insulin-dependent diabetes mellitus Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000305.htm

•

Signs & Symptoms for Diabetes Mellitus Ataxia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003198.htm

304 Diabetes Mellitus

Diarrhea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003126.htm Dizziness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003093.htm Edema Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm Hypotension Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003083.htm Impotence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003164.htm Pallor Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003244.htm Paresthesias Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003206.htm Sensory loss Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003206.htm Syncope Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003092.htm Ulcers Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003228.htm Weakness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003174.htm •

Background Topics for Diabetes Mellitus Exercise Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001941.htm Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Peripheral Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002273.htm Physical examination Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002274.htm

Online Glossaries 305

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

307

DIABETES MELLITUS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 1-phosphate: A drug that halts cell suicide in human white blood cells. [NIH] 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] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablation: The removal of an organ by surgery. [NIH] Abscess: Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. [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] Acculturation: Process of cultural change in which one group or members of a group assimilates various cultural patterns from another. [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] 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] Acetylcysteine: The N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. [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] Actin: Essential component of the cell skeleton. [NIH] Acuity: Clarity or clearness, especially of the vision. [EU] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH]

308 Diabetes Mellitus

Acyl: Chemical signal used by bacteria to communicate. [NIH] Acylation: The addition of an organic acid radical into a molecule. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Deaminase: An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Since there are wide tissue and species variations in the enzyme, it has been used as a tool in the study of human and animal genetics and in medical diagnosis. EC 3.5.4.4. [NIH] Adenosine Monophosphate: Adenylic acid. Adenine nucleotide containing one phosphate group esterified to the sugar moiety in the 2'-, 3'-, or 5'-position. [NIH] Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [NIH] 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] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a wound. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [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,

Dictionary 309

androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [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] Adrenergic beta-Antagonists: Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic betaantagonists are used for treatment of hypertension, cardiac arrythmias, angina pectoris, glaucoma, migraine headaches, and anxiety. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerobic Exercise: A type of physical activity that includes walking, jogging, running, and dancing. Aerobic training improves the efficiency of the aerobic energy-producing systems that can improve cardiorespiratory endurance. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [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] Aged, 80 and Over: A person 80 years of age and older. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Akathisia: 1. A condition of motor restlessness in which there is a feeling of muscular

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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] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Albuminuria: More than normal amounts of a protein called albumin in the urine. Albuminuria may be a sign of kidney disease. [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] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1. [NIH] Allantois: An embryonic diverticulum of the hindgut of reptiles, birds, and mammals; in man its blood vessels give rise to those of the umbilical cord. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Alpha Cell: A type of cell in the pancreas (in areas called the islets of Langerhans). Alpha cells make and release a hormone called glucagon, which raises the level of glucose (sugar) in the blood. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons,

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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 Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [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] Aminopyridines: Pyridines substituted in any position with an amino group. May be hydrogenated, but must retain at least one double bond. [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] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]

Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Amylase: An enzyme that helps the body digest starches. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Amyloid Neuropathies: Protein found in the senile plaques. [NIH] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some

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types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anabolic: Relating to, characterized by, or promoting anabolism. [EU] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] 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. [NIH]

Anaphylactic: Pertaining to anaphylaxis. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anaphylaxis: An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. [NIH] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anastomosis: A procedure to connect healthy sections of tubular structures in the body after the diseased portion has been surgically removed. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH]

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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] Angiodysplasia: Degenerative, acquired lesions consisting of distorted, dilated, thin-walled vessels lined by vascular endothelium. This pathological state is seen especially in the gastrointestinal tract and is frequently a cause of upper and lower gastrointestinal hemorrhage in the elderly. [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] Angiogenesis Factor: Substance causing proliferation of new blood vessels. It is found in tissues with high metabolic requirements, such as the retina, and in certain cancers. The factor is also released by hypoxic macrophages at the edges or outer surfaces of wounds and initiates revascularization in wound healing. [NIH] Angiography: Radiography of blood vessels after injection of a contrast medium. [NIH] Angiopathy: Disease of the blood vessels (arteries, veins, and capillaries) that occurs when someone has diabetes for a long time. There are two types of angiopathy: macroangiopathy and microangiopathy. In macroangiopathy, fat and blood clots build up in the large blood vessels, stick to the vessel walls, and block the flow of blood. In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. Then the cells, for example, the ones in the center of the eye, do not get enough blood and may be damaged. [NIH] Angiotensin converting enzyme inhibitor: A drug used to decrease pressure inside blood vessels. [NIH] Angiotensin-Converting Enzyme Inhibitors: A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. [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] Ankle: That part of the lower limb directly above the foot. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anorectal: Pertaining to the anus and rectum or to the junction region between the two. [EU] 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

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supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antecedent: Existing or occurring before in time or order often with consequential effects. [EU]

Anterior Cerebral Artery: Artery formed by the bifurcation of the internal carotid artery. Branches of the anterior cerebral artery supply the caudate nucleus, internal capsule, putamen, septal nuclei, gyrus cinguli, and surfaces of the frontal lobe and parietal lobe. [NIH] Antiallergic: Counteracting allergy or allergic conditions. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Antidepressant: A drug used to treat depression. [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] Antihypertensive Agents: Drugs used in the treatment of acute or chronic hypertension regardless of pharmacological mechanism. Among the antihypertensive agents are diuretics (especially diuretics, thiazide), adrenergic beta-antagonists, adrenergic alpha-antagonists, angiotensin-converting enzyme inhibitors, calcium channel blockers, ganglionic blockers, and vasodilator agents. [NIH] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH]

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Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] 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 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] Antipsychotic Agents: Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in schizophrenia, senile dementia, transient psychosis following surgery or myocardial infarction, etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. [NIH] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Apnea: A transient absence of spontaneous respiration. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes

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associated with tumor growth. [NIH] Appendicitis: Acute inflammation of the vermiform appendix. [NIH] Aqueous: Having to do with water. [NIH] Aqueous fluid: Clear, watery fluid that flows between and nourishes the lens and the cornea; secreted by the ciliary processes. [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] Aromatic: Having a spicy odour. [EU] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arsenicals: Inorganic or organic compounds that contain arsenic. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriography: A procedure to x-ray arteries. The arteries can be seen because of an injection of a dye that outlines the vessels on an x-ray. [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] Arthropathy: Any joint disease. [EU] Articular: Of or pertaining to a joint. [EU] Asbestos: Fibrous incombustible mineral composed of magnesium and calcium silicates with or without other elements. It is relatively inert chemically and used in thermal insulation and fireproofing. Inhalation of dust causes asbestosis and later lung and gastrointestinal neoplasms. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asymptomatic: Having no signs or symptoms of disease. [NIH]

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Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atherogenic: Causing the formation of plaque in the lining of the arteries. [NIH] Atopic: Pertaining to an atopen or to atopy; allergic. [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 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] 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] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] B cells: White blood cells that develop from bone marrow and produce antibodies. Also called B lymphocytes. [NIH] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [NIH] Backcross: A cross between a hybrid and either one of its parents. [NIH]

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Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] 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] 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] Behavior Therapy: The application of modern theories of learning and conditioning in the treatment of behavior disorders. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [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 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]

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Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biochemical reactions: In living cells, chemical reactions that help sustain life and allow cells to grow. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Birth Order: The sequence in which children are born into the family. [NIH] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [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 Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood 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.

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[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 Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Boron: A trace element with the atomic symbol B, atomic number 5, and atomic weight 10.81. Boron-10, an isotope of boron, is used as a neutron absorber in boron neutron capture therapy. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] 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] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchoconstriction: Diminution of the caliber of a bronchus physiologically or as a result of pharmacological intervention. [NIH] Buformin: An oral hypoglycemic agent that inhibits gluconeogenesis, increases glycolysis, and decreases glucose oxidation. [NIH] Bursitis: Inflammation of a bursa, occasionally accompanied by a calcific deposit in the underlying supraspinatus tendon; the most common site is the subdeltoid bursa. [EU]

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Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium channel blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools. Since they are inducers of vascular and other smooth muscle relaxation, they are used in the drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms. [NIH] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [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 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] Capillary Fragility: The lack of resistance, or susceptibility, of capillaries to damage or disruption under conditions of increased stress. [NIH] 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] 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] Carboxy: Cannabinoid. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both

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genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carpal Tunnel Syndrome: A median nerve injury inside the carpal tunnel that results in symptoms of pain, numbness, tingling, clumsiness, and a lack of sweating, which can be caused by work with certain hand and wrist postures. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] 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] Catechin: Extracted from Uncaria gambier, Acacia catechu and other plants; it stabilizes collagen and is therefore used in tanning and dyeing; it prevents capillary fragility and abnormal permeability, but was formerly used as an antidiarrheal. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU]

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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] Celiac Disease: A disease characterized by intestinal malabsorption and precipitated by gluten-containing foods. The intestinal mucosa shows loss of villous structure. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell 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] Cell Cycle Proteins: Proteins that control the cell division cycle. This family of proteins includes a wide variety of classes, including cyclin-dependent kinases, mitogen-activated kinases, cyclins, and phosphoprotein phosphatases (phosphoprotein phosphatase) as well as their putative substrates such as chromatin-associated proteins, cytoskeletal proteins, and transcription factors. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Membrane Structures: Structures which are part of the cell membrane or have cell membrane as a major part of their structure. [NIH] Cell 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 Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [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] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw

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material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [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] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [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] Checkup: A general physical examination. [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] 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] 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]

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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] Chorion: The outermost extraembryonic membrane. [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] 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 Arteries: Three groups of arteries found in the eye which supply the iris, pupil, sclera, conjunctiva, and the muscles of the iris. [NIH] Ciliary processes: The extensions or projections of the ciliary body that secrete aqueous humor. [NIH] Circulatory system: The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system. [NIH] 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] 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,

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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 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] Coal: A natural fuel formed by partial decomposition of vegetable matter under certain environmental conditions. [NIH] Cod Liver Oil: Oil obtained from fresh livers of the cod family, Gadidae. It is a source of vitamins A and D. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognitive behavior therapy: A system of psychotherapy based on the premise that distorted or dysfunctional thinking, which influences a person's mood or behavior, is common to all psychosocial problems. The focus of therapy is to identify the distorted thinking and to replace it with more rational, adaptive thoughts and beliefs. [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] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is

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differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colony-Stimulating Factors: Glycoproteins found in a subfraction of normal mammalian plasma and urine. They stimulate the proliferation of bone marrow cells in agar cultures and the formation of colonies of granulocytes and/or macrophages. The factors include interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), macrophage colonystimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GMCSF). [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Colorectal Neoplasms: Tumors or cancer of the either the colon or rectum or both. The most frequent malignant tumor in the United States. Etiological factors which increase the risk of colorectal cancer include chronic ulcerative colitis, familial polyposis of the colon, exposure to asbestos, irradiation of the cervix. [NIH] 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] Communis: Common tendon of the rectus group of muscles that surrounds the optic foramen and a portion of the superior orbital fissure, to the anterior margin of which it is attached at the spina recti lateralis. [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [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

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including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] 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] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] 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] Confidence Intervals: A range of values for a variable of interest, e.g., a rate, constructed so that this range has a specified probability of including the true value of the variable. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] 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

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body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Connexins: A group of homologous proteins which form the intermembrane channels of gap junctions. The connexins are the products of an identified gene family which has both highly conserved and highly divergent regions. The variety contributes to the wide range of functional properties of gap junctions. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contraceptive: An agent that diminishes the likelihood of or prevents conception. [EU] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] Contracture: A condition of fixed high resistance to passive stretch of a muscle, resulting from fibrosis of the tissues supporting the muscles or the joints, or from disorders of the muscle fibres. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

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] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments,

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etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary Circulation: The circulation of blood through the coronary vessels of the heart. [NIH]

Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] 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] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] C-Peptide: A 31-amino acid peptide which connects the A and B chains of proinsulin. The exact composition of the peptide is species dependent. In beta cells proinsulin is enzymatically converted to insulin with the liberation of the C-peptide. An immunoassay has been developed for assessing pancreatic beta cell secretory function in diabetic patients in whom circulating insulin antibodies and exogenous insulin interfere with insulin immunoassay. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Croton Oil: Viscous, nauseating oil obtained from the shrub Croton tiglium (Euphorbaceae). It is a vesicant and skin irritant used as pharmacologic standard for skin inflammation and allergy and causes skin cancer. It was formerly used as an emetic and cathartic with frequent mortality. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU]

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Curcumin: A dye obtained from tumeric, the powdered root of Curcuma longa Linn. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. [NIH] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclin-Dependent Kinases: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with cyclins to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events. [NIH]

Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytomegalovirus Infections: Infection with Cytomegalovirus, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]

Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxins: Substances elaborated by microorganisms, plants or animals that are specifically

332 Diabetes Mellitus

toxic to individual cells; they may be involved in immunity or may be contained in venoms. [NIH]

Daclizumab: A monoclonal antibody that is being studied for treatment of adult T-cell leukemia. Also called dacliximab. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. [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] Deamination: The removal of an amino group (NH2) 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] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delirium: (DSM III-R) an acute, reversible organic mental disorder characterized by reduced ability to maintain attention to external stimuli and disorganized thinking as manifested by rambling, irrelevant, or incoherent speech; there are also a reduced level of consciousness, sensory misperceptions, disturbance of the sleep-wakefulness cycle and level of psychomotor activity, disorientation to time, place, or person, and memory impairment. Delirium may be caused by a large number of conditions resulting in derangement of cerebral metabolism, including systemic infection, poisoning, drug intoxication or withdrawal, seizures or head trauma, and metabolic disturbances such as hypoxia, hypoglycaemia, fluid, electrolyte, or acid-base imbalances, or hepatic or renal failure. Called also acute confusional state and acute brain syndrome. [EU] 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] Demyelinating Diseases: Diseases characterized by loss or dysfunction of myelin in the central or peripheral nervous system. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling

Dictionary 333

it rapidly causes the two complementary strands to separate. [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 Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [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] Depth Perception: Perception of three-dimensionality. [NIH] Dermatitis: Any inflammation of the skin. [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] DHEA: Dehydroepiandrosterone. A substance that is being studied as a cancer prevention drug. It belongs to the family of drugs called steroids. [NIH] Diabetes Insipidus: A metabolic disorder due to disorders in the production or release of vasopressin. It is characterized by the chronic excretion of large amounts of low specific gravity urine and great thirst. [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

334 Diabetes Mellitus

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] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastole: Period of relaxation of the heart, especially the ventricles. [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]

Dietary Proteins: Proteins obtained from foods. They are the main source of the essential amino acids. [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] Digitalis: A genus of toxic herbaceous Eurasian plants of the Scrophulaceae which yield cardiotonic glycosides. The most useful are Digitalis lanata and D. purpurea. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disaccharides: Sugars composed of two monosaccharides linked by glycoside bonds. [NIH] 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

Dictionary 335

determinant of therapy and prognosis. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disparity: Failure of the two retinal images of an object to fall on corresponding retinal points. [NIH] Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diuretic: A drug that increases the production of urine. [NIH] Diuretics, Thiazide: Diuretics characterized as analogs of 1,2,4-benzothiadiazine-1,1dioxide. All have a common mechanism of action and differ primarily in the dose required to produce a given effect. They act directly on the kidney to increase the excretion of sodium chloride and water and also increase excretion of potassium ions. [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] 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] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH] Doxycycline: A synthetic tetracycline derivative with a range of antimicrobial activity and mode of action similar to that of tetracycline, but more effective against many species. Animal studies suggest that it may cause less tooth staining than other tetracyclines. [NIH] Drip: The continuous slow introduction of a fluid containing nutrients or drugs. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given

336 Diabetes Mellitus

stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] 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] 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] Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Eicosanoids: A class of oxygenated, endogenous, unsaturated fatty acids derived from arachidonic acid. They include prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acid compounds (HETE). They are hormone-like substances that act near the site of synthesis without altering functions throughout the body. [NIH] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocardiogram: Measurement of electrical activity during heartbeats. [NIH]

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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] Electromyography: Recording of the changes in electric potential of muscle by means of surface or needle electrodes. [NIH] 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] Ellagic Acid: A fused four ring compound occurring free or combined in galls. Isolated from the kino of Eucalyptus maculata Hook and E. Hemipholia F. Muell. Activates Factor XII of the blood clotting system which also causes kinin release; used in research and as a dye. [NIH]

Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emesis: Vomiting; an act of vomiting. Also used as a word termination, as in haematemesis. [EU]

Empiric: Empirical; depending upon experience or observation alone, without using scientific method or theory. [EU] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Enalapril: An angiotensin-converting enzyme inhibitor that is used to treat hypertension. [NIH]

Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [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]

Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [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]

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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] Endometrium: The layer of tissue that lines the uterus. [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] 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] Enhancer: Transcriptional element in the virus genome. [NIH] Enteroglucagon: Glucagon-like polypeptide secreted in the intestinal tract. It does not share a common receptor site with pancreatic glucagon. The peptide has glycogenolytic activity. [NIH]

Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]

Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH]

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Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] 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] Epithelial ovarian cancer: Cancer that occurs in the cells lining the ovaries. [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] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

Equine Infectious Anemia: Viral disease of horses caused by the equine infectious anemia virus (EIAV). It is characterized by intermittent fever, weakness, and anemia. Chronic infection consists of acute episodes with remissions. [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] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach.

