ITRIC XIDE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Nitric Oxide: 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: 0-597-84528-X 1. Nitric Oxide-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on nitric oxide. 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 NITRIC OXIDE ........................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Nitric Oxide .................................................................................. 5 E-Journals: PubMed Central ....................................................................................................... 64 The National Library of Medicine: PubMed ................................................................................ 90 CHAPTER 2. NUTRITION AND NITRIC OXIDE ............................................................................... 139 Overview.................................................................................................................................... 139 Finding Nutrition Studies on Nitric Oxide............................................................................... 139 Federal Resources on Nutrition ................................................................................................. 145 Additional Web Resources ......................................................................................................... 146 CHAPTER 3. ALTERNATIVE MEDICINE AND NITRIC OXIDE ......................................................... 147 Overview.................................................................................................................................... 147 National Center for Complementary and Alternative Medicine................................................ 147 Additional Web Resources ......................................................................................................... 169 General References ..................................................................................................................... 171 CHAPTER 4. DISSERTATIONS ON NITRIC OXIDE ........................................................................... 173 Overview.................................................................................................................................... 173 Dissertations on Nitric Oxide.................................................................................................... 173 Keeping Current ........................................................................................................................ 176 CHAPTER 5. CLINICAL TRIALS AND NITRIC OXIDE ...................................................................... 177 Overview.................................................................................................................................... 177 Recent Trials on Nitric Oxide.................................................................................................... 177 Keeping Current on Clinical Trials ........................................................................................... 183 CHAPTER 6. PATENTS ON NITRIC OXIDE ...................................................................................... 185 Overview.................................................................................................................................... 185 Patents on Nitric Oxide ............................................................................................................. 185 Patent Applications on Nitric Oxide ......................................................................................... 219 Keeping Current ........................................................................................................................ 258 CHAPTER 7. BOOKS ON NITRIC OXIDE.......................................................................................... 259 Overview.................................................................................................................................... 259 Book Summaries: Federal Agencies............................................................................................ 259 Book Summaries: Online Booksellers......................................................................................... 261 Chapters on Nitric Oxide........................................................................................................... 266 CHAPTER 8. PERIODICALS AND NEWS ON NITRIC OXIDE ............................................................ 269 Overview.................................................................................................................................... 269 News Services and Press Releases.............................................................................................. 269 Newsletters on Nitric Oxide ...................................................................................................... 272 Newsletter Articles .................................................................................................................... 273 Academic Periodicals covering Nitric Oxide ............................................................................. 273 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 277 Overview.................................................................................................................................... 277 NIH Guidelines.......................................................................................................................... 277 NIH Databases........................................................................................................................... 279 Other Commercial Databases..................................................................................................... 281 The Genome Project and Nitric Oxide....................................................................................... 281 APPENDIX B. PATIENT RESOURCES ............................................................................................... 285 Overview.................................................................................................................................... 285 Patient Guideline Sources.......................................................................................................... 285 Finding Associations.................................................................................................................. 288
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APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 291 Overview.................................................................................................................................... 291 Preparation................................................................................................................................. 291 Finding a Local Medical Library................................................................................................ 291 Medical Libraries in the U.S. and Canada ................................................................................. 291 ONLINE GLOSSARIES................................................................................................................ 297 Online Dictionary Directories ................................................................................................... 297 NITRIC OXIDE DICTIONARY .................................................................................................. 299 INDEX .............................................................................................................................................. 411
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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 nitric oxide 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 nitric oxide, 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 nitric oxide, 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 nitric oxide. 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 nitric oxide, 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 nitric oxide. 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 NITRIC OXIDE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on nitric oxide.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and nitric oxide, 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 “nitric oxide” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •
Effect of Diabetes on Nitric Oxide Metabolism During Cardiac Surgery Source: Diabetes. 50(11): 2603-2610. November 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The metabolism of nitric oxide (NO) during cardiac surgery is unclear. This article reports on a study of the effect of diabetes on NO metabolism during cardiac surgery in 40 subjects (20 with diabetes and 20 without diabetes). The patients were randomized to receive an infusion of physiological saline or nitroglycerin (GTN) starting 10 minutes before the initiation of cardiopulmonary (heart-lung) bypass and then continuing for a period of four hours. Blood and urine samples were collected at several time points for up to 8 hours. NO metabolites (NOx) were determined by measuring
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plasma and urine. Plasma insulin levels were also determined at selected time points. Plasma NOx levels before surgery were significantly elevated in the group with diabetes compared with the group without diabetes, and values were further increased during surgery in the former but not in the latter. Interestingly, infusion of GTN, a nitric oxide donor, significantly reduced plasma NOx and its urine elimination in patients with diabetes. Cardiac surgery increased plasma insulin in patients with and without diabetes; this increase was delayed by the infusion of GTN, but it was not related to the changes in NO production. In conclusion, NO production during cardiac surgery is increased in patients with diabetes, and this elevation can be blunted by the infusion of GTN in a rapid and reversible manner. 6 figures. 4 tables. 45 references. •
Nitric Oxide as a Modulator of Penile Erection Source: Current Opinion in Urology. 2(6): 446-449. December 1992. Summary: The role of nitric oxide as a modulator of penile erection has recently been the subject of extensive investigation. Nitric oxide is synthesized by both the endothelium that lines the lacunar spaces and the autonomic dilator nerves of the corpora cavernosa, and it mediates smooth muscle relaxation. This article summarizes the current knowledge of the role of nitric oxide in penile erection. 49 annotated references. (AA).
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Role of Nitric Oxide and Other Neurotransmitters in Erectile Function Source: Current Opinion in Urology. 6(6): 347-351. November 1996. Contact: Available from Rapid Science Publishers. 400 Market Street, Suite 750, Philadelphia, PA 19106. (800) 552-5866 or (215) 574-2210. Fax (215) 574-3533. Summary: This article reviews recent research on the role of nitric oxide and other neurotransmitters in erectile function. Nitric oxide (NO) is now established as the major peripheral relaxant neurotransmitter in human corpus cavernosum. The rationale for identification of neurotransmitters involved in erectile function is to allow pharmacological manipulation of messenger pathways in order to treat clinically important disorders such as impotence and priapism. Topics include central neurotransmission, including erectile pathways in the central nervous system, dopamine, oxytocin, serotonin, and nitric oxide; and peripheral neurotransmission, including nitric oxide, acetylcholine, noradrenaline, and neuropeptides. Current research suggests that erection occurs following release of nitric oxide from peripheral nerves, which causes cavernosal smooth muscle relaxation by elevation of cGMP and decrease in intracellular calcium. The activity of this pathway is probably modulated by various other local factors. Central mechanisms that interact to stimulate these nerves are incompletely understood but appear to involve channeling of facilitatory impulses through integrating areas and descending pathways involving several neurotransmitters. It is likely that diminished release of NO or changes in smooth muscle contractility are involved in the etiology of impotence in older men and such changes may be common to age-related dysfunction of other autonomically innervated organs such as the bladder and vascular system. 47 references (7 annotated). (AA-M).
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Elevated Nitric Oxide Production in Rheumatoid Arthritis: Detection Using the Fasting Urinary Nitrate:Creatinine Ratio Source: Arthritis and Rheumatism. 39(4):643-647; April 1996.
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Summary: This journal article for health professionals describes a study that was conducted to develop a simple method for assessing endogenous nitric oxide (NO) production applicable to routine clinical practice in rheumatology. NO production was assessed in 19 patients with rheumatoid arthritis (RA) as serum nitrate levels and as the urinary nitrate:creatinine ratio in morning samples of urine following an overnight fast. The influence of dietary intake of nitrate on these measurements was investigated in 12 healthy volunteers. The clinical value of the urinary nitrate: creatinine ratio was validated in patients with infectious gastroenteritis, in whom its production is known to be increased. Results show that urinary nitrate:creatinine ratios were significantly elevated in patients with RA or infectious gastroenteritis and that serum nitrate was significantly elevated only in patients with infectious gastroenteritis. Dietary intake of nitrate had no significant influence on the fasting morning urinary nitrate:creatinine ratio in the healthy volunteers, showing that this particular parameter was a useful indicator of endogenous NO production. 20 references and 3 figures. (AA-M).
Federally Funded Research on Nitric Oxide The U.S. Government supports a variety of research studies relating to nitric oxide. 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 nitric oxide. 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 nitric oxide. The following is typical of the type of information found when searching the CRISP database for nitric oxide: •
Project Title: ABNORMALITIES IN KERATOCONUS CORNEAS Principal Investigator & Institution: Kenney, Maria C.; Director,Molecular Eye Reseach Lab.; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 900481804 Timing: Fiscal Year 2002; Project Start 01-MAY-1987; Project End 31-OCT-2002 Summary: (provided by applicant): Keratoconus is a corneal disorder characterized by excessive thinning of the stroma, severe irregular astigmatism and decreased visual acuity. It is a leading indication for corneal transplantation within the United States. Its pathogenesis is characterized by increased activities of degradative enzymes, altered processing of oxidative stress-related molecules, increased focal fibrosis and apoptosis. The underlying defect(s) that initiates these changes or ties them together is still not clear. During the past three years we have applied differential display technology, Smart cDNA synthesis and nucleic acid array analysis to keratoconus corneas and cell cultures.