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[NIH]

Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethylene Glycol: A colorless, odorless, viscous dihydroxy alcohol. It has a sweet taste, but is poisonous if ingested. Ethylene glycol is the most important glycol commercially available and is manufactured on a large scale in the United States. It is used as an antifreeze and coolant, in hydraulic fluids, and in the manufacture of low-freezing dynamites and resins. [NIH]

Ethylnitrosourea: A nitrosourea compound with alkylating, carcinogenic, and mutagenic properties. [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] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excrete: To get rid of waste from the body. [NIH] Exercise Test: Controlled physical activity, more strenuous than at rest, which is performed in order to allow assessment of physiological functions, particularly cardiovascular and pulmonary, but also aerobic capacity. Maximal (most intense) exercise is usually required but submaximal exercise is also used. The intensity of exercise is often graded, using criteria such as rate of work done, oxygen consumption, and heart rate. Physiological data obtained from an exercise test may be used for diagnosis, prognosis, and evaluation of disease severity, and to evaluate therapy. Data may also be used in prescribing exercise by determining a person's exercise capacity. [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] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Exotoxins: Toxins produced, especially by bacterial or fungal cells, and released into the culture medium or environment. [NIH] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [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

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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] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [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] Familial polyposis: An inherited condition in which numerous polyps (tissue masses) develop on the inside walls of the colon and rectum. It increases the risk for colon cancer. [NIH]

Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] 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] Febrile: Pertaining to or characterized by fever. [EU] Fecal Incontinence: Failure of voluntary control of the anal sphincters, with involuntary passage of feces and flatus. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Artery: The main artery of the thigh, a continuation of the external iliac artery. [NIH] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fetal Development: Morphologic and physiologic growth and development of the mammalian embryo or fetus. [NIH] Fetal Macrosomia: A complication of several conditions including diabetes mellitus and prolonged pregnancy. A macrosomic fetus is defined as weighing more than 4000 grams. [NIH]

Fetal Membranes: Thin layers of tissue which surround the embryo or fetus and provide for its nutrition, respiration, excretion and protection; they are the yolk sac, allantois, amnion, and chorion. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of

342 Diabetes Mellitus

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] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibrinolytic Agents: Fibrinolysin or agents that convert plasminogen to fibrinolysin (plasmin). [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [NIH] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Flexor: Muscles which flex a joint. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and

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megaloblastic anemia. [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] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [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] Fundus: The larger part of a hollow organ that is farthest away from the organ's opening. The bladder, gallbladder, stomach, uterus, eye, and cavity of the middle ear all have a fundus. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallic Acid: A colorless or slightly yellow crystalline compound obtained from nutgalls. It is used in photography, pharmaceuticals, and as an analytical reagent. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Ganciclovir: Acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglionic Blockers: Agents having as their major action the interruption of neural transmission at nicotinic receptors on postganglionic autonomic neurons. Because their actions are so broad, including blocking of sympathetic and parasympathetic systems, their therapeutic use has been largely supplanted by more specific drugs. They may still be used in the control of blood pressure in patients with acute dissecting aortic aneurysm and for the induction of hypotension in surgery. [NIH] Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [NIH] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of

344 Diabetes Mellitus

proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gasoline: Volative flammable fuel (liquid hydrocarbons) derived from crude petroleum by processes such as distillation reforming, polymerization, etc. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Bypass: Surgical procedure in which the stomach is transected high on the body. The resulting proximal remnant is joined to a loop of the jejunum in an end-to-side anastomosis. This procedure is used frequently in the treatment of morbid obesity. [NIH] Gastric Emptying: The evacuation of food from the stomach into the duodenum. [NIH] Gastric Inhibitory Polypeptide: A gastrointestinal hormone consisting of a 43-amino acid polypeptide (molecular weight 5105). It inhibits gastric secretion and motility and stimulates release of insulin. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

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] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] 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] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH]

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Genital: Pertaining to the genitalia. [EU] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geriatric: Pertaining to the treatment of the aged. [EU] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] 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] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [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] Glomerular Mesangium: The thin membrane which helps to support the capillary loops in a renal glomerulus. It is connective tissue composed of mesangial cells - myofibroblasts phenotypically related to vascular smooth muscle cells (muscle, smooth, vascular), phagocytes, and the mesangial extracellular matrix. [NIH] Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and kidney failure. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glossitis: Inflammation of the tongue. [NIH] Glucagonoma: Glucagon-secreting tumor of the pancreatic alpha cells characterized by a distinctive rash, weight loss, stomatitis, glossitis, diabetes, hypoaminoacidemia, and normochromic normocytic anemia. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids

346 Diabetes Mellitus

(steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Gluconeogenesis: The process by which glucose is formed from a non-carbohydrate source. [NIH]

Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Gluten: The protein of wheat and other grains which gives to the dough its tough elastic character. [EU] 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 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] Glycols: A generic grouping for dihydric alcohols with the hydroxy groups (-OH) located on different carbon atoms. They are viscous liquids with high boiling points for their

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molecular weights. [NIH] Glycolysis: The pathway by which glucose is catabolized into two molecules of pyruvic acid with the generation of ATP. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [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] Gonadal: Pertaining to a gonad. [EU] Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-Negative Bacteria: Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. [NIH] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Granulocyte Colony-Stimulating Factor: A glycoprotein of MW 25 kDa containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. [NIH] Granulocyte-Macrophage Colony-Stimulating Factor: An acidic glycoprotein of MW 23 kDa with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of

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neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. [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] Haemodialysis: The removal of certain elements from the blood by virtue of the difference in the rates of their diffusion through a semipermeable membrane, e.g., by means of a haemodialyzer. [EU] Haemostasis: The arrest of bleeding, either by the physiological properties of vasoconstriction and coagulation or by surgical means. [EU] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Haloperidol: Butyrophenone derivative. [NIH] Hammer: The largest of the three ossicles of the ear. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Health Behavior: Behaviors expressed by individuals to protect, maintain or promote their health status. For example, proper diet, and appropriate exercise are activities perceived to influence health status. Life style is closely associated with health behavior and factors influencing life style are socioeconomic, educational, and cultural. [NIH] Health 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 Education: Education that increases the awareness and favorably influences the attitudes and knowledge relating to the improvement of health on a personal or community basis. [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

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shared among the patient, insurers, and/or employers. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] 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] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhoids: Varicosities of the hemorrhoidal venous plexuses. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatobiliary: Pertaining to the liver and the bile or the biliary ducts. [EU] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hepatotoxicity: How much damage a medicine or other substance does to the liver. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the

350 Diabetes Mellitus

formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterodimers: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] 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] Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] 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] Host: Any animal that receives a transplanted graft. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] 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]

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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] Hydroxides: Inorganic compounds that contain the OH- group. [NIH] Hydroxyl Radical: The univalent radical OH that is present in hydroxides, alcohols, phenols, glycols. [NIH] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] 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] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycaemia: Abnormally increased content of sugar in the blood. [EU] 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] Hyperostosis: Increase in the mass of bone per unit volume. [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] Hypersensitivity, Immediate: Hypersensitivity reactions which occur within minutes of exposure to challenging antigen due to the release of histamine which follows the antigenantibody reaction and causes smooth muscle contraction and increased vascular permeability. [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

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inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hyperuricaemia: Excess of uric acid or urates in the blood; it is a prerequisite for the development or gout and may lead to renal disease. Called also uricacidaemia and, formerly, lithemia. [EU] Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Hypesthesia: Absent or reduced sensitivity to cutaneous stimulation. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypoglycaemia: An abnormally diminished concentration of glucose in the blood, which may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache, accompanied by irritability, confusion, hallucinations, bizarre behaviour, and ultimately, convulsions and coma. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Hypoglycemic: An orally active drug that produces a fall in blood glucose concentration. [NIH]

Hypoglycemic Agents: Agents which lower the blood glucose level. [NIH] Hypolipidemic: A drug that lowers abnormally high plasma concentrations of cholesterol or triglycerides or both. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypothermia: Lower than normal body temperature, especially in warm-blooded animals; in man usually accidental or unintentional. [NIH] 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] 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] Iliac Artery: Either of two large arteries originating from the abdominal aorta; they supply blood to the pelvis, abdominal wall and legs. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune 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]

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Immune Tolerance: The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [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]

Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] 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] Immunologic Factors: Biologically active substances whose activities affect or play a role in the functioning of the immune system. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU]

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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] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indinavir: A potent and specific HIV protease inhibitor that appears to have good oral bioavailability. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infant, Newborn: An infant during the first month after birth. [NIH] 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]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]

Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH]

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Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Insertional: A technique in which foreign DNA is cloned into a restriction site which occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [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] Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-3: A multilineage cell growth factor secreted by lymphocytes, epithelial cells, and astrocytes which stimulates clonal proliferation and differentiation of various types of blood and tissue cells. Also called multi-CSF, it is considered one of the hematopoietic colony stimulating factors. [NIH]

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Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Intermediate Filaments: Cytoplasmic filaments intermediate in diameter (about 10 nanometers) between the microfilaments and the microtubules. They may be composed of any of a number of different proteins and form a ring around the cell nucleus. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intervention Studies: Epidemiologic investigations designed to test a hypothesized causeeffect relation by modifying the supposed causal factor(s) in the study population. [NIH] 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] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] 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] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Intussusception: A rare disorder. A part of the intestines folds into another part of the intestines, causing blockage. Most common in infants. Can be treated with an operation. [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]

Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a

Dictionary 357

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] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Irradiation: The use of high-energy radiation from x-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 from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Ischemic Colitis: Decreased blood flow to the colon. Causes fever, pain, and bloody diarrhea. [NIH] Islet: Cell producing insulin in pancreas. [NIH] Isoleucine: An essential branched-chain amino acid found in many proteins. It is an isomer of LEUCINE. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels. [NIH] Isomaltose: A disaccharide consisting of two glucose units in an alpha (1-6) glycosidic linkage. [NIH] Isozymes: The multiple forms of a single enzyme. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

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] Juniper: A slow growing coniferous evergreen tree or shrub, genus Juniperus. The Juniper is cultivated for its berries, which take up to three years to ripen. The resinous, sweetly flavored berries are borne only by the female juniper, and can be found in various stages of ripeness on the same plant. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal

358 Diabetes Mellitus

layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Keratolytic: An agent that promotes keratolysis. [EU] 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 Cortex: The outer zone of the kidney, beneath the capsule, consisting of kidney glomerulus; kidney tubules, distal; and kidney tubules, proximal. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney 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 Transplantation: The transference of a kidney from one human or animal to another. [NIH] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lactobacillus: A genus of gram-positive, microaerophilic, rod-shaped bacteria occurring widely in nature. Its species are also part of the many normal flora of the mouth, intestinal tract, and vagina of many mammals, including humans. Pathogenicity from this genus is rare. [NIH] 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]

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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]

Least-Squares Analysis: A principle of estimation in which the estimates of a set of parameters in a statistical model are those quantities minimizing the sum of squared differences between the observed values of a dependent variable and the values predicted by the model. [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 fat cells in the feedback system that controls body fat stores. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [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] Likelihood Functions: Functions constructed from a statistical model and a set of observed data which give the probability of that data for various values of the unknown model parameters. Those parameter values that maximize the probability are the maximum likelihood estimates of the parameters. [NIH] Linear Models: Statistical models in which the value of a parameter for a given value of a factor is assumed to be equal to a + bx, where a and b are constants. The models predict a linear regression. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH]

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Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipolysis: The hydrolysis of lipids. [NIH] Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Lisinopril: An orally active angiotensin-converting enzyme inhibitor that has been used in the treatment of hypertension and congestive heart failure. [NIH] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]

Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]

Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Logistic Models: Statistical models which describe the relationship between a qualitative dependent variable (that is, one which can take only certain discrete values, such as the presence or absence of a disease) and an independent variable. A common application is in epidemiology for estimating an individual's risk (probability of a disease) as a function of a given risk factor. [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

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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] 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] Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view and on which the outline of the object may be traced. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] 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] Lymphocyte Subsets: A classification of lymphocytes based on structurally or functionally different populations of cells. [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] Lysophospholipids: Derivatives of phosphatidic acids that lack one of its fatty acyl chains due to its hydrolytic removal. [NIH] Macronutrients: Nutrients in the diet that are the key sources of energy, namely protein, fat, and carbohydrates. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes

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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] Macula: A stain, spot, or thickening. Often used alone to refer to the macula retinae. [EU] Macula Lutea: An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the superior pole of the eye and slightly below the level of the optic disk. [NIH] Macular Degeneration: Degenerative changes in the macula lutea of the retina. [NIH] 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] 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] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant Hyperthermia: Rapid and excessive rise of temperature accompanied by muscular rigidity following general anesthesia. [NIH] Malignant tumor: A tumor capable of metastasizing. [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]

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Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Manometry: Tests that measure muscle pressure and movements in the GI tract. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Median Nerve: A major nerve of the upper extremity. In humans, the fibers of the median nerve originate in the lower cervical and upper thoracic spinal cord (usually C6 to T1), travel via the brachial plexus, and supply sensory and motor innervation to parts of the forearm and hand. [NIH] 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] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] 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] Megacolon: Pathological enlargement of the colon. [NIH] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Melanin: The substance that gives the skin its color. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] 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]

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Mental Health: The state wherein the person is well adjusted. [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] Mesolimbic: Inner brain region governing emotion and drives. [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] Metallothionein: A low-molecular-weight (approx. 10 kD) protein occurring in the cytoplasm of kidney cortex and liver. It is rich in cysteinyl residues and contains no aromatic amino acids. Metallothionein shows high affinity for bivalent heavy metals. [NIH] Metaplasia: A condition in which there is a change of one adult cell type to another similar adult cell type. [NIH] 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] Methanol: A colorless, flammable liquid used in the manufacture of formaldehyde and acetic acid, in chemical synthesis, antifreeze, and as a solvent. Ingestion of methanol is toxic and may cause blindness. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] 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] Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [NIH] 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] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microsomal: Of or pertaining to microsomes : vesicular fragments of endoplasmic reticulum formed after disruption and centrifugation of cells. [EU]

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Microtubule-Associated Proteins: High molecular weight proteins found in the microtubules of the cytoskeletal system. Under certain conditions they are required for tubulin assembly into the microtubules and stabilize the assembled microtubules. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Micturition: The passage of urine; urination. [EU] Mifepristone: A progestational and glucocorticoid hormone antagonist. Its inhibition of progesterone induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua. As a glucocorticoid receptor antagonist, the drug has been used to treat hypercortisolism in patients with nonpituitary Cushing syndrome. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [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] 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] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Evolution: Multiple rounds of selection, amplification, and mutation leading to molecules with the desired properties. [NIH] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] 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

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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] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Monogenic: A human disease caused by a mutation in a single gene. [NIH] Monokines: Soluble mediators of the immune response that are neither antibodies nor complement. They are produced largely, but not exclusively, by monocytes and macrophages. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monophosphate: So called second messenger for neurotransmitters and hormones. [NIH] Monotherapy: A therapy which uses only one drug. [EU] Mood Disorders: Those disorders that have a disturbance in mood as their predominant feature. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Morula: The early embryo at the developmental stage in which the blastomeres, resulting from repeated mitotic divisions of the fertilized ovum, form a compact mass. [NIH] Motility: The ability to move spontaneously. [EU] 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] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscle, Smooth, Vascular: The nonstriated, involuntary muscle tissue of blood vessels. [NIH]

Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging,

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reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] 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] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelin Sheath: The lipid-rich sheath investing many axons in both the central and peripheral nervous systems. The myelin sheath is an electrical insulator and allows faster and more energetically efficient conduction of impulses. The sheath is formed by the cell membranes of glial cells (Schwann cells in the peripheral and oligodendroglia in the central nervous system). Deterioration of the sheath in demyelinating diseases is a serious clinical problem. [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 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] Myoglobin: A conjugated protein which is the oxygen-transporting pigment of muscle. It is made up of one globin polypeptide chain and one heme group. [NIH] Myopathy: Any disease of a muscle. [EU]

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Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myxedema: A condition characterized by a dry, waxy type of swelling with abnormal deposits of mucin in the skin and other tissues. It is produced by a functional insufficiency of the thyroid gland, resulting in deficiency of thyroid hormone. The skin becomes puffy around the eyes and on the cheeks and the face is dull and expressionless with thickened nose and lips. The congenital form of the disease is cretinism. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [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] Neocortex: The largest portion of the cerebral cortex. It is composed of neurons arranged in six layers. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephrogenic: Constant thirst and frequent urination because the kidney tubules cannot respond to antidiuretic hormone. The result is an increase in urine formation and excessive urine flow. [NIH] Nephropathy: Disease of the kidneys. [EU] 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] Nerve Fibers: Slender processes of neurons, especially the prolonged axons that conduct nerve impulses. [NIH] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural tube defects: These defects include problems stemming from fetal development of

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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] Neuritis: A general term indicating inflammation of a peripheral or cranial nerve. Clinical manifestation may include pain; paresthesias; paresis; or hypesthesia. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [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] Neurofibrillary Tangles: Abnormal structures located in various parts of the brain and composed of dense arrays of paired helical filaments (neurofilaments and microtubules). These double helical stacks of transverse subunits are twisted into left-handed ribbon-like filaments that likely incorporate the following proteins: (1) the intermediate filaments: medium- and high-molecular-weight neurofilaments; (2) the microtubule-associated proteins map-2 and tau; (3) actin; and (4) ubiquitin. As one of the hallmarks of Alzheimer disease, the neurofibrillary tangles eventually occupy the whole of the cytoplasm in certain classes of cell in the neocortex, hippocampus, brain stem, and diencephalon. The number of these tangles, as seen in post mortem histology, correlates with the degree of dementia during life. Some studies suggest that tangle antigens leak into the systemic circulation both in the course of normal aging and in cases of Alzheimer disease. [NIH] Neurofilaments: Bundle of neuronal fibers. [NIH] Neurogenic: Loss of bladder control caused by damage to the nerves controlling the bladder. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] 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] 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

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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] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Normotensive: 1. Characterized by normal tone, tension, or pressure, as by normal blood pressure. 2. A person with normal blood pressure. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleic Acid Probes: Nucleic acid which complements a specific mRNA or DNA molecule, or fragment thereof; used for hybridization studies in order to identify microorganisms and for genetic studies. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in

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providing medical care under the supervision of a physician. [NIH] Obstetrics: A medical-surgical specialty concerned with management and care of women during pregnancy, parturition, and the puerperium. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] Odour: A volatile emanation that is perceived by the sense of smell. [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] Oligodendroglia: A class of neuroglial (macroglial) cells in the central nervous system. Oligodendroglia may be called interfascicular, perivascular, or perineuronal satellite cells according to their location. The most important recognized function of these cells is the formation of the insulating myelin sheaths of axons in the central nervous system. [NIH] Oligomenorrhea: Abnormally infrequent menstruation. [NIH] Oligonucleotide Probes: Synthetic or natural oligonucleotides used in hybridization studies in order to identify and study specific nucleic acid fragments, e.g., DNA segments near or within a specific gene locus or gene. The probe hybridizes with a specific mRNA, if present. Conventional techniques used for testing for the hybridization product include dot blot assays, Southern blot assays, and DNA:RNA hybrid-specific antibody tests. Conventional labels for the probe include the radioisotope labels 32P and 125I and the chemical label biotin. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Omega-3 fatty acid: A type of fat obtained in the diet and involved in immunity. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Ophthalmic: Pertaining to the eye. [EU] Ophthalmoscope: A lighted instrument used to examine the inside of the eye, including the retina and the optic nerve. [NIH] Opsin: A visual pigment protein found in the retinal rods. It combines with retinaldehyde to form rhodopsin. [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

372 Diabetes Mellitus

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] Optic nerve head: The circular area (disc) where the optic nerve connects to the retina. [NIH] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organ Procurement: The administrative procedures involved with acquiring organs for transplantation through various programs, systems, or organizations. It includes obtaining consent and arranging for transportation of donor organs, after tissue harvesting, to the hospital for processing and transplant. [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] 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] Ossicles: The hammer, anvil and stirrup, the small bones of the middle ear, which transmit the vibrations from the tympanic membrane to the oval window. [NIH] Osteoarthritis: Degeneration of articular cartilage. Primary osteoarthritis is very common in older persons, especially affecting weight-bearing joints. Articular cartilage becomes soft, frayed and thinned. [NIH] Osteomyelitis: Inflammation of bone caused by a pyogenic organism. It may remain localized or may spread through the bone to involve the marrow, cortex, cancellous tissue, and periosteum. [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] Ouabain: A cardioactive glycoside consisting of rhamnose and ouabagenin, obtained from the seeds of Strophanthus gratus and other plants of the Apocynaceae; used like digitalis. It is commonly used in cell biological studies as an inhibitor of the NA(+)-K(+)-exchanging atpase. [NIH] 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] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [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]

Dictionary 373

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] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] 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] Pancreaticoduodenectomy: The excision of the head of the pancreas and the encircling loop of the duodenum to which it is connected. [NIH]

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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] Papilloma: A benign epithelial neoplasm which may arise from the skin, mucous membranes or glandular ducts. [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] Paresis: A general term referring to a mild to moderate degree of muscular weakness, occasionally used as a synonym for paralysis (severe or complete loss of motor function). In the older literature, paresis often referred specifically to paretic neurosyphilis. "General paresis" and "general paralysis" may still carry that connotation. Bilateral lower extremity paresis is referred to as paraparesis. [NIH] Paresthesias: Abnormal touch sensations, such as burning or prickling, that occur without an outside stimulus. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Paronychia: Inflammation involving the folds of tissue surrounding the nail. Called also perionychia. [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] Parturition: The act or process of given birth to a child. [EU] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] 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 Satisfaction: The degree to which the individual regards the health care service or product or the manner in which it is delivered by the provider as useful, effective, or beneficial. [NIH] 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

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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] 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] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously 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] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [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 blood: Blood circulating throughout the body. [NIH] Peripheral Nerves: The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. [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 stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [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

376 Diabetes Mellitus

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] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneal Dialysis: Dialysis fluid being introduced into and removed from the peritoneal cavity as either a continuous or an intermittent procedure. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Peritonitis: Inflammation of the peritoneum; a condition marked by exudations in the peritoneum of serum, fibrin, cells, and pus. It is attended by abdominal pain and tenderness, constipation, vomiting, and moderate fever. [EU] Peroral: Performed through or administered through the mouth. [EU] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] 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] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacology, Clinical: The branch of pharmacology that deals directly with the effectiveness and safety of drugs in humans. [NIH] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [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

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of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phorbol Esters: Tumor-promoting compounds obtained from croton oil (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. [NIH] Phosphatidic Acids: Fatty acid derivatives of glycerophosphates. They are composed of glycerol bound in ester linkage with 1 mole of phosphoric acid at the terminal 3-hydroxyl group and with 2 moles of fatty acids at the other two hydroxyl groups. [NIH] 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] Phosphoprotein Phosphatase: A group of enzymes removing the serine- or threoninebound phosphate groups from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. (Enzyme Nomenclature, 1992) EC 3.1.3.16. [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] Phosphorylate: 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] Photodynamic therapy: Treatment with drugs that become active when exposed to light. These drugs kill cancer cells. [NIH] Photosensitizer: A drug used in photodynamic therapy. When absorbed by cancer cells and exposed to light, the drug becomes active and kills the cancer cells. [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] 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] Piloerection: Involuntary erection or bristling of hairs. [NIH]

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Pilot Projects: Small-scale tests of methods and procedures to be used on a larger scale if the pilot study demonstrates that these methods and procedures can work. [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] 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] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [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] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Activating Factor: A phospholipid derivative formed by platelets, basophils, neutrophils, monocytes, and macrophages. It is a potent platelet aggregating agent and inducer of systemic anaphylactic symptoms, including hypotension, thrombocytopenia, neutropenia, and bronchoconstriction. [NIH] Platelet 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

Dictionary 379

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] Podiatry: A specialty concerned with the diagnosis and treatment of foot disorders and injuries and anatomic defects of the foot. [NIH] 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] Polygenic Inheritance: A phenotypic outcome that is determined by more than one gene, such as a variety of physical characteristics or diseases. [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] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [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] 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] Polyradiculoneuropathy: Diseases characterized by injury or dysfunction involving multiple peripheral nerves and nerve roots. The process may primarily affect myelin or nerve axons. Two of the more common demyelinating forms are acute inflammatory polyradiculopathy (Guillain-Barre syndrome) and polyradiculoneuropathy, chronic inflammatory demyelinating. Polyradiculoneuritis refers to inflammation of multiple peripheral nerves and spinal nerve roots. [NIH] Polyradiculopathy: Disease or injury involving multiple spinal nerve roots. Polyradiculitis refers to inflammation of multiple spinal nerve roots. [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from

380 Diabetes Mellitus

plants, including safflower, sunflower, corn, and soybean oils. [NIH] Porphyria: A group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [NIH]

Porphyrins: A group of compounds containing the porphin structure, four pyrrole rings connected by methine bridges in a cyclic configuration to which a variety of side chains are attached. The nature of the side chain is indicated by a prefix, as uroporphyrin, hematoporphyrin, etc. The porphyrins, in combination with iron, form the heme component in biologically significant compounds such as hemoglobin and myoglobin. [NIH] Port: An implanted device through which blood may be withdrawn and drugs may be infused without repeated needle sticks. Also called a port-a-cath. [NIH] Port-a-cath: An implanted device through which blood may be withdrawn and drugs may be infused without repeated needle sticks. Also called a port. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [NIH] Post partum: After childbirth, or after delivery. [EU] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] Postprandial Blood Glucose: Blood taken 1-2 hours after eating to see the amount of glucose (sugar) in the blood. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Postural: Pertaining to posture or position. [EU] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] 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] Pravastatin: An antilipemic fungal metabolite isolated from cultures of Nocardia autotrophica. It acts as a competitive inhibitor of HMG CoA reductase (hydroxymethylglutaryl CoA reductases). [NIH]

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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] 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 Tests: Tests to determine whether or not an individual is pregnant. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [NIH] Primary Biliary Cirrhosis: A chronic liver disease. Slowly destroys the bile ducts in the liver. This prevents release of bile. Long-term irritation of the liver may cause scarring and cirrhosis in later stages of the disease. [NIH] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection, as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] 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] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [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] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential

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component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostaglandins F: (9 alpha,11 alpha,13E,15S)-9,11,15-Trihydroxyprost-13-en-1-oic acid (PGF(1 alpha)); (5Z,9 alpha,11,alpha,13E,15S)-9,11,15-trihydroxyprosta-5,13-dien-1-oic acid (PGF(2 alpha)); (5Z,9 alpha,11 alpha,13E,15S,17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1oic acid (PGF(3 alpha)). A family of prostaglandins that includes three of the six naturally occurring prostaglandins. All naturally occurring PGF have an alpha configuration at the 9carbon position. They stimulate uterine and bronchial smooth muscle and are often used as oxytocics. [NIH] 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] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] 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

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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 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] 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] Provirus: Virus that is integrated into the chromosome of a host cell and is transmitted in that form from one host cell generation to another without leading to the lysis of the host cells. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Proximate cause: The abnormal event in a causal chain lying closest to an accidental event. [NIH]

Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [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] Psychosomatic: Pertaining to the mind-body relationship; having bodily symptoms of psychic, emotional, or mental origin; called also psychophysiologic. [EU]

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Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH] Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [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]

Puerperium: Period from delivery of the placenta until return of the reproductive organs to their normal nonpregnant morphologic state. In humans, the puerperium generally lasts for six to eight weeks. [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 Fibrosis: Chronic inflammation and progressive fibrosis of the pulmonary alveolar walls, with steadily progressive dyspnea, resulting finally in death from oxygen lack or right heart failure. [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] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Pyogenic: Producing pus; pyopoietic (= liquid inflammation product made up of cells and a thin fluid called liquor puris). [EU] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Pyruvate Kinase: ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results

Dictionary 385

in hemolytic anemia. EC 2.7.1.40. [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] Quiescent: Marked by a state of inactivity or repose. [EU] 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] 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] 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] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] 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, Cytokine: Cell surface proteins that bind cytokines and trigger intracellular changes influencing the behavior of cells. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectal Prolapse: Protrusion of the rectal mucous membrane through the anus. There are various degrees: incomplete with no displacement of the anal sphincter muscle; complete with displacement of the anal sphincter muscle; complete with no displacement of the anal sphincter muscle but with herniation of the bowel; and internal complete with rectosigmoid or upper rectum intussusception into the lower rectum. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflective: Capable of throwing back light, images, sound waves : reflecting. [EU] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [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] Regression Analysis: Procedures for finding the mathematical function which best describes the relationship between a dependent variable and one or more independent variables. In linear regression (see linear models) the relationship is constrained to be a straight line and least-squares analysis is used to determine the best fit. In logistic regression (see logistic models) the dependent variable is qualitative rather than continuously variable and likelihood functions are used to find the best relationship. In multiple regression the dependent variable is considered to depend on more than a single independent variable. [NIH]

Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with

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risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [NIH] Relaxin: Hormone produced by the ovaries during pregnancy that loosens ligaments that hold the hip bones together. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Renin-Angiotensin System: A system consisting of renin, angiotensin-converting enzyme, and angiotensin II. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. The converting enzyme contained in the lung acts on angiotensin I in the plasma converting it to angiotensin II, the most powerful directly pressor substance known. It causes contraction of the arteriolar smooth muscle and has other indirect actions mediated through the adrenal cortex. [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory 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] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [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]

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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 Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoblastoma Protein: Product of the retinoblastoma tumor suppressor gene. It is a nuclear phosphoprotein hypothesized to normally act as an inhibitor of cell proliferation. Rb protein is absent in retinoblastoma cell lines. It also has been shown to form complexes with the adenovirus E1A protein, the SV40 T antigen, and the human papilloma virus E7 protein. [NIH]

Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retrospective: Looking back at events that have already taken place. [NIH] Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rhabdomyolysis: Necrosis or disintegration of skeletal muscle often followed by myoglobinuria. [NIH] Rhamnose: A methylpentose whose L- isomer is found naturally in many plant glycosides and some gram-negative bacterial lipopolysaccharides. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] 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] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU]

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Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk patient: Patient who is at risk, because of his/her behaviour or because of the type of person he/she is. [EU] 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] 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] 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] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] 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] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [NIH]

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Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Secular trends: A relatively long-term trend in a community or country. [NIH] 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] 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] 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] Senile Plaques: Spherical masses consisting of amyloid fibrils and neuronal processes. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Septicemia: Systemic disease associated with the presence and persistence of pathogenic microorganisms or their toxins in the blood. Called also blood poisoning. [EU] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [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] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [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]

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Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

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] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Class: A stratum of people with similar position and prestige; includes social stratification. Social class is measured by criteria such as education, occupation, and income. [NIH]

Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH]

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Social Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [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] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] 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] Soybean Oil: Oil from soybean or soybean plant. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [NIH] Spasticity: A state of hypertonicity, or increase over the normal tone of a muscle, with heightened deep tendon reflexes. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by

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refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Sphincter: A ringlike band of muscle fibres that constricts a passage or closes a natural orifice; called also musculus sphincter. [EU] 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 Nerve Roots: The paired bundles of nerve fibers entering and leaving the spinal cord at each segment. The dorsal and ventral nerve roots join to form the mixed segmental spinal nerves. The dorsal roots are generally afferent, formed by the central projections of the spinal (dorsal root) ganglia sensory cells, and the ventral roots efferent, comprising the axons of spinal motor and autonomic preganglionic neurons. There are, however, some exceptions to this afferent/efferent rule. [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] Spinous: Like a spine or thorn in shape; having spines. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Splenic Vein: Vein formed by the union (at the hilus of the spleen) of several small veins from the stomach, pancreas, spleen and mesentery. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sprue: A non febrile tropical disease of uncertain origin. [NIH] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] Stasis: A word termination indicating the maintenance of (or maintaining) a constant level; preventing increase or multiplication. [EU] Steatosis: Fatty degeneration. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] 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]

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Stereoscopic: Accurate depth perception in the presence of binocular single vision, due to the slight disparity in the two retinal images of the same object. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] 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] Stomatitis: Inflammation of the oral mucosa, due to local or systemic factors which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae. [EU]

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] 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] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

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Substrate: A substance upon which an enzyme acts. [EU] 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] 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] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [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] Synapses: Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate through direct electrical connections which are sometimes called electrical synapses; these are not included here but rather in gap junctions. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the