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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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Approximately 3,000 genes have been screened for differential expression between normal and keratoconus. We found abnormalities in two distinct signal transduction pathways, (1) a receptor-like protein tyrosine phosphatase (leukocyte common antigen related protein- LAR) and (2) a receptor tyrosine kinase (ErbB3), its ligand (heregulin) and downstream factors, PYK2, EPB-l and TOB. Our data also show that KC corneas have increased inducible nitric oxide synthase (iNOS) and accumulation of peroxynitrite, a cytotoxic by-product of nitric oxide. We hypothesize that KC corneas have a defect in their ability to process free radicals and have up-regulation of these signal transduction pathways. This results in abnormal protein phosphorylation patterns, which contributes heavily to the pathogenesis of keratoconus. To test this hypothesis we propose the following specific aims: Specific Aim #1 will identify the LAR isoforms within the normal and keratoconus corneas and charactize changes in tyrosine phosphorylation patterns as a result of LAR activity. Specific Aim #2 will identify specific ErbB family members and heregulin isoforms present within keratoconus corneas and in vitro KC cell cultures. The nucleic acid array data demonstrating up-regulation of PYK2, JNK, EPB-l and TOB will be confirmed at the RNA (RT-PCR, Northern analyses, in situ hybridization) and protein levels (immunohistochemistry and Western blot analysis). Specific Aim #3 will address whether nitric oxide donors or peroxynitrites can affect the tyrosine phosphatase (LAR) or the tyrosine kinase (ErbBIPYK2/JNK) pathways. Proteins that undergo changes in nitration as a result of peroxynitrite accumulation will be identified. Specific Aim #4 will determine if the addition of heregulins, nitric oxide donors or peroxynitrites are capable of causing normal cells to change to the phenotype associated with KC. These studies will provide fundamental insights into KC pathogensis and may provide a basis for therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ARGINASE AND REGULATION OF NITRIC OXIDE SYNTHASE IN ALS Principal Investigator & Institution: Ratan, Rajiv R.; Director; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-JUL-2005 Summary: (Adapted from applicant's abstract): Amyotrophic lateral sclerosis is a prevalent neurological disorder characterized by inexorable muscle weakness leading to death. The principal pathological finding in amyotrophic lateral sclerosis is loss of nerve cells in the anterior horns of the spinal cord, the motor nuclei of the brainstem, and the upper motor neurons of the cerebral cortex. Investigations aimed at preventing or limiting progression of amyotrophic lateral sclerosis have thus focused on the mechanisms by which neurons degenerate. A transgenic mouse model has been developed that possesses many of the pathological and clinical features of human familial and sporadic amyotrophic lateral sclerosis. As nitric oxide (NO) has been shown to mediate neuronal loss in other neurodegenerative conditions, several groups have investigated the role that NO may play in disease progression | in the transgenic model. The results have been conflicting likely because currently available inhibitors of nitric oxide synthase do not permit optimal control of NO generation within particular cell types and subcellular compartments. A novel potential strategy for regulating nitric oxide synthesis involves the enzyme arginase that can | regulate availability of arginine in the cytoplasm or mitochondria. In preliminary studies, we have shown that: 1) extracellular arginase blocks neuronal apoptosis and 2) arginase immunoreactivity is, upregulated in the spinal cord of ALS transgenic mice as well as humans with the
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sporadic and familial forms of amyotrophic lateral sclerosis. These preliminary results lead to the overall hypothesis to be tested in this proposal: about Interventions aimed at promoting arginase activities in microglia, astrocytes and/or motor neurons will limit availability of cell arginine for toxic NO generation and thereby diminish cell death and disease progression in amyotrophic lateral sclerosis but permit NO to, mediate its survival promoting effects in each of these cell types. We propose to test this hypothesis by: 1) determining the cell types and subcellular compartments where arginase is expressed in the normal central nervous system of humans and mice, and how the localization and levels of these isoforms change in amyotrophic lateral sclerosis as well as in a transgenic mouse! Model of amyotrophic lateral sclerosis and how this compares to the localization of NOS (all forms) in these tissues; and 2) determining whether increased arginase activity in microglia, astrocytes or neurons from control mice or mice over expressing SOD1 mutant (G93A) will abrogate NO mediated toxicity of motor neurons induced by growth factor deprivation, excitotoxins or LPS/IFN-gamma treatment. These studies promise to enhance our understanding of how arginine about metabolism, including the synthesis of NO, is regulated in the normal and abnormal nervous system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ASTROCYTE-NEURON SIGNALING Principal Investigator & Institution: Haydon, Philip G.; Professor; Neuroscience; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-JUL-2006 Summary: (provided by applicant): During the past decade a growing body of evidence has accumulated to indicate that glial cells, and in particular astrocytes, play active roles in information processing (Haydon, 2001). Since astrocytes are juxtaposed with the capillaries and with end-feet on endothelia, and since astrocytic processes enwrap synaptic terminals, it is likely that astrocytes serve regulatory functions in controlling blood flow and synaptic transmission (Haydon, 2001; Raichle, 2001). We hypothesize that astrocytic calcium levels are the key integrative signal for the regulation of these two diverse functions. Specifically, we hypothesize that neuronal activity-induced astrocytic calcium signaling regulates: 1) the synthesis within the astrocyte of the vasodilator nitric oxide (NO), and 2) a feedback regulation of the synapse mediated by the calcium-dependent release of glutamate from astrocytes. Using calcium and nitric oxide imaging, confocal microscopy, electrophysiology, photolysis and adenovirus to overexpress SNARE protein fragments and G-protein-coupled receptors we will test four hypotheses: 1: Physiological calcium signaling in astrocytes stimulates nitric oxide production, which in turn regulates calcium homeostasis. 2: Neuronal activity causes the synthesis of nitric oxide in astrocytes. 3: SNARE proteins are essential for the release of glutamate from astrocytes. 4: The release of glutamate from astrocytes modulates synaptic transmission in hippocampal slices. By performing these studies we will obtain new insights into the roles of astrocytes in the CNS. Since astrocytes can integrate neuronal inputs and release glutamate in response to elevated internal calcium, the demonstration of a role for astrocytes in the control of the synapse will change the way we view information processing in the nervous system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BLOOD FLOW AND METABOLIC CONTROLS IN THE FETAL BRAIN Principal Investigator & Institution: Power, Gordon G.; Center for Perinatal Biology; Loma Linda University Loma Linda, Ca 92350 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Scanned from the applicant's description): Cerebral blood flow is of fundamental importance for normal development of the brain during fetal life. Oxygen stores of the body are minimal yet cerebral metabolic rate is high, and thus prompt adjustments of flow are necessary to match oxygen supply with oxygen need. Inadequate blood flow and oxygen delivery in the perinatal period cause tragic lifelong consequences including cerebral palsy and mental retardation. Until the present time, there has not been any method to measure cerebral blood flow in utero on a continuous basis. In the last two years, we have successfully adapted laser Doppler flowmetry to measure cerebral blood flow in the chronically prepared, near-term fetal sheep. Using the method, we have shown that nitric oxide mediates about 60 percent of the increase in flow that occurs in response to hypoxic stress. We have also obtained early evidence that the brain enters a state of regulated hypometabolism upon hypoxic stress, presumably by curtailing nonessential metabolic activities, and thereby rations oxygen use. In this reapplication, we propose six specific aims. First, we will compare the results of laser Doppler flowmetry with those obtained with fluorescent microspheres. We believe this comparison is an essential step for a complete validation of the new methodology. At the same time, we will validate a new method we have developed to measure heat production and oxygen use by the fetal brain. Second, we will continue to investigate the role of nitric oxide in mediating the increases of cerebral blood flow and reductions in metabolic rate in response to acute hypoxia. Third, we will test whether adenosine mediates the flow increases and hypometabolism that compensate during fetal hypoxia, i.e. whether it plays a role similar to that which we have already shown for nitric oxide. Fourth, we will test the importance of carbon dioxide in regulation of the fetal circulation and inquire about its interactions with nitric oxide and adenosine. Fifth, we will carry out experiments to distinguish between regulated hypometabolism of the fetal brain and the inevitable reduction of 02 use that accompanies oxygen starvation. Sixth, we will test whether the mechanisms controlling blood flow and metabolic rate in the brain are blunted after gestation at high elevations with exposure of the fetus to hypoxemia for several months. These studies will provide continuous measurements of cerebral perfusion and local heat production from a small region of the fetal brain for the first time. Our broad goal is to establish the control factors for oxygen delivery and use by the fetal brain and thereby to optimize brain development and minimize hypoxic injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BLOOD RECONSTRUCTION
NO
REFLOW
AFTER
MICROSURGICAL
Principal Investigator & Institution: Urbaniak, James R.; Professor; Surgery; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 01-FEB-1988; Project End 31-JAN-2005 Summary: (Verbatim from the application): Over the past three NIH grant periods we have identified numerous factors involved in the chain of events leading to the reperfusion failure of replanted tissues. Most recently, we have recognized that insufficient nitric oxide (NO) production by the endothelium as well as an excessive,
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toxic level of NO produced by extravasated leukocytes may contribute to the reperfusion failure of revascularized skeletal muscle. The central hypothesis of this proposal is that ischemia/reperfusion (i/r) leads to an imbalanced production of nitric oxide in skeletal muscle microdomains, and that supplementation with nitric oxide donor and/or selective pharmacological manipulation of nitric oxide synthase (NOS) isoenzymes will reduce the incidence of reperfusion failure. The proposed studies will determine the role of individual NOS isoenzyme in the pathophysiology of reperfusion failure and to assess efficacies of different NO-related agents in improving the outcome of reperfused skeletal muscle. Specifically, we will: 1) Determine the dynamic expressions and activities of NOS isoenzymes in representative rodent skeletal muscles following ischemia and reperfusion; 2) Determine the effects of NO donors and NOS inhibitors on thrombus formation at arterial and venous anastomosis sites following vessel repair; 3) Determine the effects of NO donors and NOS inhibitors on leukocyte adhesion and microcirculation of skeletal muscle after I/R injury; and 4) Determine the potential benefits of NO donors and NOS inhibitors based on the functional outcome of reperfused muscle. Our comprehensive study will include the judicial use of NOSisoform "knockout" mice to confirm the role of particular NOS isoenzyme in the pathophysiology of reperfusion failure of skeletal muscle. The results of these studies will provide a scientific basis for potential clinical applications of NO-related agents to improve the functional outcome of microvascular procedures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CEREBRAL CIRCULATION: NO AND REACTIVE OXYGEN SPECIES Principal Investigator & Institution: Heistad, Donald D.; Director; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-DEC-1976; Project End 31-MAR-2006 Summary: (Verbatim from the application): The goal of this project is to evaluate effects of inducible nitric oxide synthase (iNOS) on vascular function. The investigators have been studying effects of iNOS, using pharmacological inhibitors and iNOS-deficient mice, and have made a recombinant adenovirus, which will provide a novel approach to study vasomotor effects of iNOS. Preliminary data are the first studies of vasomotor effects of iNOS, using adenovirus-mediated gene transfer. Studies are proposed (based on preliminary data) to test the hypothesis that iNOS at high levels of expression, produces superoxide in blood vessels and thereby impairs endothelial function. Studies also are proposed to test the hypothesis that, at low levels of expression, gene transfer of iNOS may generate primarily nitric oxide (NO) that quenches superoxide and thereby improves endothelial function. These latter studies will be performed in vessels with high levels of superoxide, after exposure to lipopolysaccharide or from diabetic rabbits. Studies are proposed to study vessels in vitro and in vivo, and to examine mechanisms by which iNOS impairs vasomotor function. Approaches that will be used to address these aims are gene transfer of iNOS in vitro and in vivo, generally to the carotid or basilar artery of rabbits; measurement of vasomotor responses ex vivo in vascular rings in an organ bath, and responses in vivo using sonimicrometry; measurement of activity of nitric oxide synthase with labeled citrulline; detection of superoxide with hydroethidine in the vessel wall in situ; and quantitation of superoxide with lucigenin (5 uM). It is well recognized that iNOS is expressed in vessels in response to injury and in disease states, and that these disease states generally are associated with endothelial dysfunction. The use of gene transfer of iNOS to vessels to study vasomotor function is novel, and is likely to provide new insight into mechanisms by which iNOS alters vasomotor function.