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activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. [NIH] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Technetium: The first artificially produced element and a radioactive fission product of uranium. The stablest isotope has a mass number 99 and is used diagnostically as a radioactive imaging agent. Technetium has the atomic symbol Tc, atomic number 43, and atomic weight 98.91. [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] Temporal Lobe: Lower lateral part of the cerebral hemisphere. [NIH] Tenosynovitis: Inflammation of a tendon sheath. [EU] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] 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] Thinness: A state of insufficient flesh on the body usually defined as having a body weight less than skeletal and physical standards. [NIH] Thioredoxin: A hydrogen-carrying protein that participates in a variety of biochemical reactions including ribonucleotide reduction. Thioredoxin is oxidized from a dithiol to a disulfide during ribonucleotide reduction. The disulfide form is then reduced by NADPH in a reaction catalyzed by thioredoxin reductase. [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]

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Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombolytic Therapy: Use of infusions of fibrinolytic agents to destroy or dissolve thrombi in blood vessels or bypass grafts. [NIH] Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [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] Thyroiditis: Inflammation of the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [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 Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tissue Harvesting: The removal of organs or tissue for reuse, for example, for transplantation. [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] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tonicity: The normal state of muscular tension. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH]

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Total pancreatectomy: Surgery to remove the entire pancreas. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] 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] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] 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] Transforming Growth Factor alpha: Factor isolated in a variety of tissues including epithelium, and maternal decidua. It is closely related to epidermal growth factor and binds to the EGF receptor. TGF-alpha acts synergistically with TGF-beta in inducing phenotypic transformation, but its physiological role is unknown. [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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Transposase: An enzyme that binds to single-stranded DNA. It is thought to recognize the repetitive ends of a transposon and to participate in the cleavage of the recipient site into which the new transposon copy inserts. EC 2.7.7.-. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [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] Trivalent: Having a valence of three. [EU] 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] 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] Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [NIH] Tropomyosin: A protein found in the thin filaments of muscle fibers. It inhibits contraction of the muscle unless its position is modified by troponin. [NIH] Troponin: One of the minor protein components of skeletal muscle. Its function is to serve as the calcium-binding component in the troponin-tropomyosin B-actin-myosin complex by conferring calcium sensitivity to the cross-linked actin and myosin filaments. [NIH] Truncal: The bilateral dissection of the abdominal branches of the vagus nerve. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tuberculin: A sterile liquid containing the growth products of, or specific substances extracted from, the tubercle bacillus; used in various forms in the diagnosis of tuberculosis. [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] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH]

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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] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [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 megahertz. [NIH] Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein, which connects the embryo or fetus to the placenta. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Univalent: Pertaining to an unpaired chromosome during the zygotene stage of prophase to first metaphase in meiosis. [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]

Uranium: A radioactive element of the actinide series of metals. It has an atomic symbol U, atomic number 92, and atomic weight 238.03. U-235 is used as the fissionable fuel in nuclear weapons and as fuel in nuclear power reactors. [NIH] Urban Population: The inhabitants of a city or town, including metropolitan areas and suburban areas. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the

Dictionary 401

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] 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 to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagal: Pertaining to the vagus nerve. [EU] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vagus Nerve: The 10th cranial nerve. The vagus is a mixed nerve which contains somatic afferents (from skin in back of the ear and the external auditory meatus), visceral afferents (from the pharynx, larynx, thorax, and abdomen), parasympathetic efferents (to the thorax and abdomen), and efferents to striated muscle (of the larynx and pharynx). [NIH] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]

Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] 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] VE: The total volume of gas either inspired or expired in one minute. [NIH] 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] Venoms: Poisonous animal secretions forming fluid mixtures of many different enzymes, toxins, and other substances. These substances are produced in specialized glands and secreted through specialized delivery systems (nematocysts, spines, fangs, etc.) for disabling prey or predator. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide

402 Diabetes Mellitus

back for gas exchange. [NIH] Venous Thrombosis: The formation or presence of a thrombus within a vein. [NIH] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Dysfunction: A condition in which the ventricles of the heart exhibit a decreased functionality. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villous: Of a surface, covered with villi. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] 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] 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] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [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] Volvulus: A twisting of the stomach or large intestine. May be caused by the stomach being in the wrong position, a foreign substance, or abnormal joining of one part of the stomach or intestine to another. Volvulus can lead to blockage, perforation, peritonitis, and poor blood flow. [NIH]

Dictionary 403

Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] Weight-Bearing: The physical state of supporting an applied load. This often refers to the weight-bearing bones or joints that support the body's weight, especially those in the spine, hip, knee, and foot. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] 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] Yolk Sac: An embryonic membrane formed from endoderm and mesoderm. In reptiles and birds it incorporates the yolk into the digestive tract for nourishing the embryo. In placental mammals its nutritional function is vestigial; however, it is the source of most of the intestinal mucosa and the site of formation of the germ cells. It is sometimes called the vitelline sac, which should not be confused with the vitelline membrane of the egg. [NIH] Zoonoses: Diseases of non-human animals that may be transmitted to man or may be transmitted from man to non-human animals. [NIH] Zygote: The fertilized ovum. [NIH]

405

INDEX 1 1-phosphate, 206, 307 A Abdomen, 307, 319, 320, 339, 356, 360, 376, 393, 394, 396, 401 Abdominal, 15, 64, 168, 236, 251, 307, 308, 352, 373, 374, 376, 399, 400, 402 Abdominal fat, 64, 307, 402 Abdominal Pain, 307, 376, 400 Aberrant, 226, 307 Ablation, 38, 307 Abscess, 251, 307 Acceptor, 307, 360, 373, 398 Acculturation, 28, 307 Acetaminophen, 156, 307 Acetic Acids, 210, 307 Acetohexamide, 219, 307 Acetylcholine, 307, 324, 370 Acetylcysteine, 204, 307 Acidosis, 18, 112, 188, 197, 226, 238, 239, 255, 307, 333 Actin, 307, 368, 369, 399 Acuity, 99, 307 Acute renal, 17, 75, 307, 349 Acyl, 25, 224, 308, 361 Acylation, 64, 308 Adaptability, 308, 323 Adaptation, 56, 146, 308 Adenine, 308, 384 Adenocarcinoma, 308, 349 Adenosine, 76, 190, 196, 212, 308, 377 Adenosine Deaminase, 212, 308 Adenosine Monophosphate, 190, 308 Adenosine Triphosphate, 196, 308, 377 Adenovirus, 13, 47, 181, 199, 308, 388 Adhesions, 251, 308 Adipocytes, 42, 64, 72, 217, 308, 329, 359 Adipose Tissue, 14, 49, 180, 200, 217, 307, 308 Adjustment, 144, 147, 238, 239, 308 Adjuvant, 66, 308, 344 Adolescence, 87, 308 Adoptive Transfer, 33, 52, 308 Adrenal Cortex, 308, 310, 330, 351, 381, 387 Adrenal Glands, 309, 312 Adrenal Medulla, 309, 322, 339, 370 Adrenergic, 10, 309, 314, 315, 335, 339, 395

Adrenergic beta-Antagonists, 309, 314 Adverse Effect, 29, 60, 158, 254, 309, 326, 391 Aerobic, 46, 49, 151, 309, 340, 365 Aerobic Exercise, 46, 49, 309 Afferent, 309, 359, 393 Affinity, 68, 186, 309, 326, 362, 364, 392 Agar, 309, 327, 378 Age Groups, 201, 309 Age of Onset, 198, 222, 309, 399 Aged, 80 and Over, 309 Agonist, 26, 186, 200, 203, 309, 335 Airway, 309, 391 Akathisia, 309, 315 Alanine, 206, 209, 310 Albumin, 62, 80, 289, 310, 372, 378 Albuminuria, 31, 74, 105, 112, 114, 310 Aldose Reductase Inhibitor, 182, 210, 310 Aldosterone, 79, 87, 104, 310 Algorithms, 162, 175, 310, 319 Alimentary, 115, 310, 374 Alkaline, 18, 182, 307, 310, 311, 321, 376 Alkaline Phosphatase, 182, 310 Allantois, 310, 341 Alleles, 19, 30, 33, 37, 73, 197, 221, 310 Allergen, 212, 310, 390 Allogeneic, 12, 58, 310 Allograft, 12, 159, 181, 310 Alpha Cell, 310, 345 Alpha Particles, 310, 385 Alpha-1, 80, 311 Alternative medicine, 259, 311 Ameliorating, 215, 311 Amenorrhea, 136, 311, 379 Amino Acid Sequence, 208, 220, 311, 314, 340, 344 Amino Acid Substitution, 11, 311 Amino Acids, 207, 225, 311, 313, 326, 334, 344, 364, 375, 379, 383, 388, 390, 395, 398, 400 Aminopyridines, 203, 311 Ammonia, 308, 311, 395, 400 Amnion, 311, 341 Amniotic Fluid, 311, 345 Amplification, 311, 365 Amputation, 23, 43, 65, 100, 184, 187, 294, 311 Amylase, 207, 311

406 Diabetes Mellitus

Amyloid, 73, 203, 213, 311, 390 Amyloid Neuropathies, 203, 311 Amyloidosis, 251, 311 Anabolic, 233, 312, 334 Anaerobic, 188, 312 Anaesthesia, 102, 312, 354 Anal, 6, 251, 312, 341, 342, 360, 386 Analgesic, 307, 312 Analog, 194, 254, 312, 343 Analogous, 31, 33, 185, 312, 398 Analytes, 278, 312 Anaphylactic, 73, 312, 378 Anaphylatoxins, 312, 328 Anaphylaxis, 312 Anaplasia, 312 Anastomosis, 312, 344 Anatomical, 312, 329, 334, 337, 353, 389 Androgens, 309, 312, 330, 351 Anemia, 105, 312, 339, 343, 345, 362, 385 Anesthesia, 60, 173, 238, 309, 312, 362 Anesthetics, 312, 339 Aneurysm, 312, 343, 401 Angina, 154, 229, 238, 309, 313 Angina Pectoris, 229, 309, 313 Angiodysplasia, 251, 313 Angiogenesis, 48, 57, 210, 313, 363 Angiogenesis Factor, 48, 313 Angiography, 245, 313 Angiopathy, 205, 313 Angiotensin converting enzyme inhibitor, 210, 313 Angiotensin-Converting Enzyme Inhibitors, 82, 108, 117, 313, 314 Angiotensinogen, 30, 50, 64, 313, 387 Animal model, 11, 25, 28, 29, 32, 37, 38, 44, 52, 54, 246, 313 Anions, 310, 313, 357 Ankle, 108, 313 Annealing, 313, 379 Anorectal, 6, 251, 313 Anovulation, 313, 379 Antagonism, 313, 326 Antecedent, 12, 35, 314 Anterior Cerebral Artery, 314, 324 Antiallergic, 314, 330 Antibacterial, 314, 393 Antibiotic, 156, 168, 251, 314, 375, 393, 396 Antidepressant, 8, 314 Antidiabetic, 99, 104, 182, 188, 205, 209, 230, 264, 314, 346 Antidiabetic Agent, 182, 188, 205, 209, 264, 314

Antidiuretic, 314, 368 Antiemetic, 314, 315 Antigen-Antibody Complex, 314, 327 Antigen-presenting cell, 314, 333 Antihypertensive, 24, 238, 314 Antihypertensive Agents, 24, 314 Anti-infective, 314, 351 Anti-inflammatory, 159, 209, 307, 314, 316, 330, 346 Anti-Inflammatory Agents, 315, 316, 330 Antimicrobial, 315, 335 Antineoplastic, 315, 330 Antioxidant, 41, 43, 50, 86, 106, 123, 124, 130, 133, 315, 373 Antipsychotic, 15, 77, 86, 315, 326, 369, 389 Antipsychotic Agents, 86, 315 Antipyretic, 307, 315 Antiviral, 168, 307, 315, 355, 375 Anuria, 315, 358 Anus, 312, 313, 315, 320, 386 Anxiety, 6, 78, 94, 150, 226, 309, 310, 315 Aorta, 315, 330, 352, 402 Apnea, 315 Apolipoproteins, 315, 360 Apoptosis, 13, 16, 50, 79, 197, 206, 209, 315 Appendicitis, 251, 316 Aqueous, 88, 122, 124, 131, 204, 207, 316, 318, 325, 331, 337, 351, 359, 360 Aqueous fluid, 204, 316 Arachidonic Acid, 218, 316, 336, 359, 382 Arginine, 25, 156, 168, 246, 312, 316, 370, 399 Aromatic, 214, 316, 364, 376 Arrhythmia, 182, 208, 316 Arsenicals, 41, 316 Arterial, 23, 47, 92, 116, 117, 245, 316, 321, 324, 351, 383, 395 Arteriography, 245, 316 Arteriolar, 316, 320, 387 Arterioles, 204, 316, 319, 321, 364, 367, 401 Arteriolosclerosis, 316 Arteriosclerosis, 185, 188, 208, 209, 213, 214, 225, 316, 352 Arteriovenous, 251, 316, 364 Arthropathy, 260, 316 Articular, 316, 372 Asbestos, 316, 327 Aspirin, 280, 316 Assay, 13, 21, 22, 57, 183, 190, 212, 316, 353 Asymptomatic, 86, 134, 274, 316, 374 Ataxia, 203, 303, 317, 396 Atherogenic, 214, 317

Index 407

Atopic, 192, 317 Atrophy, 197, 235, 317, 369 Attenuated, 16, 50, 317 Atypical, 244, 258, 317, 326, 389 Auditory, 80, 317, 401 Autoantibodies, 13, 14, 27, 54, 70, 317 Autoantigens, 216, 317 Autodigestion, 317, 374 Autoimmunity, 11, 27, 46, 47, 52, 54, 160, 184, 242, 317 Autonomic, 11, 35, 99, 107, 118, 182, 208, 307, 315, 317, 343, 370, 375, 392, 393, 395 Autonomic Nervous System, 11, 36, 182, 208, 317, 375, 392, 395 Autonomic Neuropathy, 11, 99, 107, 317 Autosuggestion, 317, 352 Axons, 317, 367, 368, 371, 375, 379, 388, 393 B B cells, 41, 47, 317, 331 Bacillus, 317, 399 Backcross, 33, 317 Bacterial Physiology, 308, 318 Bactericidal, 318, 340 Bacteriophage, 318, 378, 398 Basal Ganglia, 315, 317, 318, 325 Basal Ganglia Diseases, 317, 318, 325 Base, 22, 56, 67, 220, 292, 308, 318, 321, 332, 333, 344, 357, 358, 376, 396, 400 Basement Membrane, 105, 318, 340, 358 Basophils, 318, 348, 359, 378 Behavior Therapy, 318 Benign, 251, 316, 318, 348, 368, 374 Benzene, 224, 318 Beta-pleated, 311, 318 Bilateral, 79, 318, 374, 379, 399 Bile, 318, 343, 349, 350, 357, 360, 381, 394, 396 Bile Acids, 318, 394, 396 Bile Ducts, 318, 343, 381 Biliary, 5, 105, 318, 321, 327, 349, 374 Biliary Tract, 318, 321, 374 Bilirubin, 310, 318, 343, 351 Binding Sites, 224, 319 Bioavailability, 25, 43, 165, 319, 354 Biochemical reactions, 319, 396 Biological response modifier, 319, 355 Biological therapy, 319, 348 Biopsy, 4, 62, 158, 319, 375 Biosynthesis, 191, 225, 316, 319, 361, 390 Biotechnology, 69, 74, 243, 259, 271, 319 Biotin, 127, 319, 371

Birth Order, 28, 319 Bivalent, 319, 364 Bladder, 29, 218, 238, 317, 319, 343, 354, 366, 369, 382, 400, 401 Blastocyst, 20, 319, 328, 378, 399 Bloating, 319, 344 Blood Coagulation, 319, 321 Blot, 319, 353, 371 Blotting, Western, 320, 353 Body Composition, 15, 46, 49, 320 Body Fluids, 320, 321, 336, 392 Body Mass Index, 120, 320, 373 Bone Marrow, 33, 49, 173, 317, 318, 320, 327, 347, 348, 353, 361, 363, 366, 392, 394 Bone Marrow Cells, 49, 320, 327, 348, 363 Bone scan, 320, 389 Boron, 320, 331 Bowel, 5, 246, 251, 312, 320, 334, 354, 356, 359, 369, 376, 386, 394, 400 Bowel Movement, 320, 334, 394 Brachial, 101, 320, 363 Bradykinin, 320, 370, 378 Brain Stem, 320, 369 Branch, 301, 320, 361, 374, 376, 384, 392, 396 Breakdown, 320, 333, 334, 344 Bronchi, 320, 339, 398 Bronchitis, 192, 320 Bronchoconstriction, 320, 378 Buformin, 219, 320 Bursitis, 116, 320 Bypass, 154, 245, 321, 367, 397 C Cachexia, 192, 223, 224, 321 Calcification, 316, 321 Calcium, 190, 191, 197, 314, 316, 321, 327, 363, 367, 391, 399 Calcium channel blocker, 314, 321 Calcium Channel Blockers, 314, 321 Calculi, 321, 347 Canonical, 19, 321 Capillary, 136, 320, 321, 322, 345, 402 Capillary Fragility, 136, 321, 322 Capsules, 163, 321, 335, 344, 345 Captopril, 24, 321 Carbohydrate, 26, 38, 40, 45, 50, 56, 193, 203, 207, 214, 253, 321, 330, 346, 347, 379, 390 Carboxy, 214, 321 Carcinogenic, 318, 321, 340, 355, 371, 382, 394 Carcinogens, 41, 321, 325, 373