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Nitric Oxide
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHOLINERGIC MECHANISMS OF BREATHING DURING SLEEP Principal Investigator & Institution: Lydic, Ralph B.; Bert La Du Professor of Anesthesia; Anesthesiology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-JUL-1989; Project End 31-MAR-2005 Summary: An overarching conceptual framework that continues to enrich sleep and respiratory neurobiology is the widely recognized importance of brain stem cholinergic neurotransmission. Within this framework, the long-term objectives of this renewal application are to elucidate signal transduction processes modulating pontine acetylcholine (ACh) release, sleep, and breathing. The four aims are unified conceptually and related to the long-term objectives by focusing on ACh release from laterodorsal tegmental (LDT) and pedunculopontine tegmental (PPT) neurons and LDT/PPT axon terminals projecting to the medial pontine reticular formation (mPRF). Specific Aims l and 2 will study the modulatory role of nitric oxide and soluble guanylyl cyclase. Aims 3 and 4 will determine whether adenosine A1 agonists and antagonists can significantly alter pontine ACh release and cholinergic activation of guanine nucleotide binding proteins (G proteins). Specific Aim 1 will use microdialysis to simultaneously measure nitric oxide levels and ACh release during wakefulness, NREM sleep, and REM sleep. Aim 1 will test the hypothesis that nitric oxide levels in the LDT/PPT and mPRF are state-dependent and account for significant variance in ACh release and respiratory rate. Aim 2 will use microdialysis delivery of a nitric oxide-sensitive soluble guanylyl cyclase inhibitor (ODQ) to the mPRF and the LDT/PPT during wakefulness, NREM sleep, and REM sleep while measuring ACh release, sleep, and breathing. Aim 2 will test the hypothesis that nitric oxide decreases ACh release via soluble guanylyl cyclase. Aim 3 will test the hypothesis that mPRF ACh release and sleep are altered by microdialysis delivery of an adenosine A agonist and an antagonist to the mPRF and the LDT/PPT. Aim 4 will quantify G protein activation in 14 sleep and breathing related nuclei using the [35S]GTPgammaS binding assay. The Aim 4 in vitro studies will test the hypothesis that cholinergic activation of G proteins is enhanced by an A1 adenosine agonist and decreased by an A1 adenosine antagonist. Together, these four aims will advance scientific knowledge by providing the first data evaluating the roles of soluble guanylyl cyclase, adenosine, and directly measured nitric oxide as modulators of pontine ACh release, sleep, and breathing. These basic studies are potentially health related because the pharmacological management of disrupted sleep and breathing can alter adenosine, nitric oxide, and cholinergic neurotransmission. A better understanding of these molecules will advance sleep and respiratory neurobiology and contribute to rational drug development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CIRCULATORY TETRAHYDROBIOPTERIN
SHOCK,
NITRIC
OXIDE
AND
Principal Investigator & Institution: Gross, Steven S.; Professor; Pharmacology; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 01-JUL-1994; Project End 31-MAY-2004 Summary: Nitric oxide (NO) is a potent endothelium-derived vasodilator that serves a physiological role in the regulation of blood pressure and vascular tone. Immunostimulants, such as bacterial lipopolysaccharide (LPS), act on many mammalian
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cell types to trigger transcription of the gene encoding the inducible form of NO synthase (iNOS). In the blood vessel, this results in NO over-production, hypotension and often vascular collapse and death. Induction of iNOS is considered to be the etiological basis for septic shock, a condition caused by systemic bacterial infection and which is the leading cause in intensive care units throughout the U.S.A. While iNOS gene expression is necessary for LPS-induced hypotension, we now know that is not sufficient. Indeed, immunostimulants also act on vascular cells to induce expression of GTP cyclohydrolase I (GTPCH), the rate limiting enzyme for the synthesis of the essential NOS co-factor, tetrahydrobiopterin (BH4). Immunostimulant- induced NO synthesis in vascular cells can be prevented by inhibitors of BH4 synthesis and accelerated by provision of exogenous BH4. Thus, BH4 availability limits iNOS activity. During the initial grant period, we cloned the GTPCH gene and found its transcription is upregulated by immunostimulants in vascular smooth muscle. However, additional important mechanisms have been uncovered that may have profound impact on intracellular levels of BH4. The overall goal of the proposed research is to elucidate how intracellular levels of BH4. The overall goal of the proposed research is to elucidate how intracellular levels of BH4 are regulated in vascular smooth muscle cells and how BH4 functions for iNOS catalysis. Toward this end, Specific Aims of our research are: 1) to specify post-translational modifications of GTPCH regulation by "GFRP", a recently cloned GTPCH-binding protein that serves to balance BH4 with cellular needs; 3) to characterize processes that mediate cellular uptake and efflux of reduced pterins and the contribution of pterin transport to regulation of BH4 levels in vascular smooth muscle; 4) to elucidate structural requirements of pterin analogs for binding and function in iNOS catalysis. These studies will improve our understanding of BH4 regulation and function and may provide insights that lead to novel biopterin-based strategies for pharmacotherapy of septic shock and other conditions arising from NO excess. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COCAINE AND APOPTOSIS IN THE DEVELOPING HEART Principal Investigator & Institution: Zhang, Lubo; Professor; Center for Perinatal Biology; Loma Linda University Loma Linda, Ca 92350 Timing: Fiscal Year 2002; Project Start 15-JUL-2001; Project End 31-MAY-2005 Summary: Cocaine use during pregnancy has been associated with numerous adverse perinatal outcomes. Among other effects, cocaine clearly predisposes the fetus and neonate to various cardiovascular dysfunctions. Our preliminary studies indicated that prenatal cocaine exposure caused an increase in apoptosis in near-term fetal rat heart and a decrease in cardiac contractility in newborn rats. Compelling evidence indicates that apoptosis plays a key role in heart development and in several cardiovascular diseases. Yet the cellular/molecular mechanisms underlying cocaine-induced apoptosis in the developing heart are unknown. The proposed studies focus on these mechanisms, and will address the general hypothesis that cocaine increases apoptosis in myocardial cells of the developing heart through nitric oxide (NO) and mitogen-activated protein kinases (MAPKs), leading to mitochondrial cytochrome c release and subsequent activation of the caspase cascade. Four of its main corollaries will be addressed by 4 Specific Aims which will test whether cocaine 1) activates constitutive nitric oxide synthase (NOS) and up-regulates inducible NOS (iNOS), resulting in apoptosis, 2) increases the balance of activities of p38 MAPK/JNK versus ERK resulting in apoptosis, 3) affects Bcl-2 family proteins by increasing the balance of proapoptotic/antiapoptotic proteins and inducing the translocation of proapoptotic proteins to mitochondria, and 4) induces mitochondrial cytochrome c release and subsequent activation of the caspase
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Nitric Oxide
cascade. To achieve these aims, we propose a series of experiments in primary cultures of fetal rat cardiac myocytes. We will measure NO release and expression of eNOS, nNOS, and iNOS; activities of p38 MAPK, JNK, and ERK; protein levels and subcellular distribution of Bcl-2, Bcl-xL, Bax, and Bad; mitochondrial cytochrome c release; and activities of caspase-3, caspase-8, and caspase-9. The results of the proposed studies will provide a comprehensive and novel assessment of the dynamic interactions among nitric oxide, MAPKs, Bcl-2 family proteins, mitochondrial cytochrome c, and the caspase cascade in cocaine-induced myocyte apoptosis, and will improve our understanding of the adverse effects of cocaine on the developing heart. They will also provide exciting new information to fill the important gaps in our understanding of signaling mechanisms in myocyte apoptosis in general. Such an understanding has obvious clinical implications because the increasing information has pointed to an important role of apoptosis in cardiovascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTROL OF NEONATAL CIRCULATION Principal Investigator & Institution: Leffler, Charles W.; Professor; Physiology; University of Tennessee Health Sci Ctr Memphis, Tn 38163 Timing: Fiscal Year 2002; Project Start 01-APR-1985; Project End 31-MAR-2007 Summary: (Provided By Applicant) Preliminary data suggest that carbon monoxide (CO) is an important messenger in the neonatal cerebral circulation that interacts with nitric oxide (NO) and prostacyclin (PGI2). These data include: cerebral microvessels produce CO that dilates arterioles via a mechanism involving KCa channels, inhibition of either nitric oxide synthase (NOS) or cyclooxygenase (COX) inhibits dilation to CO, and NO, and the PGL, analog, iloprost, can restore dilation to CO following inhibition of NOS and COX. The research will pursue the unifying hypothesis that cerebromicrovascular functions of CO involve interactions with NO and PGI2 via modification of KCa channel activity. Four specific aims will be addressed: 1. Evaluate, in vivo, the hypothesis that NO and PGI2 are permissive factors for CO-induced cerebromicrovascular dilation, 2. Test, in vitro, the hypothesis that NO and PGI2 augment CO activation of KCa channels, 3. Examine the mechanisms by which NO and PGI2 increase KCa channel responses to CO, and 4. Test the hypothesis that NO and/or PGI2 affects KCa channels, membrane potential, and CO induced hyperpolarization via activation of localized Ca2+ transients (Ca sparks). Techniques allowing investigation of intact cerebral microcirculation, isolated, pressurized, perfused cerebral arterioles, and freshly isolated cerebral artenolar myocytes from newborn pigs will be employed. Such research is unique by studying intact cerebral circulation and investigating, at the cellular and molecular levels, the mechanisms by which CO, NO, and PGI2 can interact to affect vascular tone. Cranial windows allow investigation of intact cerebral circulation. Isolated myocytes and perfused pressurized arterioles coupled with microelectrode and patch clamp techniques will be used to examine KCa channel activity and membrane potential. Global cytosolic Ca and Ca sparks in intact arterioles and isolated myocytes will be studied using fluorescent indicator technology with a dual excitation, single emission system and laser scanning confocal microscopy, respectively. Cerebral circulatory disorders in newborns are major causes of morbidity and mortality and can result in life long disabilities in survivors. Control of cerebrovascular circulation is easily impaired by pathological conditions. Better understanding of mechanisms of cerebromicrovascular humoral communication is needed badly. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORONARY ARTERY REGULATION BY CA2+SIGNALING & ESTROGEN Principal Investigator & Institution: Nelson, Mark T.; Professor and Chair; Pharmacology; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 31-JUL-2004 Summary: (Verbatim from the application): The cardioprotective effect of estrogen is complex, and incompletely understood. We have identified one potentially important action of physiological circulating estrogen on coronary arteries, which involved an elevation of basal nitric oxide release from the endothelium and an ensuing smooth muscle relaxation through activation of one type of calcium-sensitive (large conductance; BK) potassium channel in the smooth muscle. Our results indicate that estrogen causes fundamental alterations in Ca2+ signaling in the coronary endothelium, which leads to an elevation of nitric oxide production, which in turns alters Ca2+ signaling in the smooth muscle. This proposal focuses on novel, interlinked Ca2+ signaling mechanisms to explain the effects of estrogen and nitric oxide on coronary artery diameter. Specifically, Aim 1 will determine the mechanisms by which estrogen leads to an elevation of endothelial [Ca2+]i; Specific Aim 2 will explore positive feedback regulation of endothelial Ca2+ by local and global Ca2+ signaling from ryanodine receptors (RyRs) in the endoplasmic reticulum to small conductance calciumsensitive (SK) and BK channels; Specific Aim 3 will determine the negative feedback mechanisms by which endogenously produced nitric oxide activates RyRs and BK channels in coronary artery smooth muscle, with a focus on the key roles of phospholamban, which regulates SR Ca2+-ATPase activity, and on the beta-subunit of the BK channel. To address these issues, we have developed techniques to measure global and local calcium in the endothelium and smooth muscle of intact pressurized coronary arteries, including coronary arteries from phospholamban and beta-subunit gene-ablated mice, and developed novel, selective peptide inhibitors of cGMPdependent protein kinase. The proposed study should significantly deepen our understanding of the regulation of Ca2+ signaling in coronary arteries, and the important influences of physiological estrogen and nitric oxide on coronary artery function. This work should also suggest novel mechanisms for therapeutic interventions to mimic the beneficial effects of estrogen and nitric oxide on calcium signaling in coronary arteries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENDOTHELIAL BARRIER DYSFUNCTION IN THE ALCOHOLIC LUNG Principal Investigator & Institution: Hart, C Michael.; Assistant Professor; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Chronic alcohol (ETOH) ingestion increases the risk and severity of the Acute Respiratory Distress Syndrome, a condition caused by inflammatory insults that disrupt the alveolar-capillary barrier leading to severe derangements in pulmonary function and gas exchange. This project focuses on the pulmonary microvascular endothelial component of the alveolar-capillary barrier to clarify the mechanisms by which ETOH increases susceptibility to lung injury. Preliminary data obtained using a well-characterized rat model of chronic ETOH ingestion demonstrate that ETOH increases pulmonary microvascular endothelial cell
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(MVEC) nitric oxide synthase expression and nitric oxide (NO) production. Publications by the Principal Investigator recently demonstrated that NO either promotes or disrupts endothelial barrier function depending in part on the degree of coincident oxidant stress. Therefore, this project will examine the hypothesis that chronic ETOH ingestion in vivo increases MVEC NO production and that stimulation of NO production promotes endothelial barrier function. However, subsequent inflammatory stimuli further increase NO and superoxide production to enhance peroxynitrite formation, cytoskeletal protein modifications, and endothelial barrier dysfunction. The specific aims will be to: 1) Determine how chronic ETOH ingestion alters pulmonary MVEC NO production, 2) Determine how ETOH-induced alterations in NO production alter MVEC cytoskeletal architecture and barrier function, 3) Determine if ETOH-induced alterations in NO production and cytoskeletal architecture enhance MVEC barrier dysfunction in response to inflammatory mediators, 4) Determine if ETOH-induced GSH depletion contributes to increased MVEC NO production, cytoskeletal protein alterations, and barrier dysfunction. Rats will be fed Control or ETOH diets for 2-12 weeks with or without inhibitors of nitric oxide synthase, inhibitors of reactive oxygen species, or glutathione precursors. MVEC NO metabolism, cytoskeletal proteins and barrier function will be examined in vitro and in vivo. These studies will clarify mechanisms of ETOH-induced toxicity in the lung and identify novel targets for potential therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENOS ENDOTHELIUM
REGULATION
BY
CALPAIN
IN
HYPOXIC
LUNG
Principal Investigator & Institution: Block, Edward R.; Medicine; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: (provided by applicant): The Principal Investigator (PI) hypothesizes that calpain, a family of Ca++-regulated neutral cysteine proteases, regulates the activity and subcellular localization of the constitutive isoform of nitric oxide synthase (eNOS) in hypoxic lung endotheial cells (LEC). To test this hypothesis, the PI proposes a multidisciplinary approach focusing on the following four interrelated specific aims. Aim #1: to verify that calpain is responsible for loss of eNOS activity in hypoxic LEC. To address this, the PI will study the effects on eNOS activity and nitric oxide (NO) production in porcine LEC of calpain inhibition mediated by (1) pharmacologic agents, (2) ovrexpression of calpastatin, the endogenous biologic inhibitor of calpain, and (3) antisense depletion of calpain. Aim #2: To determine whether calpain affects the subcellular localization of eNOS in hypoxic LEC. To address this aim, the PI will study the effects of calpain inhibition on eNOS subcellular localization in normoxic and hypoxic porcine LEC using (1) laser scanning confocal microscopy with deconvolution capability and (2) subcellular fractionation studies. Defining factors that regulate eNOS subcellular localization will greatly advance our understanding of NO biology because subcellular localization of eNOS determines optimal NO production by endothelial cells and affects the function of NO as a messenger molecule. Aim #3: To identify the role of the actin binding proteins fodrin and heatshock protein 90 (Hsp90) in the calpainmediated changes in eNOS in hypoxic LEC. To address this aim, the PI will examine the effects of normoxia and hypoxia in the presence and absence of calpain inhibition on Hsp9O and fodrin contents and on the protein: protein associations between Hsp90 and eNOS and fodrin and eNOS using immunoblot and co-immunoprecipitation analyses, sucrose gradient ultracentrifugation, and deconvolution microscopy. The PI will also
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evaluate the effects of calpain inhibition and actin stabilization on the actin-cytoskeleton architecture in normoxic and hypoxic LEC using fluorescence microscopy. Aim #4: To evaluate whether calpain inhibition prevents or attenuates the decrease in NO production and/or endothelium-dependent vasodilation in intact hypoxic pulmonary arteries. To address this aim, the PI will assess whether alpain inhibition prevents or attenuates endothelium-dependent vasorelaxation, NO production, and eNOS activity in intact porcine pulmonary arteries exposed directly to hypoxia. The results of these studies will advance our understanding of the mechanisms by which hypoxia alters pulmonary endothelial and vascular physiology in patients with lung disease and will lead to more effective care and to new and improved ways to reverse or attenuate pulmonary vascular complications such as hypertension, cor pulmonale, and impaired hypoxic vasoconstriction in these patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EXERCISE, MUSCLE NUTRITIVE BLOOD FLOW AND ENOS IN AGING Principal Investigator & Institution: Hickner, Robert C.; Assistant Professor; Physiology; East Carolina University 1000 E 5Th St Greenville, Nc 27858 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Cardiovascular disease is the leading cause of death in the United States, with the incidence of cardiovascular disease increasing rapidly after 60 years of age. A primary risk factor for cardiovascular disease is hypertension, which also increases in prevalence in older individuals. Nitric oxide (NO) induced vasodilatation is reduced with age, resulting in increased blood pressure and reduced limb blood flow, particularly in light of the increased muscle sympathetic tone in older individuals. Impaired production of NO is also associated with peripheral vascular disease, insulin resistance, and Type 2 diabetes. However, there is some evidence that exercise training improves NO induced limb blood flow response at rest. The effect of exercise on the content of endothelial nitric oxide synthase (eNOS), the key enzyme in NO production, has not been investigated in muscle in vivo in humans. We hypothesize that there are reductions in eNOS expression and increases in muscle sympathetic tone in older individuals, resulting in reduced nitric oxide dependent skeletal muscle nutritive blood flow and alterations in muscle metabolism; furthermore, these ageassociated NO-mediated changes can be counteracted, or reversed, by endurance exercise training. We will investigate 24 (20-30 yr) sedentary individuals (men and women), as well as 24 sedentary older (60-70 yr) individuals (men and women) in the sedentary state, as well as after one day and seven days of endurance exercise training. Ten of these sedentary older individuals will also be studied after an additional seven weeks of endurance training. A muscle biopsy will be taken to measure eNOS content, and nutritive skeletal muscle blood flow will be monitored using microdialysis under resting conditions. These investigations will determine if endurance exercise improves nitric oxide dependent nutritive blood flow in skeletal muscle at rest, and will determine if this improvement is associated with increases in eNOS in skeletal muscle biopsy samples. The mediation of NO-dependent vasodilation by muscle sympathetic tone, endothelin, and prostacyclin will also be investigated. The long-term objectives of these investigations are: 1) to identify mechanisms responsible for a reduced nitric oxide-dependent vasodilatation in older men and women and 2) to find practical means of reversing vasodilator decrements in older men and women, thereby reducing the incidence of cardiovascular-related diseases in this population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Nitric Oxide
Project Title: FAST KINETICS OF BIOLOGICAL REACTIONS INVOLVING NO Principal Investigator & Institution: Esquerra, Raymond M.; San Francisco State University 1600 Holloway Ave San Francisco, Ca 94132 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006 Summary: Fast multichannel time-resolved absorption measurements from 300-700 nm with nanosecond resolution will be used to examine the kinetics and mechanism of nitric oxide (NO) generation and ligand binding in nitric oxide synthase (NOS). The kinetics of NOS following ligand photolysis will be examined to determine details about the kinetics of protein relaxation and ligand recombination, providing structural information about protein function. Using multichannel time-resolved absorption spectroscopy, the fast kinetics of NOS catalysis following photoinduced electrontransfer and the rapid activation of oxygen by NOS after initiation by flow-flash mixing will be measured. These experiments will provide important information about how NOS produces NO endogenously. NO biology has been an intensive area of biomedical research as NO physiologically plays many significant roles in human physiology, including neurotransmission, vasodilation regulation, and cytotoxic actions of the immune system. Understanding NO synthesis will aid in drug development (for hypertension, atherosclerosis, diabetes) and therapeutic treatments (sickle cell anemia, blood substitutes, and septic shock) that utilize NO bioactivity. The fast multichannel experiments proposed here will help in elucidating the kinetics of how NOS produces NO endogenously, while providing research opportunities to undergraduate and master's students in biochemical methods and biophysical techniques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GLUTAMATE RECEPTORS AND CEREBELLAR AFFERENTS Principal Investigator & Institution: Beitz, Alvin J.; Professor; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: The long term goal of this project is to define the glutamate receptor subtypes associated with synapses in the cerebellar cortex and to elucidate the role of these receptor subtypes in nitric oxide production. Although it is known that multiple glutamate receptor subtypes exist in the cerebellar cortex, the specific subtypes associated with different parallel fiber versus climbing fiber synapses remains to be defined. There is currently no information available as to whether the number or subtypes of glutamate receptors differ between synapses located in zebrin positive parasagittal binds versus zebrin negative bands. The proposed studies will test the hypothesis that: 1) Glutamate receptor subtypes differ between the parallel fiber/Purkinje cell synapse and the parallel fiber/stellate cell synapse and between the parallel fiber/Purkinje cell and climbing fiber/Purkinje cell synapses; and 2) Climbing fiber activation causes nitric oxide (NO) production in the cerebellar cortex via activation of glutamate receptors on stellate cells, while parallel fiber activation produces NO directly. In Specific Aim 1 the first hypothesis will be tested by using immunocytochemistry and electron microscopy to determine the molecular subtypes of glutamate receptors associated with climbing fiber and parallel fiber synapses. In Specific Aim 2 the second hypothesis will be tested by using electrical or chemical stimulation of climbing and parallel fibers in combination with in vivo microdialysis and administration of glutamate receptor antagonists. These studies will provide new data on the synaptic distribution of glutamate receptors in the mouse and rat cerebellar cortex and will determine if differences in receptor subtypes exist between zebrin