408 Diabetes Mellitus

Carcinoma, 4, 321, 322 Cardiac, 24, 26, 50, 73, 99, 132, 181, 196, 197, 215, 229, 238, 309, 322, 339, 367, 394 Cardiomyopathy, 24, 26, 42, 136, 232, 322 Cardiorespiratory, 151, 309, 322 Cardiovascular System, 24, 246, 317, 322 Carnitine, 127, 322 Carotene, 322, 388 Carpal Tunnel Syndrome, 260, 322 Case report, 93, 322, 325 Case series, 322, 325 Cataract, 205, 215, 322 Catechin, 207, 322 Catecholamine, 10, 322, 335 Cations, 322, 357 Caudal, 322, 334, 352, 380 Causal, 5, 322, 356, 383 Cause of Death, 43, 184, 187, 195, 323 Caveolae, 26, 323 Caveolins, 323 Celiac Disease, 4, 71, 323 Cell Adhesion, 323, 355 Cell Cycle, 17, 48, 323, 331 Cell Cycle Proteins, 18, 323 Cell Death, 37, 50, 315, 323, 368 Cell Differentiation, 323, 391 Cell Division, 318, 323, 348, 365, 378, 390 Cell membrane, 190, 209, 210, 321, 323, 333, 343, 367, 377, 380 Cell Membrane Structures, 323 Cell proliferation, 194, 206, 209, 316, 323, 356, 388, 391 Cell Respiration, 323, 365, 387 Cell Size, 17, 323 Cell Survival, 159, 323, 348 Cell Transplantation, 109, 173, 174, 323 Cellulose, 323, 378 Centrifugation, 324, 364 Ceramide, 208, 209, 324 Cerebellar, 317, 324, 386 Cerebral Infarction, 214, 324 Cerebrovascular, 147, 219, 318, 321, 322, 324, 396 Cerebrum, 324 Cervix, 324, 327 Character, 313, 324, 332, 346 Checkup, 215, 324 Chemokines, 68, 324 Chemoreceptor, 315, 324 Chemotactic Factors, 324, 328 Chemotherapy, 168, 324 Chest Pain, 82, 324

Cholesterol Esters, 324, 360 Cholinergic, 213, 315, 324 Chorea, 315, 325 Chorion, 325, 341 Choroid, 325, 387 Chromatin, 315, 323, 325, 339, 370 Chromium, 127, 134, 325 Chromosomal, 36, 311, 325, 378, 388 Chromosome, 37, 41, 70, 184, 207, 216, 217, 325, 348, 359, 383, 390, 400 Chronic Disease, 8, 55, 66, 150, 181, 187, 218, 240, 284, 286, 321, 325 Chronic renal, 195, 325, 379, 400 Chylomicrons, 325, 360 Ciliary, 204, 316, 325 Ciliary Arteries, 204, 325 Ciliary processes, 316, 325 Circulatory system, 222, 325, 338 CIS, 325, 388 Clamp, 10, 43, 49, 156, 325 Clinical Medicine, 325, 381 Clinical study, 13, 81, 84, 243, 325, 329 Clinical trial, 8, 23, 75, 153, 159, 172, 173, 176, 271, 325, 329, 335, 366, 375, 383, 385 Clone, 19, 37, 326 Cloning, 33, 65, 70, 198, 221, 319, 326, 355 Clozapine, 15, 326 Coagulation, 182, 208, 319, 326, 348, 349, 378, 397 Coal, 318, 326 Cod Liver Oil, 326, 337 Codon, 74, 326, 344 Coenzyme, 138, 326, 361 Cofactor, 326, 383 Cognitive behavior therapy, 59, 326 Cohort Studies, 23, 272, 326 Colitis, 251, 326 Collagen, 57, 260, 318, 322, 326, 341, 342, 344, 363, 379, 382 Collapse, 312, 320, 327, 391 Colloidal, 310, 327, 376 Colony-Stimulating Factors, 221, 327, 347 Colorectal, 251, 327 Colorectal Cancer, 327 Colorectal Neoplasms, 251, 327 Combination Therapy, 182, 183, 201, 238, 254, 255, 327 Common Bile Duct, 327, 373 Communis, 189, 228, 327 Comorbidity, 74, 327 Complement, 20, 312, 327, 328, 344, 355, 362, 366, 378, 390

Index 409

Complementary and alternative medicine, 60, 129, 130, 135, 141, 328 Complementary medicine, 130, 328 Complete remission, 328, 387 Computational Biology, 271, 328 Computed tomography, 49, 76, 134, 328, 389 Computerized axial tomography, 328, 389 Computerized tomography, 328 Conception, 43, 328, 329, 341, 394 Concomitant, 91, 235, 236, 244, 328 Conduction, 328, 367 Cones, 328, 388 Confidence Intervals, 80, 328 Confusion, 328, 352, 369, 400 Congestion, 315, 328 Congestive heart failure, 182, 208, 238, 328, 360 Conjugated, 218, 329, 331, 367 Conjunctiva, 325, 329 Connective Tissue, 182, 208, 320, 326, 329, 342, 343, 344, 345, 361, 364, 375, 388, 394, 395 Connective Tissue Cells, 329 Connexins, 28, 329, 343 Consciousness, 312, 329, 332, 335 Constipation, 246, 315, 329, 376 Constriction, 329, 357, 401 Constriction, Pathologic, 329, 401 Consultation, 88, 245, 329 Consumption, 4, 56, 329, 333, 373 Contraceptive, 119, 272, 329 Contractility, 313, 329 Contracture, 260, 329 Contraindications, ii, 287, 329 Control group, 4, 46, 57, 175, 329, 385 Controlled clinical trial, 51, 329 Controlled study, 62, 166, 329 Convulsions, 329, 352 Coordination, 329, 366 Cornea, 316, 329, 389 Coronary Arteriosclerosis, 330, 367 Coronary Artery Bypass, 108, 117, 330 Coronary Circulation, 26, 313, 330 Coronary heart disease, 26, 34, 133, 180, 187, 218, 229, 322, 330 Coronary Thrombosis, 330, 364, 367 Coronary Vessels, 330 Cortex, 80, 317, 330, 342, 350, 368, 372, 386 Corticosteroid, 111, 132, 330 Cortisol, 36, 310, 330 C-Peptide, 168, 330

Cranial, 330, 348, 369, 371, 375, 401 Crossing-over, 330, 386 Croton Oil, 330, 377 Cultured cells, 41, 231, 330 Curative, 235, 330, 370, 396 Curcumin, 217, 331 Cutaneous, 238, 331, 352, 361 Cyclic, 38, 190, 229, 331, 348, 370, 377, 380, 382, 389 Cyclin, 17, 323, 331 Cyclin-Dependent Kinases, 323, 331 Cysteine, 204, 235, 307, 324, 331, 395 Cystine, 331 Cytochrome, 197, 331, 373 Cytokine, 46, 54, 159, 197, 206, 221, 223, 331 Cytomegalovirus, 100, 331, 343 Cytomegalovirus Infections, 331, 343 Cytoplasm, 24, 50, 315, 318, 323, 331, 339, 348, 364, 366, 369, 370, 388 Cytoskeletal Proteins, 323, 331 Cytoskeleton, 331, 355, 365 Cytotoxic, 58, 223, 331, 353, 391 Cytotoxins, 41, 331 D Daclizumab, 168, 173, 332 Data Collection, 67, 94, 332 Databases, Bibliographic, 271, 332 Day Care, 171, 332 De novo, 58, 332 Deamination, 332, 400 Decidua, 332, 365, 378, 398 Defense Mechanisms, 50, 332, 355 Degenerative, 183, 188, 191, 196, 199, 202, 313, 332, 349, 362, 366, 388 Deletion, 72, 315, 332 Delirium, 315, 332 Delivery of Health Care, 332, 348 Dementia, 7, 213, 315, 332, 369 Demyelinating Diseases, 202, 332, 367 Denaturation, 332, 379 Dendrites, 333, 369 Dendritic, 24, 46, 333, 388 Dendritic cell, 24, 46, 333 Density, 15, 24, 88, 214, 320, 324, 333, 336, 360, 371, 392 Dental Caries, 81, 333 Depolarization, 333, 391 Depth Perception, 333, 394 Dermatitis, 192, 333 Detoxification, 43, 333 Deuterium, 333, 350

410 Diabetes Mellitus

Developed Countries, 183, 191, 333 DHEA, 138, 333 Diabetes Insipidus, 293, 333 Diabetes, Gestational, 158, 333 Diabetic Foot, 110, 239, 333 Diabetic Ketoacidosis, 9, 15, 238, 239, 333 Diabetic Retinopathy, 11, 33, 57, 63, 81, 112, 188, 211, 232, 246, 288, 333, 377 Diagnostic procedure, 179, 259, 334 Dialyzer, 334, 349 Diarrhea, 5, 246, 251, 304, 334, 357 Diastole, 334 Diastolic, 26, 34, 42, 86, 334, 351 Diencephalon, 334, 352, 369 Dietary Fats, 334, 360 Dietary Proteins, 134, 334 Diffusion, 334, 348, 354 Digestion, 216, 231, 253, 310, 318, 320, 334, 344, 356, 360, 394, 401 Digestive system, 176, 334 Digestive tract, 317, 334, 391, 403 Digitalis, 334, 372 Dihydrotestosterone, 334, 386 Dihydroxy, 310, 334, 340 Dilatation, 312, 334, 381, 401 Dilatation, Pathologic, 334, 401 Dilation, 320, 334, 401 Diploid, 334, 378 Disaccharides, 218, 334 Discrimination, 283, 334 Disease Progression, 5, 11, 68, 334 Disinfectant, 335, 340 Disparity, 335, 394 Dissection, 30, 143, 335, 399 Dissociation, 309, 335 Distal, 4, 5, 245, 330, 335, 358, 375, 383 Diuretic, 335, 392 Diuretics, Thiazide, 314, 335 Dopamine, 315, 326, 335, 377, 389 Dorsal, 335, 380, 393 Dosage Forms, 186, 335 Dose-dependent, 224, 335 Double-blinded, 135, 335 Doxycycline, 133, 335 Drip, 156, 335 Drive, ii, vi, 4, 5, 97, 121, 237, 246, 249, 253, 287, 288, 289, 335 Drug Interactions, 266, 336 Drug Tolerance, 336, 397 Duct, 327, 336, 340, 389 Duodenum, 318, 336, 344, 357, 373, 394 Dyes, 311, 318, 336, 370

Dyskinesia, 315, 336 Dyslipidemia, 15, 30, 58, 75, 89, 103, 117, 118, 154, 165, 180, 217, 235, 236, 238, 239, 258, 336 Dyspnea, 336, 384 Dystonia, 197, 315, 336 Dystrophy, 260, 336 E Echocardiography, 86, 336 Edema, 117, 212, 304, 334, 336, 367, 400 Effector, 12, 16, 46, 50, 307, 327, 336, 369, 377 Effector cell, 336, 369 Eicosanoids, 218, 336 Elasticity, 316, 330, 336 Elastin, 327, 336, 341 Elective, 5, 43, 154, 336 Electrocardiogram, 156, 168, 336 Electrocoagulation, 326, 337 Electrolyte, 255, 310, 330, 332, 337, 358, 365, 380, 392, 400 Electromyography, 6, 337 Electrons, 315, 318, 337, 356, 357, 373, 385 Ellagic Acid, 207, 337 Embolus, 337, 354 Embryo, 311, 319, 323, 337, 341, 354, 366, 400, 403 Emesis, 315, 337 Empiric, 28, 337 Empirical, 51, 337 Emulsion, 227, 228, 337, 342 Enalapril, 62, 337 Enamel, 333, 337, 357 Encephalocele, 337, 369 Encephalopathy, 197, 337 Endemic, 41, 337, 362, 393 Endocrine System, 338, 369 Endocytosis, 197, 221, 323, 338 Endometrium, 332, 338, 365, 399 Endothelial cell, 25, 48, 57, 229, 338 Endothelium, 43, 246, 313, 338, 370, 378 Endothelium, Lymphatic, 338 Endothelium, Vascular, 338 Endothelium-derived, 43, 246, 338, 370 Endotoxic, 223, 338, 360 Endotoxin, 338, 399 End-stage renal, 32, 40, 100, 187, 325, 338, 379 Energy balance, 20, 338, 359 Enhancer, 189, 338 Enteroglucagon, 5, 338 Enteropeptidase, 338, 399

Index 411

Environmental Exposure, 41, 338 Environmental Health, 270, 272, 338 Enzymatic, 50, 71, 190, 321, 322, 328, 331, 333, 338, 342, 350, 379, 388 Enzyme Inhibitors, 41, 186, 213, 339, 378 Eosinophils, 339, 348, 359 Epidemic, 22, 34, 74, 246, 339, 393 Epidemiological, 21, 41, 61, 63, 64, 74, 149, 273, 339 Epidermal, 200, 339, 357, 398 Epidermal Growth Factor, 200, 339, 398 Epidermis, 339, 357, 381 Epigastric, 339, 373 Epinephrine, 38, 309, 335, 339, 370, 400 Epithelial, 17, 38, 194, 272, 308, 332, 339, 349, 355, 358, 374 Epithelial Cells, 17, 38, 194, 339, 349, 355, 358 Epithelial ovarian cancer, 272, 339 Epithelium, 17, 318, 338, 339, 357, 398 Epitope, 13, 339 Equine Infectious Anemia, 13, 339 Erectile, 108, 111, 238, 258, 283, 339 Erection, 339, 377 Erythrocytes, 312, 320, 339, 386, 390 Esophageal, 246, 339 Esophagus, 334, 339, 394 Ethanol, 45, 207, 340 Ethylene Glycol, 14, 340 Ethylnitrosourea, 30, 340 Eukaryotic Cells, 331, 340, 354, 372, 400 Evacuation, 329, 340, 344, 359 Excitatory, 340, 346 Excrete, 315, 340, 358 Exercise Test, 168, 340 Exercise Therapy, 188, 340 Exhaustion, 313, 340, 362 Exocrine, 194, 340, 373 Exogenous, 58, 194, 211, 214, 231, 233, 321, 330, 340, 344, 399 Exon, 76, 340 Exotoxins, 223, 340 Extensor, 340, 383 Extracellular, 57, 185, 186, 189, 190, 206, 311, 329, 338, 340, 341, 342, 345, 355, 363, 364, 392 Extracellular Matrix, 57, 329, 340, 342, 345, 355, 363 Extracellular Matrix Proteins, 340, 363 Extracellular Space, 340, 341, 364 Extrapyramidal, 310, 315, 335, 341 Extremity, 23, 65, 238, 294, 341, 363, 374

Eye Infections, 308, 341 F Familial polyposis, 327, 341 Family Planning, 271, 341 Fatigue, 147, 226, 341, 349 Fatty acids, 38, 40, 91, 197, 218, 221, 310, 333, 336, 341, 346, 377, 382 Fatty Liver, 246, 341 Febrile, 341, 362, 393 Fecal Incontinence, 6, 246, 341, 354 Feces, 329, 341, 394 Femoral, 245, 341 Femoral Artery, 245, 341 Femur, 341 Fetal Development, 341, 368 Fetal Macrosomia, 204, 341 Fetal Membranes, 53, 341 Fetus, 341, 353, 378, 400, 401 Fibrin, 319, 341, 342, 376, 378, 397 Fibrinogen, 341, 342, 378 Fibrinolysis, 57, 91, 342 Fibrinolytic, 342, 397 Fibrinolytic Agents, 342, 397 Fibroblasts, 193, 329, 342, 356 Fibrosis, 129, 246, 329, 342, 384, 389 Fissure, 327, 342 Fistula, 251, 342 Fixation, 342, 390 Flatus, 341, 342, 344 Flexor, 260, 340, 342 Fluorescence, 227, 342 Folate, 123, 124, 342 Fold, 5, 11, 33, 187, 201, 211, 342, 364 Folic Acid, 342 Foot Care, 149, 250, 253, 343 Foot Ulcer, 23, 169, 238, 245, 333, 343 Foramen, 327, 343, 376 Forearm, 44, 116, 319, 343, 363 Fractionation, 26, 60, 343 Frontal Lobe, 314, 324, 343 Fructosamine, 186, 343 Fructose, 26, 213, 218, 343, 347, 356 Fundus, 33, 343, 371 G Gallbladder, 246, 307, 318, 334, 343, 373 Gallic Acid, 207, 343 Gallstones, 246, 343 Ganciclovir, 168, 343 Ganglia, 307, 318, 343, 368, 375, 393, 395 Ganglionic Blockers, 314, 343 Gangrene, 187, 195, 343 Gap Junctions, 329, 343, 395

412 Diabetes Mellitus

Gas, 311, 334, 342, 344, 350, 370, 401, 402 Gasoline, 318, 344 Gastric, 45, 71, 88, 89, 99, 131, 148, 194, 246, 317, 322, 335, 339, 344, 350 Gastric Bypass, 88, 344 Gastric Emptying, 88, 99, 131, 148, 246, 344 Gastric Inhibitory Polypeptide, 194, 344 Gastrin, 200, 201, 344, 350 Gastrointestinal, 45, 89, 96, 238, 246, 313, 316, 320, 339, 340, 344, 359, 362, 390, 392, 393, 394 Gastrointestinal tract, 246, 313, 340, 344, 359, 390, 393 Gastroparesis, 246, 280, 344 Gelatin, 344, 346, 396 Gene Expression, 15, 19, 22, 29, 38, 62, 68, 154, 223, 224, 344 Gene Targeting, 20, 22, 37, 344 Genetic Code, 344, 370 Genetic Counseling, 238, 344 Genetic Engineering, 185, 198, 319, 326, 344 Genetic Markers, 167, 344 Genetic testing, 158, 344, 379 Genetics, 28, 33, 36, 48, 52, 77, 119, 184, 187, 308, 344 Genital, 317, 345 Genomics, 68, 345 Genotype, 32, 33, 64, 230, 345, 376 Geriatric, 238, 240, 251, 345 Germ Cells, 345, 372, 403 Gestation, 42, 60, 345, 375, 378 Gestational Age, 53, 203, 345 Ginseng, 60, 138, 345 Gland, 185, 308, 309, 345, 351, 361, 373, 378, 382, 389, 390, 394, 397 Gliclazide, 94, 219, 345 Glipizide, 106, 139, 219, 345 Glomerular, 17, 31, 62, 345, 356, 358, 387 Glomerular Filtration Rate, 62, 345, 358 Glomerular Mesangium, 17, 345 Glomeruli, 31, 345 Glomerulonephritis, 32, 197, 221, 345 Glomerulosclerosis, 231, 345 Glomerulus, 345, 358 Glossitis, 345 Glucagonoma, 105, 345 Glucocorticoid, 36, 345, 365 Gluconeogenesis, 320, 346 Glucose Intolerance, 18, 46, 93, 200, 333, 346

Glucose Tolerance Test, 39, 43, 107, 180, 239, 279, 346 Glutamate, 69, 71, 346 Glutamic Acid, 24, 70, 73, 216, 342, 346, 381 Glutathione Peroxidase, 44, 346 Gluten, 4, 5, 95, 323, 346 Glyburide, 78, 139, 164, 165, 219, 248, 264, 346 Glycerol, 346, 377 Glycerophospholipids, 209, 346, 377 Glycine, 204, 346, 390 Glycogen, 49, 72, 207, 213, 222, 246, 346 Glycogen Synthase, 213, 346 Glycols, 346, 351 Glycolysis, 26, 188, 320, 347 Glycoprotein, 342, 347, 358, 362, 366, 399 Glycoside, 334, 347, 372, 389 Glycosidic, 347, 357 Glycosuria, 185, 347 Glycosylation, 50, 347 Gonadal, 347, 394 Gout, 137, 235, 236, 260, 347, 352 Governing Board, 347, 380 Gp120, 347, 375 Graft, 181, 223, 347, 350, 353, 367 Grafting, 108, 117, 330, 347, 353 Graft-versus-host disease, 223, 347 Gram-negative, 223, 338, 347, 388 Gram-Negative Bacteria, 338, 347, 388 Gram-positive, 223, 347, 358 Granulocyte Colony-Stimulating Factor, 327, 347 Granulocyte-Macrophage ColonyStimulating Factor, 327, 347 Granulocytes, 327, 347, 348, 359, 391, 403 Growth factors, 17, 32, 55, 190, 193, 221, 348 Guanylate Cyclase, 348, 370 H Haemodialysis, 92, 348 Haemostasis, 101, 103, 348 Hair follicles, 348, 403 Haloperidol, 15, 348 Hammer, 44, 348, 372 Haploid, 348, 378 Haptens, 309, 348 Headache, 348, 352 Health Behavior, 148, 170, 348 Health Care Costs, 8, 59, 162, 184, 348 Health Education, 170, 348 Health Expenditures, 348

Index 413

Health Status, 70, 145, 148, 168, 348, 349 Heart attack, 154, 160, 322, 349 Heart failure, 26, 34, 72, 84, 86, 182, 208, 313, 349, 384 Heme, 318, 331, 349, 367, 380 Hemodialysis, 32, 91, 99, 100, 260, 334, 349, 358 Hemoglobin, 9, 100, 112, 135, 147, 153, 175, 195, 196, 211, 312, 339, 349, 357, 359, 380 Hemolytic, 349, 385 Hemorrhage, 313, 337, 348, 349, 367, 394, 402 Hemorrhoids, 251, 349 Hemostasis, 349, 355, 390 Hepatic, 22, 41, 45, 58, 71, 96, 181, 191, 219, 246, 310, 327, 332, 346, 349, 380 Hepatitis, 3, 4, 77, 115, 150, 349, 402 Hepatobiliary, 246, 349 Hepatocellular, 4, 349 Hepatocellular carcinoma, 4, 349 Hepatocytes, 38, 130, 349 Hepatotoxicity, 76, 349 Hereditary, 195, 197, 199, 202, 203, 347, 349, 366, 369, 388 Heredity, 250, 344, 349 Herpes, 13, 349, 350 Herpes Zoster, 350 Heterodimers, 350, 355 Heterogeneity, 60, 309, 350 Hippocampus, 350, 369 Hirsutism, 350, 351 Histamine, 312, 315, 350, 351 Histology, 4, 350, 369 Homeostasis, 12, 16, 45, 47, 49, 60, 180, 197, 198, 212, 216, 217, 220, 221, 231, 350, 392 Homologous, 310, 319, 329, 330, 344, 350, 390, 395 Hormonal, 5, 45, 97, 148, 231, 317, 330, 350 Host, 13, 98, 181, 209, 222, 223, 318, 350, 353, 359, 383, 388, 401, 402 Humoral, 144, 221, 350 Humour, 350 Hybrid, 317, 326, 350, 371 Hybridization, 16, 350, 370, 371 Hybridomas, 350, 356 Hydrogen, 197, 224, 307, 318, 321, 332, 333, 340, 346, 350, 351, 360, 365, 369, 370, 373, 376, 383, 396 Hydrogen Peroxide, 197, 346, 351, 360

Hydrolysis, 308, 351, 360, 377, 379, 383, 399 Hydrophilic, 200, 351 Hydrophobic, 200, 346, 351, 360 Hydroxides, 351 Hydroxyl Radical, 197, 351 Hydroxylysine, 327, 351 Hydroxyproline, 327, 351 Hyperandrogenism, 272, 351 Hyperbilirubinemia, 204, 351, 357 Hypercholesterolemia, 137, 154, 180, 197, 213, 221, 336, 351 Hyperglycaemia, 185, 230, 351 Hyperlipidaemia, 185, 226, 351 Hyperlipidemia, 44, 98, 104, 180, 210, 213, 214, 336, 351 Hyperlipoproteinemia, 351, 352 Hyperostosis, 260, 351 Hyperplasia, 17, 351 Hypersensitivity, 310, 312, 351, 359, 388, 390 Hypersensitivity, Immediate, 351 Hypertriglyceridemia, 180, 336, 351 Hypertrophy, 17, 74, 182, 208, 229, 351, 352 Hyperuricaemia, 235, 236, 352 Hyperuricemia, 347, 352 Hypesthesia, 352, 369 Hypnotic, 129, 352 Hypoglycaemia, 101, 230, 231, 332, 352 Hypoglycemic Agents, 119, 123, 125, 188, 195, 200, 219, 233, 238, 248, 255, 352 Hypolipidemic, 224, 225, 352 Hypotension, 238, 304, 315, 329, 343, 352, 378 Hypothalamus, 317, 334, 352, 378 Hypothermia, 352 I Iatrogenic, 35, 352 Id, 126, 136, 203, 279, 280, 281, 283, 284, 287, 290, 291, 292, 294, 300, 302, 352 Idiopathic, 85, 251, 257, 260, 274, 352 Iliac Artery, 341, 352, 400 Immune function, 168, 352, 353 Immune Sera, 352, 353 Immune Tolerance, 157, 216, 353 Immunity, 129, 144, 310, 332, 353, 371, 398 Immunization, 24, 308, 353, 381, 390 Immunoassay, 330, 353 Immunoblotting, 26, 353 Immunodeficiency, 13, 52, 100, 103, 224, 353

414 Diabetes Mellitus

Immunofluorescence, 4, 353 Immunogenic, 12, 353, 360 Immunoglobulin, 212, 314, 353, 365 Immunologic, 5, 13, 21, 31, 46, 54, 254, 308, 324, 345, 353 Immunologic Factors, 5, 353 Immunology, 308, 309, 353 Immunosuppressive, 4, 155, 173, 249, 346, 353, 395 Immunosuppressive Agents, 156, 353 Immunosuppressive therapy, 4, 353 Immunotherapy, 308, 319, 353 Impairment, 11, 69, 71, 185, 215, 317, 332, 336, 341, 353, 363, 383 Implantation, 109, 185, 211, 328, 353, 399 Impotence, 304, 339, 354 In situ, 16, 29, 50, 69, 201, 354 In Situ Hybridization, 16, 29, 354 In vitro, 14, 17, 19, 44, 57, 64, 354, 379, 396, 397 Incision, 354, 356 Incontinence, 6, 29, 354 Incubated, 43, 354 Indicative, 240, 354, 374, 401 Indinavir, 114, 354 Induction, 10, 24, 25, 26, 39, 41, 50, 209, 216, 222, 223, 312, 315, 343, 354 Infant, Newborn, 309, 354 Infarction, 43, 78, 83, 84, 85, 97, 110, 111, 154, 182, 195, 208, 238, 315, 324, 330, 354, 364, 367, 387 Infertility, 4, 354 Infiltration, 14, 24, 52, 64, 345, 354 Inflammatory bowel disease, 251, 354 Informed Consent, 174, 354 Infusion, 43, 83, 119, 131, 163, 173, 355, 367 Ingestion, 45, 199, 346, 355, 364, 379 Inhalation, 162, 316, 355, 379 Initiation, 24, 50, 52, 74, 355, 398 Inlay, 355, 387 Inorganic, 41, 316, 351, 355, 366 Insertional, 20, 355 Insight, 49, 55, 102, 240, 355 Insulator, 355, 366, 367 Insulin-like, 272, 355 Integrins, 65, 355 Interferon, 68, 115, 159, 205, 206, 355 Interferon-alpha, 159, 205, 355 Interleukin-3, 327, 355 Interleukin-6, 90, 356 Interleukins, 353, 356 Intermediate Filaments, 356, 369

Intermittent, 339, 356, 376 Internal Medicine, 3, 15, 17, 37, 39, 77, 80, 82, 86, 88, 110, 111, 135, 184, 245, 246, 338, 356 Interstitial, 73, 341, 356, 357, 387 Intervention Studies, 66, 129, 356 Intestinal, 38, 191, 219, 245, 246, 322, 323, 338, 346, 356, 358, 362, 403 Intestine, 194, 210, 218, 320, 327, 356, 358, 402 Intoxication, 332, 356 Intramuscular, 356, 374 Intraocular, 204, 356 Intraocular pressure, 204, 356 Intravascular, 109, 356 Intravenous, 24, 43, 45, 156, 161, 163, 355, 356, 374 Intrinsic, 148, 193, 309, 318, 356 Intussusception, 356, 386 Inulin, 272, 345, 356 Invasive, 187, 212, 353, 356, 362 Involuntary, 318, 325, 341, 356, 366, 367, 377, 386, 392 Ion Channels, 356, 369 Ionizing, 311, 338, 356 Ions, 190, 318, 335, 337, 350, 356, 365, 380 Iris, 71, 325, 329, 357, 384 Irradiation, 327, 357 Ischemia, 182, 196, 197, 208, 245, 317, 357, 367, 387 Ischemic Colitis, 251, 357 Isoleucine, 210, 357 Isomaltose, 207, 357 Isozymes, 357, 384 J Jaundice, 351, 357 Jejunum, 344, 357 Joint, 65, 169, 316, 342, 357, 395 Juniper, 189, 228, 357 K Kb, 37, 270, 357 Keratin, 357 Keratinocytes, 65, 198, 357 Keratolytic, 333, 358 Ketone Bodies, 333, 358 Ketosis, 102, 333, 358 Kidney Cortex, 358, 364 Kidney Failure, 60, 62, 160, 198, 222, 273, 338, 345, 358 Kidney Failure, Acute, 358 Kidney Failure, Chronic, 358 Kidney Transplantation, 104, 151, 358

Index 415

Kinetics, 15, 37, 42, 123, 125, 147, 358 L Labile, 327, 358 Lactobacillus, 160, 358 Laminin, 57, 65, 318, 341, 358 Large Intestine, 327, 334, 356, 358, 386, 391, 402 Latent, 193, 227, 228, 244, 359, 381 Laxative, 309, 359, 392 Least-Squares Analysis, 359, 386 Lens, 210, 316, 322, 359, 402 Leprosy, 343, 359 Leptin, 31, 40, 64, 76, 359 Lesion, 44, 330, 343, 359, 360, 396, 400 Lethal, 35, 220, 318, 359 Leucine, 123, 125, 359 Leucocyte, 311, 359 Leukemia, 332, 359 Leukocytes, 86, 109, 318, 320, 324, 339, 348, 355, 356, 359, 366, 370, 399 Leukotrienes, 316, 336, 359 Library Services, 300, 359 Ligament, 359, 382 Ligands, 58, 188, 218, 355, 359 Likelihood Functions, 359, 386 Linear Models, 359, 386 Linkage, 19, 30, 32, 33, 37, 41, 64, 93, 162, 344, 357, 359, 377 Lipase, 88, 131, 360 Lipid A, 24, 40, 360 Lipid Peroxidation, 89, 90, 197, 360, 373 Lipolysis, 15, 40, 45, 360 Lipopolysaccharides, 360, 388 Lipoprotein, 15, 64, 73, 103, 104, 180, 203, 214, 336, 347, 360, 361 Liposome, 198, 360 Lisinopril, 87, 360 Lithium, 315, 360 Liver cancer, 4, 360 Liver scan, 360, 389 Lobe, 47, 314, 324, 360 Localization, 24, 55, 104, 360 Localized, 311, 333, 342, 350, 354, 358, 360, 372, 378, 400 Locomotion, 360, 378 Logistic Models, 360, 386 Longitudinal study, 6, 27, 360 Loop, 344, 361, 373 Lovastatin, 89, 361 Low-density lipoprotein, 88, 102, 117, 214, 336, 360, 361 Lucida, 358, 361