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positive and zebrin negative parasagittal bands. In addition these studies will elucidate the glutamate receptor subtypes involved in cerebellar NO production in vivo. This neurochemical information is important for understanding the basic mechanisms that underlie parallel and climbing fiber neurotransmission and those involved in cerebellar NO release. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HEME/COPPER AND HEME/NONHEME IRON O2 AND NO REACTIVITY Principal Investigator & Institution: Karlin, Kenneth D.; Professor; Chemistry; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: The long-term research objective is to design, synthesize and investigate model compound systems which can help elucidate fundamental aspects of structure, metal-ligation, spectroscopy and reactivity relevant to the chemistry utilized by hemecopper oxidases (e.g., cytochrome c oxidases (CcOs)) and nitric oxide reductases. These evolutionarily related enzymes are involved in the bioenergetics of aerobic and anaerobic organisms, and have in common a heme/M (M = Cu or non-heme Fe) active site which reductively cleaves dioxygen (OZ) or nitric oxide (NO), respectively. The research can contribute to a better understanding of enzyme structure and mechanism, and provide fundamental insights into biological O2-activation, NO and nitrogen oxide chemistry and biochemistry, and issues related to nitrogen oxides in the environment. Major themes are the synthesis of discrete heme/M compounds, O2-chemistry of reduced heme/Cu assemblies, the coordination chemistry of heme/M complexes, NO reactivity studies, and use of phenol chemistry in heme/Cu mediated O2-reduction. Specific aims include (1) spectroscopic and structural characterization of heme-O2-Cu (peroxo) complexes using varied conditions of heme, axial base, or Cu-ligand, (2) study of heme/Cu/O2 adducts assembled from mononuclear components, (3) systematic comparisons of the reactivity of varying Fe-O2-Cu moieties, (4) development of the coordination chemistry of heme/M systems with mu-oxo, mu-OH- and other ligands (e.g., C1-, CN-) of interest as biochemical probes, (5) study of reduced heme/M complexes and their CO and isocyanide adducts, (6) thorough investigation and elaboration upon a NO reductase model system which produces nitrous oxide (N2O), (7) generation of new heme/Fe systems having varied Fe-ligands with three N-donors and/or with one O-donor, (8) study of nitric oxide reactivity with these and heme/Cu systems, since NO is a reversible inhibitor of CcO, (9) use of phenols as electron-proton donors and Cu-ligands in O2-reduction with heme/Cu assemblies, and (10) probing of the chemistry relevant to formation and function of an imidazole-phenol (His-Tyr) covalent link found in CcO. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HUMAN ENDOMETRIAL NITRIC OXIDE: REGULATION AND FUNCTION Principal Investigator & Institution: Khorram, Omid A.; Associate Visiting Professor; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 905022052 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (Provided by Applicant): Nitric oxide (NO) is a free radical with diverse physiological functions one of which is its smooth muscle relaxant effects. By virtue of this effect NO plays a key role in regulating vascular tone and therefore 1: flow to many
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organs including the reproductive tract. Recent identification of predominantly endothelial nitric oxide synthese (eNOS) in the human uterus with primary localization to the endometrial glands has raised the possibility that this molecule may have functions other than regulation of blood flow, such as control of endometrial glandular secretion. Additionally, the marked increase in the endometrial expression of eNOS mRNA and protein around the expected time of implantation with a decline just prior menstruation suggests that endometrial eNOS is regulated by sex steroids, and plays a role in implantation process. In this proposal we will test the hypothesis that sex hormones regulate endometrial eNOS, and NO in turn functions as a mediator of estrogenic influence on cellular proliferation, progesterone's effect in induction of endometrial decidualization. To test our hypothesis we will use in vitro approach using primary human derived endometrial cells to test the direct effects of estrogen progesterone and their combination on eNOS expression and NO secretion (Specific Aim 1) Using pharmacological tools to block the synthesis of endometrial NO, and transfection studies to upregulate eNOS gene expression we will determine if NO mediates E and P actions in the endometrium or independent of sex steroids influence cellular proliferation and endometrial secretion of decidual products (Specific Aims 2 and 3). To complement these studies we will use an ex vivo approach to determine if patients with implantation failures may have endometrial eNOS defects Specific Aim 4). This pilot study should shed light on regulation and function of human endometrial NO pathway, an uninvestigated area of research with profound clinical significance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNE RESPONSES TO GIARDIA LAMBLIA Principal Investigator & Institution: Singer, Steven M.; Assistant Professor; None; Georgetown University Washington, Dc 20057 Timing: Fiscal Year 2003; Project Start 01-FEB-2002; Project End 31-JAN-2007 Summary: (provided by the applicant):Giardia lamblia is a protozoan parasite which replicates in the small intestine of many species of mammals, and infections with G. lamblia are one of the most common human infections in the word. Most infections are self-limiting and acquired immune responses are essential for controlling G. lamblia infections in humans and other host species. Understanding the immune response to G. lamblia is therefore essential for better control of this disease. We have recently shown that B cell, gamma-delta T cell, IL-4 and IFN-gamma deficient mice can control acute infections with G. lamblia. In contrast, CD4+, alpha-beta T cells are required to control infections. Thus, a T cell-dependent, but antibody-independent. mechanism exists which can control G. lamblia. We have also shown that mast cell-deficient mice and IL-6 deficient mice cannot control G. lamblia infections. Also, in vitro studies have shown that nitric oxide and anti-microbial peptides known as defensins can inhibit G. lamblia. Based on these findings, the following hypothesis has been formulated: CD4+ T cells activate mast cells to produce IL-6 during G. lamblia infections. IL-6 production then leads to epithelial cell production of nitric oxide and defensins that control acute G. lamblia infections. We will test this hypothesis with the following specific aims: 1.To determine the importance of IL-6 production during G. lamblia infections. We will confirm the importance of IL-6 by treating immnunodeficjent mice with recombinant IL6 during infections. IL-6 production will also be measured in vivo during infections in wild type and immunodeficient mice using RT-PCR. 2. To determine the importance of mast cell IL-6 production during G. lamblia infections. We will confirm the role of mast cells during infections by measuring mast cell responses during infections, by immunodepletion of mast cells, and by reconstitution of mast cell deficient mice. We will
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examine mast cell production of IL-6 using immunohistochemistry and adoptive transfers. 3. To determine the mechanism of mast cell activation during G. lamblia infections. We will examine cytokine production by T cells in vivo and in vitro. We will also examine infections in cytokine deficient mice. We will examine intestinal epithelial cell (IEC) production of stem cell factor in vitro and in vivo. 4. To determine the mechanisms by which IL-6 production leads to control of acute G. lamblia infections. We will examine production of defensins and nitric oxide by IEC in vivo using RT-PCR and in vitro by Northern blots and biochemistry. Mice deficient in defensin expression and nitric oxide production will then be infected to determine their importance in controlling infections. Successful completion of these experiments will give us insights into immunity to G. lamblia, as well as developing this organism as a model system for understanding mucosal immune responses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMPACT OF PUBERTY ON THE KIDNEY IN DIABETES Principal Investigator & Institution: Lane, Pascale H.; Associate Professor; Pediatrics; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The prepubertal years of type 1 diabetes (DM) appear to be protected from expression of nephropathy and other microvascular complications. Only post-pubertal male rats given the diabetogenic agent streptozocin (STZ) develop renal and glomerular hypertrophy associated with increased expression and activity of transforming growth factor b (TGFb). Prepubertal rats do not develop hypertrophy or upregulation of the TGF system. Given clinical differences in the prevalence and rate of progression between the sexes, gonadal steroids seem likely to be involved in these processes. Overall hypothesis: Androgen synthesis that accompanies puberty contributes to the development of diabetic nephropathy via changes in the renal transforming growth factor (TGF(3) system. Specific Aims: I) What are the roles of androgens in diabetic kidney disease? 1)Examine sex differences in the renal reponse to STZ DM; 2)Examine the effects of gonadectomy on the post-pubertal renal response to STZ DM; 3)Determine the effect of testosterone treatment on the renal response to STZ DM; 4)Determine the role of the androgen receptor in the renal response to DM; and 5)Determine whether conversion to dihydrotestosterone is necessary for the postpubertal renal response to STZ DM. II) What is the mechanism through which puberty promotes TGFfi expression/activation? 1 )Examine the renin-angiotensin system in response to pre- and post-pubertal states and hormonal manipulation; 2)Examine the protein kinase C system in response to pre- and post-pubertal states and hormonal manipulation; 3)Examine the oxidative stress system in response to pre- and postpubertal states and hormonal manipulation; 4)Define the direct effects of sex steroids in vitro on the oxidative stress pathway; and 5)Define the direct effects of sex steroids in vitro on the PKC pathway. Methods: Rats will be given STZ DM pre- or post-puberty for 6 weeks, a duration of DM which increases TGFI3 expression and renal weight in adults. Groups will include males and females with and without earlier gonadectomy. Some groups will also receive treatment with testosterone, flutamide, an androgen receptor blocker, or finasteride, which blocks conversion of testosterone to dihydrotestosterone. in vitro studies will involve kidney slice cultures from 10 week old castrated male rats, with or without prior induction of OM. Media will include normal or high glucose conditions, as well as variable amounts of testosterone or estrogen. Measurements will include TGFJ3 proteins by ELISA and nitric oxide synthase isoforms, angiotensin II receptor, and protein kinase C isoforms by immunoblotting; superoxide generation;
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nitric oxide synthase activity; protein kinase C activity; mRNA for TGFb, nitric oxide synthases, and TGFb inducible gene-H3 by RT-PCR; plasma and renal levels of angiotensin II; and blood levels of sex steroids by RIA. Health implications: New treatments to prevent diabetic kidney disease, the most important cause of kidney failure in the US, may emerge from a better understanding of a naturally protected state such as the prepubertal animal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INDUCTION OF VASOPROTECTIVE ENDOTHELIAL NITRIC OXIDE SYNTHASE & CYCLOOXYGENASE Principal Investigator & Institution: Wu, Kenneth K.; Professor and Director; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2003 Summary: Endothelial nitric oxide synthase (eNOS) and cyclooxygenases (COX-1 and COX-2) are key enzymes that catalyze the synthesis of vasoprotective nitric oxide (NO) and prostacyclin (PGI2), respectively. our preliminary data show that lysophosphatidylcholine (lysoPC), induces the expression of eNOS and COX-2. We postulate that lysoPC induces these two different genes by distinct transcriptional mechanisms. We further postulate that the cardiovascular protective effects of estrogen are mediated by induction of eNOS and COX-2. Furthermore, the eNOS activity is regulated by vasoactive agents. To test these hypotheses, we propose three specific aims: (1) to elucidate differential transcriptional activation mechanisms by lysoPC; (2) to evaluate the effects of estrogen on eNOS and COX-2 expression; and (3) to determine eNOS structure-activity relationship and regulation. We will use strategies which strategies which encompass biochemical, cell and molecular biology, structural biology and molecular genetic approaches to achieve the goal of each specific aim. These experiments should yield important information regarding the fundamental processes of injury-coupled vasoprotection. They will enhance our understanding about the vasoprotective properties of estrogen. Furthermore, results from this project should shed light on the regulation of eNOS activity by biochemical processes that influence stability and calmodulin. Overall, this project should have a major impart on research pertaining to basic eNOS and COX research and vascular cerebral pathophysiology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INTERSTITIAL FLUID FLOW IN BONE REMODELING Principal Investigator & Institution: Frangos, John A.; Principal Scientist; La Jolla Bioengineering Institute 505 Coast Blvd South San Diego, Ca 920374616 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-MAY-2005 Summary: It has been hypothesized that fluid shear stress, induced by the flow of interstitial fluid, mediates the response of bone to loading and mediates modeling/remodeling. In vitro studies have demonstrated that bone cells are stimulated by fluid shear stress, and respond with the release of nitric oxide (NO) and prostaglandins. The in-vivo relevance of interstitial fluid flow (IFF), however, has yet to be established of the proposed research is to characterize three models of altered IFF in the absence of mechanical strain, and determine the role of nitric oxide and prostaglandins in IFF induced bone modeling/remodeling. Specifically, (1) we will characterize the effects of altered IFF induced by femoral vein ligation on histomorphometry, femoral dimensions, mechanical properties, mineral content, and mineral density in hindlimb suspended mice and rats; (2) we will determine the role of
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NO and prostaglandins if IFF-mediated modeling/remodeling by using genetically engineered mice lacking nitric oxide synthase 2 (NOS2), nitric oxide synthase 3 (NOS3), and cyclooxygenase 2 (COX2); (3) We will develop an externally applied cuff to alter IFF in bone as the first step in the clinical application of the findings. We will seek to optimize the regime of cuff pressure application and the duration of treatment to increase bone; (4) to further validate that IFF is altered in our rat models, direct measurements of IFF by magnetic resonance imaging will be performed. The long-term goal is the development of non- pharmacological methods to counter osteopenia of disuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM HYPERHOMOCYSTEINEMIA
OF
VASCULAR
REMODELING
IN
Principal Investigator & Institution: Tyagi, Suresh C.; Associate Professor; Physiology and Biophysics; University of Mississippi Medical Center 2500 N State St Jackson, Ms 39216 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2003 Summary: (provided by the applicant): The long-term objective of this project is to further the understanding of contribution of homocysteine in vascular disease. Previous studies have indicated a decrease in the bioavailability of endothelial nitric oxide and an increase in the concentration of nitrotyrosine in the aortic wall associated with hyperhomocysteinemia. The plasma levels of homocysteine have shown to be inversely related to peroxisome proliferator activated receptor (PPAR), a nuclear receptor, which ameliorates vascular dysfunction. The central hypothesis of this proposal is that increased levels of homocysteine suppress the activity of PPAR by increasing the generation of nitrotyrosine and metalloproteinase activity, and decreasing the endothelial nitric oxide concentration. The central hypothesis will be addressed by the following four specific aims: 1) To determine whether the homocysteine binds to PPAR, the competitive binding of homocysteine and agonist (fibrate) to PPAR will be measured using homocysteine-cellulose affinity chromatography and aortic nuclear extracts. Bound PPAR will be eluted with fibrate and characterized by antibody to PPAR. 2) To determine whether the increase in PPAR expression decreases nitrotyrosine levels and increases endothelial nitric oxide concentration in a murine model of hyperhomocysteinemia, the concentrations of PPAR and nitrotyrosine in the aortas of hyperhomocysteinemic mice treated with and without fibrate will be measured by Western blot analysis. The levels of nitric oxide will be measured by estimating the total nitrate/nitrite concentration. 3) To determine whether the increase in PPAR decreases the levels of metalloproteinase and elastinolysis, the matrix metalloproteinase activity will be measured using specific substrate gel zymography, and the elastinolysis by identifying elastin fragments using anti-elastin antibody. 4) To determine whether an increase in PPAR expression reverses the homocysteine-mediated vascular dysfunction, the aortic contractile function will be measured. The proposed studies will elucidate the molecular, cellular and extracellular mechanism by which homocysteine promotes arterial lesions and should provide new insights to therapeutic ramifications for vessel wall disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Nitric Oxide
Project Title: MECHANISMS FOR CARDIOVASCULAR CONTROL EARLY IN DIABETES Principal Investigator & Institution: Brands, Michael W.; Professor; Physiology and Endocrinology; Medical College of Georgia 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2003; Project Start 01-JAN-1997; Project End 31-MAR-2007 Summary: (provided by applicant): We have shown that hyperglycemia at the onset of Type I diabetes causes significant hypertension if it is induced in rats with chronic blockade of nitric oxide synthesis. The hypertension is prevented by blocking angiotensin II, or the sympathetic nervous system; but our data suggest the two systems are linked in this response and may involve superoxide and thromboxane. Blood pressure and nitric oxide also track closely with GFR. The studies in this proposal will test the central hypothesis that nitric oxide protects against hypertension at the onset of diabetes by counteracting pressor actions of the sympathetic and renin-angiotensin systems. The Specific Aims are: 1) to test the hypothesis that nitric oxide protects against AngII-induced hypertension at the onset of diabetes by: a) chronically clamping (fixing) renin-angiotensin system activity at normal levels;b) blocking AngII action in rats with chronic intravenous and intrarenal i) ramipril and ii) iosartan; c) blocking AngII action in mice with ACE gene knockout; d) determining if gradual onset of diabetes causes the same renin secretion and blood pressure responses; e) determining whether low sodium intake increases the dependence of blood pressure on nitric oxide. 2) to test the hypothesis that the SNS contributes to the hypertensive response primarily through renal mechanisms. We will: a) determine the roles of a versus b receptors in mediating the renal, renin, and blood pressure responses:b) remove the renal nerves to test the role of the kidney in mediating the sympathetic pressor effect; c) determine if a decrease in ANG II is required for adrenergic blockade to prevent the hypertension; d) determine if the SNS effect is due to increases in SNS activity, or whether it plays a permissive role, 3) to test the hypothesis that nitric oxide counteracts AngII-dependent superoxide and thromboxane production to control blood pressure at the onset of diabetes. We will determine this by: a) "blocking" superoxide with a superoxide dismutase mimetic in rats and gene overexpression in mice; b) quantifying the degree to which AngII determines whether superoxide significantly affects blood pressure: c) determining if thromboxane receptor blockade will decrease blood pressure if superoxide is not increased: d) determining whether knockout of superoxide dismutase 1 exacerbates the hypertensive response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISMS OF CUTANEOUS ACTIVE VASODILATION Principal Investigator & Institution: Kellogg, Dean L.; Associate Professor; Medicine; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 31-JUL-2004 Summary: (Adapted from the applicant's abstract):Almost 70 years ago the human cutaneous active vasodilator system was first described; however, its mechanisms remain unclear today. The long term goal of this project is to define the physiological mechanisms that effect cutaneous active vasodilation during thermoregulatory reflex responses to hyperthermia. This will contribute to our understanding of the role of the cutaneous circulation in adaptation to hot environments and understanding the increased morbidity and mortality of persons with limited cardiac output, including the aged and those with cardiac disease. An enhanced understanding of the cutaneous circulation may reduce mortality in the growing patient population that receives