Lupus, 361, 395 Luteal Phase, 361, 365 Lymph, 325, 338, 350, 361, 373, 394 Lymph node, 361, 373 Lymphatic, 338, 354, 361, 364, 392, 393, 397 Lymphatic system, 361, 392, 393, 397 Lymphocyte, 12, 14, 81, 314, 361, 362, 363 Lymphocyte Subsets, 81, 361 Lymphoid, 24, 314, 359, 361 Lysine, 351, 361, 399 Lysophospholipids, 206, 361 M Macronutrients, 56, 361 Macrophage, 327, 348, 361, 362 Macrophage Colony-Stimulating Factor, 327, 362 Macula, 362 Macula Lutea, 362 Macular Degeneration, 204, 362 Magnetic Resonance Imaging, 15, 362, 389 Major Histocompatibility Complex, 32, 53, 181, 362 Malabsorption, 323, 362 Malaria, 223, 362 Malaria, Falciparum, 362 Malaria, Vivax, 362 Malignancy, 4, 362 Malignant, 91, 105, 308, 315, 316, 327, 360, 362, 368 Malignant Hyperthermia, 91, 362 Malignant tumor, 327, 362 Malnutrition, 98, 273, 310, 317, 321, 362, 367 Mammary, 330, 362 Manic, 315, 360, 362, 383 Manifest, 212, 234, 363 Manometry, 6, 363 Matrix metalloproteinase, 57, 363 Medial, 117, 316, 363, 371 Median Nerve, 322, 363 Mediate, 54, 190, 221, 335, 363 Mediator, 44, 206, 363, 390 Medical Records, 7, 61, 363, 388 Medical Staff, 335, 363 Medicament, 189, 208, 209, 226, 228, 235, 363 MEDLINE, 271, 363 Megacolon, 251, 363 Megakaryocytes, 320, 363 Melanin, 357, 363, 377, 400 Membrane Glycoproteins, 363

416 Diabetes Mellitus

Membrane Proteins, 323, 363 Memory, 113, 129, 192, 332, 363 Meninges, 324, 363 Menopause, 49, 287, 363, 380 Menstruation, 287, 311, 332, 361, 363, 371 Mental Disorders, 177, 363, 381, 383 Mental Health, iv, 6, 8, 9, 177, 270, 275, 280, 364, 381, 384 Mesenchymal, 339, 347, 362, 364 Mesenteric, 364, 380 Mesolimbic, 315, 364 Metabolic disorder, 22, 26, 30, 91, 183, 214, 219, 227, 231, 273, 333, 347, 364 Metabolite, 45, 361, 364, 380, 381 Metallothionein, 38, 364 Metaplasia, 71, 364 Metastasis, 129, 363, 364 Methanol, 123, 133, 364 Methionine, 364, 395 MI, 34, 205, 248, 287, 305, 364 Microbe, 364, 398 Microbiology, 26, 308, 317, 364 Microcirculation, 81, 364, 378 Microdialysis, 16, 364 Microorganism, 326, 364, 374, 402 Micro-organism, 333, 364 Microscopy, 26, 318, 364 Microsomal, 89, 364 Microtubule-Associated Proteins, 365, 369 Microtubules, 356, 365, 369 Micturition, 29, 365 Mifepristone, 36, 365 Migration, 65, 365 Mineralocorticoids, 308, 330, 365 Minority Groups, 58, 162, 365 Mitochondria, 50, 183, 196, 365, 367, 372 Mitochondrial Swelling, 365, 368 Mitosis, 315, 365 Modification, 14, 42, 134, 204, 216, 344, 365, 385 Modulator, 62, 365 Molecular Evolution, 68, 365 Molecular Structure, 254, 365 Molecule, 14, 16, 58, 223, 308, 314, 318, 319, 326, 327, 331, 335, 336, 338, 339, 347, 351, 355, 365, 370, 373, 378, 386, 391, 398, 401 Monitor, 21, 61, 155, 168, 250, 365, 370 Monoclonal, 54, 67, 71, 205, 332, 350, 353, 357, 365, 385 Monoclonal antibodies, 205, 332, 353, 365 Monocytes, 24, 356, 359, 366, 378

Monogenic, 236, 366 Monokines, 221, 223, 366 Mononuclear, 159, 362, 366, 399 Monophosphate, 229, 366 Monotherapy, 254, 366 Mood Disorders, 86, 366 Morphological, 31, 39, 337, 366 Morphology, 322, 366 Morula, 319, 366 Motility, 45, 89, 206, 344, 366, 390 Movement Disorders, 315, 366, 396 Mucins, 366, 389 Mucolytic, 307, 366 Mucosa, 5, 323, 361, 366, 394, 403 Mucus, 212, 366, 400 Multicenter study, 154, 366 Multiple sclerosis, 192, 202, 228, 366 Muscle Fibers, 366, 368, 399 Muscle, Smooth, Vascular, 345, 366 Muscular Atrophy, 197, 366 Muscular Dystrophies, 336, 367 Mutagenesis, 17, 20, 367 Mutagenic, 340, 367 Mutagens, 367 Myelin, 202, 332, 366, 367, 371, 379 Myelin Sheath, 202, 367, 371 Myocardial Ischemia, 182, 208, 313, 367 Myocardial Reperfusion, 367, 387 Myocardial Reperfusion Injury, 367, 387 Myocardium, 24, 42, 313, 364, 367 Myoglobin, 212, 367, 380 Myopathy, 42, 50, 367 Myosin, 368, 399 Myxedema, 251, 368 N Naive, 75, 368 Natriuresis, 313, 368 Nausea, 314, 315, 335, 344, 358, 368, 400 NCI, 1, 176, 269, 325, 368 Necrosis, 50, 315, 324, 354, 364, 367, 368, 387, 388 Need, 3, 34, 60, 62, 66, 119, 159, 170, 173, 174, 182, 194, 196, 200, 201, 209, 210, 215, 224, 229, 230, 237, 240, 244, 247, 249, 252, 259, 260, 272, 295, 309, 325, 346, 363, 368, 397 Neocortex, 368, 369 Neonatal, 52, 59, 79, 91, 116, 119, 122, 123, 124, 125, 204, 238, 368 Neoplasm, 368, 374, 399 Nephrogenic, 293, 368 Nerve Fibers, 202, 368, 393

Index 417

Nerve Growth Factor, 193, 212, 368 Nervous System, 11, 197, 202, 307, 309, 310, 317, 318, 324, 326, 343, 346, 348, 359, 363, 366, 367, 368, 369, 371, 372, 375, 390, 395 Neural, 12, 204, 309, 311, 337, 343, 350, 368 Neural tube defects, 204, 368 Neuritis, 76, 369 Neurodegenerative Diseases, 204, 318, 369 Neuroendocrine, 36, 369 Neurofibrillary Tangles, 213, 369 Neurofilaments, 369 Neurogenic, 202, 369 Neuroleptic, 310, 315, 326, 369 Neurologic, 4, 62, 233, 337, 369 Neuronal, 24, 29, 196, 197, 208, 209, 369, 375, 390 Neurons, 16, 333, 340, 343, 368, 369, 393, 395 Neuropeptides, 16, 369 Neurotransmitters, 16, 190, 366, 369, 392 Neutrons, 310, 357, 369, 385 Neutropenia, 370, 378 Neutrophils, 347, 348, 359, 370, 378 Niacin, 126, 258, 265, 370, 399 Nitric Oxide, 25, 43, 219, 246, 370 Nitrogen, 229, 312, 340, 342, 358, 370, 399 Norepinephrine, 309, 335, 370 Normotensive, 86, 88, 370 Nuclear, 22, 87, 191, 217, 224, 318, 337, 340, 368, 370, 388, 400 Nuclei, 311, 314, 337, 344, 362, 365, 369, 370, 372, 383 Nucleic acid, 186, 197, 216, 217, 221, 223, 235, 344, 350, 354, 367, 370, 371, 384 Nucleic Acid Hybridization, 350, 370 Nucleic Acid Probes, 186, 370 Nucleus, 16, 314, 315, 318, 325, 331, 333, 339, 340, 356, 366, 370, 383, 392, 394, 396 Nurse Practitioners, 88, 175, 370 O Obstetrics, 53, 87, 91, 94, 105, 119, 120, 123, 125, 371 Ocular, 108, 205, 238, 288, 371 Odds Ratio, 272, 371, 387 Odour, 316, 371, 400 Ointments, 335, 371 Oligodendroglia, 367, 371 Oligomenorrhea, 371, 379 Oligonucleotide Probes, 197, 221, 371 Oliguria, 358, 371 Omega-3 fatty acid, 132, 134, 164, 371

Oncogenic, 355, 371 Opacity, 322, 333, 371 Ophthalmic, 239, 371 Ophthalmoscope, 117, 371 Opsin, 371, 388 Optic Chiasm, 352, 371, 372 Optic Disk, 334, 362, 371 Optic Nerve, 204, 371, 372, 387, 388, 389 Optic nerve head, 204, 372 Orbital, 327, 372 Organ Culture, 372, 397 Organ Procurement, 39, 372 Organelles, 196, 324, 331, 366, 372, 378 Orthostatic, 315, 372 Osmosis, 372 Osmotic, 210, 310, 365, 372 Ossicles, 348, 372 Osteoarthritis, 137, 218, 260, 372 Osteomyelitis, 290, 372 Osteoporosis, 4, 192, 197, 221, 372 Ouabain, 131, 372 Outpatient, 34, 61, 108, 169, 173, 187, 372 Ovalbumin, 24, 372 Ovaries, 339, 351, 372, 379, 387, 391 Ovary, 232, 272, 372, 373, 394 Overexpress, 235, 373 Overweight, 125, 161, 165, 218, 373 Ovum, 332, 345, 366, 373, 381, 399 Oxidants, 41, 373 Oxidation, 25, 26, 40, 49, 103, 307, 315, 320, 331, 333, 346, 360, 373 Oxidation-Reduction, 373 Oxidative Phosphorylation, 196, 373 Oxidative Stress, 28, 41, 50, 94, 132, 373 Oxygen Consumption, 340, 373, 387 P Palliative, 33, 235, 373, 396 Pancreas Transplant, 4, 104, 151, 249, 373 Pancreas Transplantation, 104, 151, 249, 373 Pancreatectomy, 5, 373 Pancreaticoduodenectomy, 5, 373 Pancreatitis, 5, 91, 188, 241, 374 Papilloma, 374, 388 Parenteral, 13, 46, 66, 374 Paresis, 369, 374 Paresthesias, 304, 369, 374 Parkinsonism, 315, 374 Paronychia, 97, 374 Paroxysmal, 313, 374 Partial remission, 374, 387 Particle, 199, 360, 374, 392, 398

418 Diabetes Mellitus

Parturition, 371, 374 Pathogen, 223, 374 Pathologic, 184, 219, 307, 315, 319, 330, 351, 374, 383 Pathologic Processes, 315, 374 Pathologies, 183, 201, 374 Pathophysiology, 11, 40, 52, 55, 57, 238, 239, 241, 245, 246, 254, 255, 374 Patient Care Team, 250, 374 Patient Education, 61, 148, 239, 248, 249, 253, 274, 287, 288, 298, 300, 305, 374 Patient Satisfaction, 88, 374 Patient Selection, 245, 374 Pelvic, 375, 382 Penicillin, 314, 375, 401 Peptide T, 156, 212, 375 Percutaneous, 44, 62, 88, 109, 375 Perforation, 343, 375, 402 Perfusion, 76, 134, 204, 245, 375 Pericardium, 375, 395 Perinatal, 90, 131, 203, 375 Periodontal disease, 53, 57, 106, 375 Periodontitis, 53, 57, 375 Perioperative, 108, 239, 244, 375 Peripheral blood, 109, 159, 355, 375 Peripheral Nerves, 359, 375, 379, 393 Peripheral Nervous System, 202, 332, 367, 369, 375, 394 Peripheral Neuropathy, 78, 160, 169, 375 Peripheral stem cells, 347, 375 Peripheral Vascular Disease, 60, 61, 180, 199, 219, 238, 245, 375 Peritoneal, 32, 260, 376 Peritoneal Cavity, 376 Peritoneal Dialysis, 32, 260, 376 Peritoneum, 376 Peritonitis, 376, 402 Peroral, 189, 228, 376 Petrolatum, 337, 376 PH, 76, 84, 134, 376 Phagocyte, 362, 373, 376 Pharmaceutical Solutions, 335, 376 Pharmacodynamic, 14, 229, 376 Pharmacokinetic, 14, 229, 254, 376 Pharmacologic, 10, 12, 40, 45, 106, 273, 312, 330, 376, 398 Pharmacology, Clinical, 238, 376 Phenolphthalein, 337, 376 Phenotype, 14, 15, 16, 18, 32, 36, 54, 68, 73, 74, 376 Phenyl, 224, 231, 376 Phenylalanine, 376, 400

Phorbol, 190, 377 Phorbol Esters, 190, 377 Phosphatidic Acids, 361, 377 Phosphodiesterase, 192, 232, 377 Phospholipases, 377, 391 Phospholipids, 341, 360, 377 Phosphoprotein Phosphatase, 323, 377 Phosphorus, 321, 377 Phosphorylate, 43, 44, 377 Phosphorylation, 17, 42, 43, 50, 70, 186, 222, 331, 377, 384 Photocoagulation, 326, 377 Photodynamic therapy, 377 Photosensitizer, 227, 377 Physical Examination, 156, 160, 168, 324, 345, 377 Physical Fitness, 340, 377 Physiologic, 16, 43, 45, 175, 240, 246, 309, 319, 341, 356, 363, 377, 382, 386 Physiology, 11, 42, 64, 91, 338, 377 Pigment, 318, 367, 371, 377 Piloerection, 352, 377 Pilot Projects, 49, 378 Pilot study, 28, 51, 133, 161, 378 Pituitary Gland, 330, 378 Placenta, 378, 381, 384, 400 Plants, 130, 132, 322, 331, 334, 345, 346, 347, 356, 366, 370, 372, 378, 380, 389, 398, 399 Plaque, 81, 317, 378 Plasma cells, 314, 378 Plasma protein, 310, 338, 378 Plasmid, 24, 378, 401 Plasmin, 342, 378 Plasminogen, 57, 342, 378 Plasminogen Activators, 57, 378 Plastids, 372, 378 Platelet Activating Factor, 233, 378 Platelet Activation, 90, 378, 391 Platelet Aggregation, 312, 370, 379, 397 Platelets, 363, 370, 378, 379, 390, 397 Podiatry, 170, 379 Poisoning, 332, 356, 368, 379, 390 Polycystic, 17, 232, 351, 379 Polycystic Ovary Syndrome, 232, 351, 379 Polygenic Inheritance, 18, 379 Polymerase, 16, 379 Polymerase Chain Reaction, 16, 379 Polymers, 200, 379, 383 Polymorphism, 70, 72, 73, 74, 89, 107, 110, 118, 206, 220, 379 Polyradiculoneuropathy, 203, 379

Index 419

Polyradiculopathy, 379 Polysaccharide, 207, 314, 323, 379, 383 Polyunsaturated fat, 131, 134, 218, 379, 397 Porphyria, 203, 380 Porphyrins, 380 Port, 211, 380 Port-a-cath, 380 Portal Vein, 168, 380 Post partum, 43, 380 Posterior, 204, 312, 317, 325, 335, 357, 373, 380, 389 Postmenopausal, 49, 97, 285, 372, 380 Postnatal, 380, 393 Postprandial, 146, 195, 214, 253, 380 Postprandial Blood Glucose, 214, 380 Postsynaptic, 380, 391, 395 Postural, 238, 380 Potassium, 16, 18, 29, 131, 182, 191, 192, 310, 335, 365, 380 Potassium Channels, 191, 380 Potentiate, 194, 230, 380 Potentiation, 380, 391 Practice Guidelines, 275, 289, 291, 380 Pravastatin, 88, 380 Predisposition, 35, 152, 219, 220, 381 Pregnancy in Diabetics, 333, 381 Pregnancy Tests, 345, 381 Prickle, 358, 381 Primary Biliary Cirrhosis, 75, 381 Primary Prevention, 6, 204, 381 Probe, 364, 371, 381 Prodrug, 381 Progeny, 19, 381 Progesterone, 365, 381, 394 Prognostic factor, 23, 381 Proinsulin, 69, 149, 330, 381, 384 Projection, 332, 370, 372, 381, 386 Proline, 209, 327, 351, 381 Promoter, 17, 19, 38, 77, 198, 215, 223, 224, 382 Prone, 24, 32, 134, 186, 260, 382 Prophylaxis, 220, 226, 229, 230, 382, 401 Proportional, 61, 382 Prospective study, 360, 382 Prostaglandin, 218, 313, 382, 397 Prostaglandins A, 382 Prostaglandins F, 365, 382 Prostate, 218, 219, 382 Protease, 28, 209, 258, 327, 354, 382 Protein C, 310, 311, 315, 318, 326, 357, 360, 382, 383, 399, 400