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numerous pharmacological therapies that may predispose them to iatrogenic heat intolerance, heat stroke, and death. The following specific aims will be explored. 1) Determine whether bradykinin is involved in cutaneous active vasodilation during heat stress. 2) Clarify whether nitric oxide (NO) levels increase and cause cutaneous active vasodilation during heat stress or whether NO levels remain constant and functions as a permissive factor during heat stress. 3) Determine whether the nitric oxide required for cutaneous active vasodilation during heat stress is produced by endothelial nitric oxide synthase (eNOS) or by neuronal nitric oxide synthase (nNOS). 4) Determine the role of vasoactive intestinal polypeptide (VIP) in cutaneous active vasodilation during heat stress. 5) Determine the role of cAMP in cutaneous active vasodilation during heat stress. 6) Determine the role of cGMP in cutaneous active vasodilation during heat stress. Studies will be done in healthy humans. Intradermal microdialysis will be used to treat small areas of forearm skin with specific pharmacological agents to manipulate the bradykinin, nitric oxide, VIP, and second messenger systems. Laser-Doppler flowmetry will monitor skin blood flow responses during normothermia and hyperthermia at both drug-treated, experimental sites, and at adjacent untreated, control sites. In addition intradermal microdialysis will be combined with measurements of bioavailable NO by hemoglobin-trapping to define further how the NO system functions in cutaneous active vasodilation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS OF ENDOTHELIAL DYSFUNCTION IN DIABETICS Principal Investigator & Institution: Beckman, Joshua A.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 13-AUG-1999; Project End 31-JUL-2004 Summary: Vascular disease is the principal cause of death and disability among the 12 million patients in the United States with diabetes mellitus. Macrovascular complications, including myocardial infarction, stroke, and amputation are the leading cause of morbidity and mortality among this cohort of patients. Reduced bioavailability of endothelium-derived nitric oxide has been implicated in atherogenesis and may be a fundamental factor in the development of vascular disease in diabetes. Increased degradation of nitric oxide by reactive oxygen radicals and inhibition of nitric oxide synthase via activation of protein kinase C are each potential mechanisms to account for decreased nitric oxide. The sponsor's laboratory has demonstrated impaired endothelium-dependent vasodilation in patients with diabetes mellitus and in healthy, nondiabetic subjects with experimental hyperglycemia. Further experiments showed that vitamin C improved endothelium-dependent vasodilation implicating a culpable role for superoxide. The soluble, glutathione-dependent antioxidant pathway, responsible for detoxification of polar peroxides, is also adversely affected by hyperglycemia and may represent a specific physiologic mechanism causing, in part, the impaired endothelial function demonstrated in diabetes mellitus. This proposal will examine the effect of ebselen, a glutathione peroxidase mimetic on endothelial function in subjects with diabetes mellitus (type I and type II) and healthy, age-matched controls to determine if polar peroxides play an important role in endothelial dysfunction in diabetes. Hyperglycemia causes the up-regulation of protein kinase C isoform beta2 (PKC beta2) which may phosphorylate nitric oxide synthase, reducing its activity. This proposal will also examine the role of LY333531, a PKC beta2 inhibitor, on endotheliumdependent vasodilation in forearm resistance and conduit vessels in subjects with type I and type II diabetes mellitus and age-matched health controls. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Nitric Oxide
Project Title: MECHANISMS OF NFKB ACTIVATION IN HYPOXIA AND SEPSIS Principal Investigator & Institution: Chandel, Navdeep S.; Assistant Professor of Medicine; Medicine; Northwestern University 633 Clark Street Evanston, Il 60208 Timing: Fiscal Year 2002; Project Start 10-FEB-2000; Project End 31-JAN-2005 Summary: The development of sepsis in critically ill patients is an ominous event that frequently leads to multiple organ failure and death. Increased release of cytokines has been implicated in the pathophysiology of these events, although the mechanisms underlying this relationship are not fully understood. Tissue hypoxia may also develop during sepsis, due to microvascular dysfunction and a failure to distribute capillary blood flow in accordance with tissue O2 need. A central hypothesis of this application is that tissue hypoxia will amplify the intracellular response to sepsis, by activating signaling pathways that regulate gene expression and subsequent release of cytokines and other inflammatory mediators. In sepsis, endotoxin (LPS) released from gramnegative bacteria complexes with binding proteins, which then bind to the CD14 receptor on cells. This initiates an intracellular signaling cascade leading to the activation of transcription factors that stimulate expression of genes including the cytokine TNFalpha and the inducible isoform of nitric oxide synthase (iNOS). TNFalpha can amplify the inflammatory cascade and may contribute to the pathophysiological state, while iNOS can result in unregulated release of nitric oxide, which may contribute to vascular dysfunction, organ failure and cell death. Activation of the transcription factor nuclear regulatory factor kappa B (NF-kappaB) is an important event in the expression of TNFalpah and iNOS. Previous studies demonstrate that cellular hypoxia (PO2 less than 40 torr) elicits an increase in release of reactive oxygen species (ROS) from mitochondria, which then activate transcription factors such as Hypoxia Inducible Factor-1 (HIF-1). This project will test the hypothesis that these ROS produced during hypoxia amplify the response to sepsis by independently activating NF-kappaB, thereby augmenting the TNFa and iNOS expression. Hypoxia may also heighten the cytotoxic effects of TNFa and NO, by augmenting oxidant stress and by contributing to the dissipation of mitochondrial potential. Proposed studies will clarify the role of mitochondrial ROS in amplifying NF-kappaB activation and TNFalpha and iNOS mRNA expression in a cellular model of sepsis. Additional studies will determine the significance of these events for cell death pathways in that model. Collectively, this work will shed new light on the intracellular signaling events during hypoxia and sepsis involving ROS, NF-kappaB and expression of TNFalpha and iNOS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISMS HOMOCYSTEINEMIA
OF
VASCULAR
DYSFUNCTION
IN
Principal Investigator & Institution: Lentz, Steven R.; Associate Professor; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: (Adapted from Investigator's Abstract): A large number of epidemiological studies have suggested that hyperhomocysteinemia is a risk factor for stroke, myocardial infarction, and venous thrombosis. Despite a relative wealth of epidemiological data, however, the mechanisms by which hyperhomocysteinemia predisposes to vascular events remain poorly understood. Two potential mechanisms that have received recent attention are: 1) increased oxidative stress mediated either directly by oxidation of homocysteine or indirectly by impairment of antioxidant enzyme activity and 2) decreased bioavailability of endothelial nitric oxide mediated
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either by increased oxidative inactivation of nitric oxide or decreased generation of nitric oxide. Very few studies have been performed to test the hypothesis that these mechanisms are important in the development of vascular dysfunction in vivo. Using dietary approaches in monkeys, the PI was among the first to demonstrate that moderate hyperhomocysteinemia is associated with impaired vascular function. Hyperhomocysteinemia was also associated with elevated plasma levels of asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthesis. More recently, the PI has developed dietary and genetic models to produce hyperhomocysteinemia and vascular dysfunction in mice. There are three specific aims. Aim 1 will use Murine models to determine whether vascular dysfunction is caused by specific alterations of homocysteine metabolism. Two strains of mice will be studied that have been generated through gene targeting techniques: cystathionine p-synthase (CBS) knockout mice, which have a selective defect in homocysteine trans sulfuration, and methylene tetrahydrofolate reductase (MTHFR) knockout mice, which have a selective defect in homocystine remethylation. Aim 2, will test the hypothesis that vascular dysfunction in hyperhomocysteinemic mice is caused by increased oxidative stress in vivo. Aim 3 will attempt to determine the mechanisms of elevation of ADMA in hyperhomocysteinemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MICROVASCULAR ABNORMALITIES IN SEPSIS Principal Investigator & Institution: Hollenberg, Steven M.; Rush University Medical Center Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-MAY-1998; Project End 31-JUL-2002 Summary: Septic shock, the leading cause of death in intensive care units, is characterized by vasodilation with decreased peripheral vascular resistance, which is often refractory to exogenously administered vasopressor agents. The most important determinant of peripheral vascular resistance is the tone of resistance arterioles, and modulation of tone in these arterioles results from a complex interplay of local vasodilators and vasoconstrictors. The mechanisms involved in the refractory vasodilation seen in sepsis have not been fully elucidated. The current proposal would be the first study to investigate microvascular abnormalities in a clinically relevant model of sepsis by testing responses of resistance arterioles to a range of endogenous vasoactive substances. The long-term objective of this project is to elucidate the pathophysiology of the abnormalities in vascular tone seen in patients with septic shock. The underlying hypothesis is that hypotension and abnormal distribution of blood flow in sepsis result from derangements in microvascular responses to endogenous vasoactive substances. The specific hypothesis is that responses of resistance arterioles in cremaster muscles of septic rats measured using in vivo videomicroscopy will differ from controls, and that elucidation of the mechanisms of differences in vasopressor responsiveness will aid in our understanding of important pathogenetic pathways and in the development of innovative therapies for septic shock. Specific aims: 1. To test the hypothesis that a general abnormality of microvascular reactivity is present in sepsis by comparing arteriolar responses to endogenous vasopressors in septic and control animals. 2. To evaluate potential effector mechanisms of sepsis-induced vascular hyporesponsiveness by measuring the effects of inhibitors of second messenger pathways. 3. To elucidate interactions between endogenous vasopressors and vasodilators in mediating vascular hyporesponsiveness in sepsis by testing the effects of nitric oxide synthase, cyclooxygenase, and lipoxgenase inhibitors on vasopressorinduced arteriolar constriction in septic animals. 4. To test the hypothesis that
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Nitric Oxide
overproduction of nitric oxide by cytokine- inducible nitric oxide synthase plays a pivotal role in inducing vascular hyporesponsiveness in sepsis, first by comparing the effects of selective and nonselective nitric oxide synthase inhibitors on vasopressorinduced arteriolar constriction in septic animals, and then by measuring vascular responsiveness in transgenic septic animal deficient in inducible nitric oxide synthase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACTIONS
MOLECULAR
MECHANISMS
OF
ESTROGENS
VASCULAR