Protein Conformation, 311, 357, 383 Protein S, 19, 64, 243, 319, 344, 383, 388, 396 Proteinuria, 30, 345, 383 Proteoglycans, 318, 341, 383 Proteolytic, 311, 327, 338, 342, 378, 383 Protocol, 66, 67, 160, 161, 181, 383 Protons, 310, 350, 356, 383, 385 Provirus, 225, 383 Proximal, 335, 344, 358, 383 Proximate cause, 26, 383 Pruritus, 315, 383, 400 Psoriasis, 192, 213, 383 Psychic, 383 Psychosis, 315, 345, 383 Psychosomatic, 226, 383 Psychotherapy, 326, 384 Puberty, 233, 384 Public Health, 27, 29, 51, 52, 58, 63, 135, 162, 246, 275, 278, 284, 286, 384 Public Policy, 271, 384 Publishing, 69, 384 Puerperium, 371, 384 Pulmonary, 85, 206, 243, 257, 319, 329, 340, 358, 359, 384, 402 Pulmonary Artery, 319, 384, 402 Pulmonary Edema, 358, 384 Pulmonary Embolism, 206, 384 Pulmonary Fibrosis, 85, 257, 384 Pulse, 365, 384 Pupil, 325, 329, 334, 384 Purified Insulins, 381, 384 Purines, 384, 390 Purulent, 307, 384 Putrefaction, 343, 384 Pyogenic, 372, 384 Pyridoxal, 182, 201, 208, 384 Pyruvate Kinase, 38, 384 Q Quality of Life, 9, 29, 47, 55, 83, 144, 149, 154, 170, 173, 174, 185, 188, 199, 385 Quiescent, 17, 385 R Race, 32, 53, 61, 365, 385 Radiation, 168, 199, 251, 313, 338, 342, 343, 353, 356, 357, 385, 389, 403 Radiation therapy, 343, 357, 385 Radioactive, 320, 350, 353, 357, 360, 366, 370, 371, 385, 389, 396, 400 Radiography, 313, 345, 385 Radioisotope, 371, 385 Radiological, 375, 385

420 Diabetes Mellitus

Radiology, 109, 173, 240, 290, 385 Random Allocation, 385 Randomization, 54, 385 Randomized clinical trial, 88, 122, 124, 135, 385 Reactive Oxygen Species, 25, 50, 385 Reagent, 54, 343, 386 Receptors, Cytokine, 41, 386 Recombinant, 29, 47, 65, 69, 159, 186, 198, 209, 216, 223, 386, 401 Recombination, 199, 344, 386 Rectal, 6, 251, 386 Rectal Prolapse, 251, 386 Rectum, 313, 315, 320, 327, 334, 341, 342, 344, 354, 358, 382, 386 Red blood cells, 193, 339, 349, 386, 389 Red Nucleus, 317, 386 Reductase, 41, 210, 310, 361, 380, 386, 396 Refer, 1, 8, 183, 327, 342, 350, 360, 362, 368, 369, 370, 383, 386 Reflective, 28, 386 Reflex, 29, 260, 386 Refraction, 386, 393 Regeneration, 58, 193, 194, 386 Regression Analysis, 272, 386 Relative risk, 7, 386 Relaxin, 220, 387 Reliability, 170, 387 Remission, 54, 90, 387 Renal failure, 81, 104, 187, 332, 387 Renin, 50, 62, 79, 87, 104, 230, 313, 321, 387 Renin-Angiotensin System, 50, 313, 321, 387 Reperfusion, 84, 85, 102, 182, 208, 367, 387 Reperfusion Injury, 182, 208, 387 Respiration, 315, 324, 341, 365, 387 Respiratory distress syndrome, 203, 387 Restoration, 47, 367, 387, 403 Retina, 210, 313, 325, 328, 334, 359, 362, 371, 372, 387, 388, 389, 402 Retinal, 33, 334, 335, 371, 388, 394 Retinal Ganglion Cells, 371, 388 Retinoblastoma, 17, 388 Retinoblastoma Protein, 17, 388 Retinoid, 225, 388 Retinol, 388 Retrospective, 87, 113, 388 Retrospective study, 87, 113, 388 Retrovirus, 199, 225, 388 Rhabdomyolysis, 75, 91, 388 Rhamnose, 372, 388 Rheumatism, 388

Rheumatoid, 113, 119, 192, 212, 223, 224, 228, 260, 373, 388 Rheumatoid arthritis, 113, 119, 192, 212, 223, 224, 228, 260, 388 Ribose, 308, 388 Ribosome, 388, 398 Rigidity, 362, 374, 378, 388 Risk patient, 159, 389 Risperidone, 15, 112, 389 Rod, 317, 325, 358, 389 Rosiglitazone, 164, 218, 233, 265, 389 S Saliva, 207, 212, 389 Salivary, 331, 334, 389, 394 Salivary glands, 331, 334, 389 Saphenous, 330, 389 Saphenous Vein, 330, 389 Saponins, 389, 394 Scans, 36, 389 Schizophrenia, 14, 85, 197, 226, 315, 389 Sclera, 325, 329, 389 Sclerosis, 246, 316, 366, 389 Sebaceous, 389, 403 Second Messenger Systems, 369, 389 Secretory, 12, 47, 67, 161, 220, 330, 390, 395 Secular trends, 34, 390 Sedentary, 49, 390 Segmental, 345, 390, 393 Segregation, 64, 386, 390 Self Care, 238, 390 Semen, 382, 390 Senile, 213, 311, 315, 372, 390 Senile Plaques, 213, 311, 390 Sensitization, 154, 390 Sensor, 16, 390 Sepsis, 192, 223, 390 Septic, 224, 390 Septicemia, 208, 209, 390 Sequence Analysis, 104, 390 Sequence Homology, 375, 390 Sequencing, 31, 379, 390 Serine, 43, 209, 377, 390, 399 Serotonin, 315, 326, 389, 390, 399 Serous, 338, 391 Sex Characteristics, 308, 312, 384, 391, 396 Shock, 190, 224, 312, 391, 399 Signal Transduction, 186, 190, 220, 323, 391 Signs and Symptoms, 156, 288, 289, 387, 391, 400 Skeletal, 14, 19, 40, 42, 46, 70, 186, 200, 231, 260, 312, 325, 367, 388, 391, 392, 396, 399

Index 421

Skeleton, 307, 341, 357, 382, 391 Skull, 337, 369, 391, 396 Sleep apnea, 218, 391 Small intestine, 207, 217, 318, 325, 336, 350, 356, 357, 391, 399 Smooth muscle, 44, 212, 312, 321, 329, 345, 350, 351, 382, 387, 391, 392, 394 Social Class, 113, 391 Social Environment, 385, 391 Social Support, 9, 147, 149, 169, 392 Sodium, 25, 131, 310, 335, 347, 365, 368, 392, 395 Soft tissue, 320, 391, 392 Solid tumor, 313, 392 Solitary Nucleus, 317, 392 Solvent, 207, 318, 340, 346, 364, 372, 376, 392 Somatic, 308, 350, 365, 375, 392, 401 Sorbitol, 210, 310, 392 Sound wave, 328, 386, 392 Soybean Oil, 380, 392 Spasm, 226, 392 Spasticity, 202, 392 Specialist, 113, 239, 244, 295, 334, 392 Specificity, 29, 172, 198, 309, 392 Spectrum, 68, 199, 331, 392 Sperm, 312, 325, 393 Sphincter, 6, 386, 393 Spina bifida, 369, 393 Spinal cord, 320, 324, 363, 368, 369, 375, 386, 393, 395 Spinal Nerve Roots, 379, 393 Spinal Nerves, 375, 393 Spinous, 339, 358, 393 Spleen, 24, 312, 331, 361, 373, 393 Splenic Vein, 380, 393 Sporadic, 369, 388, 393 Sprue, 5, 393 Stabilization, 194, 393 Staging, 13, 389, 393 Standard therapy, 23, 393 Stasis, 246, 393 Steatosis, 96, 246, 341, 393 Steel, 325, 393 Stem Cells, 48, 375, 393 Stent, 44, 109, 393 Stereoscopic, 33, 394 Sterile, 394, 399 Sterility, 354, 394 Steroid, 97, 168, 173, 174, 190, 330, 389, 394 Stimulant, 350, 394, 401 Stimulus, 329, 336, 356, 374, 386, 394, 396

Stomach, 156, 307, 317, 334, 339, 343, 344, 346, 350, 358, 368, 373, 376, 391, 393, 394, 402 Stomatitis, 345, 394 Stool, 354, 358, 394 Strand, 50, 379, 394 Stromal, 320, 394 Stromal Cells, 320, 394 Subacute, 354, 394 Subclinical, 114, 169, 354, 394 Subcutaneous, 45, 49, 83, 119, 185, 279, 308, 336, 374, 394, 402 Submaxillary, 339, 394 Subspecies, 392, 394 Substance P, 364, 390, 394 Substrate, 25, 43, 72, 186, 339, 395 Sulfur, 224, 340, 364, 395 Superoxide, 25, 43, 197, 395 Supplementation, 130, 131, 132, 134, 135, 246, 395 Suppression, 10, 45, 181, 200, 330, 395 Suppressive, 54, 395 Sweat, 352, 395 Sympathetic Nervous System, 313, 317, 395 Sympathomimetic, 335, 339, 370, 395 Symphysis, 382, 395 Symptomatic, 117, 160, 172, 333, 374, 381, 395 Synapses, 369, 395 Synaptic, 391, 395 Synergistic, 4, 60, 232, 395 Systemic lupus erythematosus, 206, 395 Systolic, 26, 34, 351, 395 T Tacrolimus, 156, 173, 395 Tardive, 315, 396 Taurine, 135, 140, 396 Technetium, 134, 396 Temporal, 104, 350, 362, 396 Temporal Lobe, 104, 396 Tenosynovitis, 260, 396 Terminator, 326, 396 Testosterone, 108, 386, 396 Tetracycline, 17, 335, 396 Thalamic, 317, 396 Thalamic Diseases, 317, 396 Therapeutics, 55, 75, 76, 82, 86, 90, 93, 94, 95, 106, 115, 116, 133, 266, 396 Thermal, 316, 335, 370, 379, 396 Thigh, 49, 341, 396 Thinness, 97, 396

422 Diabetes Mellitus

Thioredoxin, 41, 396 Thorax, 307, 396, 401 Threonine, 375, 377, 390, 396 Threshold, 6, 10, 147, 351, 396 Thrombocytopenia, 378, 397 Thrombolytic, 84, 378, 397 Thrombolytic Therapy, 84, 397 Thrombosis, 103, 167, 355, 383, 394, 397 Thromboxanes, 316, 336, 397 Thrombus, 330, 354, 367, 379, 397, 402 Thymus, 140, 353, 361, 397 Thyroid, 115, 132, 190, 368, 397, 400 Thyroid Gland, 368, 397 Thyroid Hormones, 132, 190, 397, 400 Thyroiditis, 118, 228, 397 Thyroxine, 310, 377, 397 Tin, 239, 322, 375, 397 Tissue Culture, 194, 397 Tissue Harvesting, 372, 397 Tolazamide, 219, 397 Tolerance, 15, 39, 42, 46, 49, 54, 60, 85, 102, 120, 163, 183, 185, 205, 210, 215, 224, 225, 226, 230, 232, 235, 236, 240, 254, 287, 308, 333, 346, 381, 397 Tomography, 397 Tonicity, 336, 397 Tooth Preparation, 308, 397 Topical, 76, 195, 264, 340, 351, 376, 397 Torsion, 354, 397 Total pancreatectomy, 373, 398 Toxic, iv, 12, 41, 209, 273, 318, 332, 334, 338, 353, 364, 369, 398 Toxicity, 50, 336, 398 Toxicology, 25, 272, 398 Toxins, 16, 314, 340, 354, 366, 390, 398, 401 Trace element, 320, 325, 397, 398 Trachea, 320, 397, 398 Traction, 325, 398 Transcriptase, 388, 398 Transcription Factors, 17, 38, 48, 62, 190, 323, 398 Transduction, 22, 186, 190, 391, 398 Transfection, 29, 319, 398 Transfer Factor, 353, 398 Transferases, 347, 398 Transforming Growth Factor alpha, 201, 398 Translation, 42, 51, 223, 398 Translational, 59, 398 Translocation, 55, 398 Transmitter, 307, 335, 356, 363, 370, 395, 398

Transposase, 198, 399 Trauma, 235, 244, 318, 332, 348, 368, 374, 396, 399 Trigger zone, 315, 399 Triglyceride, 40, 89, 210, 214, 234, 351, 399 Trivalent, 41, 399 Troglitazone, 76, 115, 218, 233, 240, 254, 399 Trophoblast, 319, 399 Tropism, 69, 399 Tropomyosin, 399 Troponin, 42, 399 Truncal, 236, 399 Trypsin, 216, 338, 399 Tryptophan, 327, 390, 399 Tubercle, 399 Tuberculin, 168, 399 Tuberculosis, 87, 156, 243, 329, 361, 399 Tumor Necrosis Factor, 12, 42, 221, 399 Tumor suppressor gene, 388, 399 Tumour, 192, 399 Tyrosine, 43, 71, 73, 186, 216, 222, 335, 400 U Ubiquitin, 369, 400 Ulcer, 23, 65, 400 Ulceration, 188, 245, 400 Ulcerative colitis, 192, 327, 354, 400 Ultrasonography, 345, 400 Umbilical Arteries, 400 Umbilical Cord, 4, 310, 400 Unconscious, 312, 332, 352, 400 Univalent, 351, 373, 400 Uraemia, 374, 400 Uranium, 396, 400 Urban Population, 96, 400 Urea, 188, 358, 395, 400 Uremia, 358, 387, 400 Ureters, 400, 401 Urethra, 382, 400, 401 Uric, 347, 352, 384, 400 Urinary, 29, 62, 80, 116, 204, 231, 321, 354, 371, 400, 401 Urinary tract, 204, 400, 401 Urinary tract infection, 204, 401 Urine, 29, 41, 156, 160, 252, 273, 289, 310, 314, 315, 319, 327, 333, 335, 339, 347, 354, 358, 365, 368, 371, 383, 400, 401 Uterus, 324, 332, 338, 343, 363, 372, 381, 401 V Vaccination, 82, 225, 401 Vaccine, 157, 225, 228, 308, 383, 401

Index 423

Vacuoles, 338, 372, 401 Vagal, 89, 401 Vagina, 324, 358, 363, 401 Vagus Nerve, 392, 399, 401 Valine, 206, 401 Vascular, 15, 23, 25, 28, 43, 44, 47, 62, 64, 72, 117, 118, 123, 124, 150, 164, 171, 180, 184, 185, 212, 219, 233, 236, 241, 243, 245, 246, 251, 312, 313, 321, 325, 333, 338, 345, 351, 354, 364, 370, 378, 397, 401 Vascular Resistance, 245, 401 Vasculitis, 374, 401 Vasoconstriction, 204, 339, 348, 401 Vasodilation, 43, 123, 124, 212, 246, 313, 401 Vasodilator, 314, 320, 335, 350, 367, 401 Vasomotor, 98, 99, 102, 401 VE, 96, 172, 401 Vector, 13, 198, 209, 222, 223, 355, 398, 401 Vein, 25, 156, 168, 245, 312, 316, 356, 370, 380, 389, 393, 400, 401, 402 Venoms, 332, 401 Venous, 47, 173, 206, 316, 324, 349, 383, 401, 402 Venous blood, 324, 401 Venous Thrombosis, 206, 402 Ventricle, 350, 352, 384, 395, 402 Ventricular, 26, 42, 112, 118, 367, 402 Ventricular Dysfunction, 42, 402 Venules, 319, 321, 338, 364, 402 Vesicular, 350, 364, 402 Veterinary Medicine, 271, 402 Villous, 323, 402

Viral, 4, 12, 32, 69, 85, 184, 187, 197, 199, 206, 221, 307, 339, 371, 388, 398, 402 Viral Hepatitis, 4, 85, 402 Virilism, 351, 402 Virulence, 317, 398, 402 Visceral, 49, 99, 217, 317, 376, 401, 402 Visceral Afferents, 317, 401, 402 Visceral fat, 99, 217, 402 Viscosity, 307, 402 Vitreous Body, 387, 402 Vitreous Hemorrhage, 334, 402 Vitro, 19, 44, 64, 402 Vivo, 12, 17, 19, 22, 27, 29, 38, 44, 57, 60, 68, 182, 194, 199, 216, 226, 231, 354, 364, 373, 395, 397, 402 Volvulus, 251, 402 Vulgaris, 189, 228, 403 W Weight Gain, 72, 148, 403 Weight-Bearing, 372, 403 White blood cell, 307, 314, 317, 354, 359, 361, 366, 370, 378, 403 Windpipe, 397, 403 Wound Healing, 117, 313, 355, 363, 403 X Xenograft, 48, 313, 403 X-ray, 15, 49, 156, 168, 173, 227, 316, 328, 342, 357, 370, 385, 389, 403 Y Yeasts, 376, 403 Yolk Sac, 341, 403 Z Zoonoses, 12, 403 Zygote, 328, 403

424 Diabetes Mellitus