Principal Investigator & Institution: Clark, Kenneth E.; Professor; Obstetrics and Gynecology; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: Although the uterine vascular effects of estrogen have been studied for over 70 years, the mechanism by which estrogen produces vasodilation remains unclear. Our laboratory was the first to show that a significant component of the uterine response to estrogen in the nonpregnant sheep is mediated by the release of nitric oxide (NO). We and others have shown that estradiol-17beta increases the expression and activity of endothelial nitric oxide synthase (eNOS) in the uterine circulation. However, it is not currently clear how this occurs or if, in addition to eNOS, neuronal nitric oxide synthase (nNOS) or inducible nitric oxide synthase (iNOS) are also important in maintaining the sustained vasodilatory response seen after estrogen administration. Furthermore, it is not clear how estrogen modulates these NOS isoforms at the cellular and molecular level. Recently a new estrogen receptor, ERbeta has been isolated and emerging data suggest that this receptor may mediate a significant portion of the effects of estrogen in the vasculature. We hypothesize that uterine vasodilation produced by estradiol-17beta is mediated by specific interaction with both ERalpha and ERbeta, which subsequently activates eNOS (and potentially nNOS) via a nongenomic pathway, and iNOS via a genomic pathway, leading to increases in NO. The present application plans to evaluate the role of ER as a modulator of the NOS isoforms in the uterine circulation using a combination of physiologic and molecular endpoints. We will monitor the uterine hemodynamic responses to locally and systemically administered pharmacological antagonists that are selective for specific isoforms of NOS using a well-characterized ovine model. We intend to evaluate the expression of ERalpha and ERbeta in the ovine uterine vasculature and explore how estrogen alters eNOS, nNOS and NOS expression in endothelial cells and vascular smooth muscle. Finally we plan to determine if endogenous estrogen, acting through the uterine vascular NOS system, plays a critical role in increasing and maintaining uterine blood flow in late pregnancy. We believe that the information obtained in this revised application will provide new and important understanding into the mechanisms regulating vascular tone and hemodynamics in the uterine circulation in both the nonpregnant and pregnant animal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR MECHANISMS OF HUMAN INOS DEGRADATION Principal Investigator & Institution: Eissa, N Tony.; Associate Professor of Medicine; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Asthma associated disability, morbidity, and mortality continue to increase. Although the causes remain unknown, asthma is now considered as a chronic inflammatory syndrome. Overproduction of nitric oxide (NO)
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by inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of airway inflammation of asthma. The long-term goal of this research is to understand the regulation of iNOS activity and devise novel methods to regulate it. Although much is known about factors affecting the synthesis and catalytic activity of iNOS, little is known about its degradation mechanisms or its subcellular localization. Potentially, acceleration of iNOS degradation is an appealing approach for NO modulation since the process of targeting a cellular protein for degradation is highly selective. The overall objective of this research proposal is to understand the mechanisms of iNOS degradation in epithelial cells. Our preliminary data suggest that human iNOS is degraded primarily by the ubiquitin-proteasome pathway, a pathway responsible for the selective degradation of a number of short-lived regulatory proteins whose activity must be tightly regulated. We hypothesize that: a) iNOS is regulated by specific degradation mechanisms primarily involving the ubiquitin-proteasome pathway and that degradation occurs at the membrane subcellular component; b) iNOS degradation can be accelerated with inhibitors that prevent iNOS dimerization. To test these hypotheses, we propose studies with the following specific aims: 1) Identification of human iNOS degradation pathway by testing the effect of specific inhibitors of various degradation pathways on iNOS half-life. 2) Characterization of possible role of ubiquitination in iNOS degradation by determining whether or not iNOS is ubiquitinated and if ubiquitination is required for targeting iNOS to degradation. 3) Elucidation of the subcellular localization of human iNOS using fluorescence microscopy in the absence or the presence of inhibitors that block iNOS degradation, leading to its accumulation. 4) Analysis of modulation of iNOS degradation by various classes of iNOS inhibitors. Studies will be conducted in epithelial cell lines expressing human iNOS and in airway bronchial epithelial cells obtained by bronchoscopy from normals. The rational for the proposed studies is that once the degradation mechanisms of iNOS are understood, therapeutic strategies can be designed to alter these pathways and accelerate iNOS degradation. The results of these studies will increase our understanding of the cellular process of iNOS regulation and thus lay the groundwork for future studies aiming at controlling NO synthesis in asthma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR PROBES OF THE MECHANISMS OF CYTOCHROME P450 Principal Investigator & Institution: Groves, John T.; Hugh Stott Taylor Professor of Chemistry; Chemistry; Princeton University 4 New South Building Princeton, Nj 085440036 Timing: Fiscal Year 2003; Project Start 01-DEC-1985; Project End 31-MAR-2007 Summary: (provided by applicant): The central theme of this program involves studies of the mechanisms of action of cytochrome P450 enzymes and nitric oxide synthase (NOS). The principal approaches involve kinetic and mechanistic studies of enzymesubstrate interactions, the synthesis and characterization of reactive iron porphyrin species as models of putative enzymic intermediates and relating the interconversions of these species toward a molecular understanding of these proteins. Cytochrome P450 is the central protein involved in drug detoxification and hormone metabolism while nitric oxide synthase is the source of the signal molecules nitric oxide and peroxynitrite. Synthetic metalloporphyrins can be employed as probes to intervene in these processes in diagnostic ways. Thus, these agents may prove to be significant tools for elaborating the biology of superoxide, peroxynitrite and NO. These same metalloporphyrins have shown impressive activity in animals suggesting their application as pharmaceutical
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Nitric Oxide
agents. Our effort seeks to provide a foundation of mechanistic and kinetic information that can be applied to in vitro models, cell culture studies and whole animal models of specific disease states such as ischemia-reperfusion, sepsis and autoimmune diseases. Experiments are aimed at determining what reactive intermediates are formed and what their biological targets are likely to be. The elaboration of these processes will facilitate the design of metal complexes for the catalytic decomposition of peroxynitrite and these other species. The studies of nitric oxide synthase aim to illuminate the range of mechanisms for NOS and to seek out new oxidation processes that may help with the rational development of NOS inhibitors. Peroxoiron(III) porphyrin species, oxoiron(IV) species and ferrous-dioxygen species are now readily accessible in aqueous solution at ambient temperature. Rapid kinetic techniques have been developed to study the reactivity of these species. A central question is how to modulate the chemistry of these complexes between nucleophilic and electrophilic pathways that are essential to understand the variety of P450 and NOS - mediated processes. Synthetic and semisynthetic phospholipid assemblies are used to model and understand the larger scale events in P450 and NOS action and to probe the permeability of membranes to reactive oxygen and nitrogen species. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MRI OF MYOCARDIAL FUNCTION IN POST-INFARCT KNOCKOUT MICE Principal Investigator & Institution: Epstein, Frederick H.; Associate Professor; Radiology; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2003; Project Start 05-SEP-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Over the past 10 years experiments utilizing transgenic and knockout mice have significantly advanced broad areas of cardiovascular disease research. The vast majority of such research has employed ex vivo methods for assessing the results of gene manipulation (phenotyping) such as immunostaining tissue samples, and, for heart function, performing catheter-based measurements of left-ventricular (LV) pressure in isolated Langendorff-perfused hearts. For studies of cardiac function in particular, noninvasive imaging offers the possibility of making measurements that directly reflect complex in vivo physiology. Basic echocardiographic and MRI techniques have already been developed and applied to mice, and MRI in particular, due to its versatility and accuracy, shows great promise. We propose to develop advanced MRI methods for imaging myocardial infarction (MI) and regional intramyocardial function in mice and to apply these methods to the study of LV dysfunction after MI. Specifically, we will use novel displacement-encoded MRI techniques to study myocardial dysfunction in the settings of acute and chronic MI, focusing on the role of excess nitric oxide (NO) derived from the inducible form of nitric oxide synthase (iNOS). While these studies focus on basic mechanisms, they are clinically relevant because post-MI LV dysfunction and remodeling are a major cause of mortality in the United States. Understanding the basic mechanisms underlying LV dysfunction and remodeling may lead to drug development and improved treatment. Accordingly, our specific aims are 1. To develop novel MRI methods for post-MI mouse heart imaging that measure two-dimensional (2D) and 3D intramyocardial tissue displacement and strain in phase-reconstructed images and simultaneously depict the area of myocardial infarction as a region of hyper enhancement in contrast-enhanced magnitude-reconstructed images. 2. To develop image analysis techniques to automatically segment the myocardium, detect the area of delayed hyper enhancement, and compute measures of myocardial function localized to the infarcted, adjacent, and
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remote regions. 3. To use MRI, including the methods developed in Aims 1 and 2, to elucidate the roles of nitric oxide (NO) and the inducible form of nitric oxide synthase (iNOS) on post-Ml LV dysfunction using knockout mice and direct gene transfer methods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NICOTINE INDUCED CEREBROVASCULAR DYSFUNCTION Principal Investigator & Institution: Mayhan, William G.; Professor; Physiology and Biophysics; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: (provided by applicant) While cigarette smoke contains many toxic substances, it appears that nicotine may be responsible for the adverse effects of tobacco products on the cardiovascular system. Recent studies suggest that nicotine impairs nitric oxide synthase-dependent, but not -independent, dilatation of peripheral arterioles. While there is evidence, which suggests that smoking is a risk factor for the pathogenesis of cerebrovascular disorders, including stroke, mechanisms, which contribute to the development of cerebrovascular disorders remain uncertain. Thus, the central hypothesis of this application is that nicotine contributes to the pathogenesis of cerebrovascular abnormalities via alterations in cellularprocesses, which govern reactivity of cerebral arterioles. We propose two specific aims. In aim #1, we will determine the effects of nicotine on nitric oxide synthase-dependent and -independent responses of cerebral resistance arterioles. In addition, we propose to examine several potential mechanisms by which acute and chronic exposure to nicotine might influence nitric oxide synthase-dependent reactivity of cerebral arterioles. Our hypothesis is that nicotine impairs dilatation of cerebral arterioles via impairment in the arginine/nitric oxide syntheses biosynthetic pathway, and/or stimulation of oxygen derived free radicals. In aim #2, we will determine the effects of nicotine on reactivity of cerebral arterioles to activation of potassium channels. Activation of potassium channels plays an important role in the regulation of cerebrovascular tone in response to a variety of stimuli. We propose to examine the effects of nicotine on reactivity of cerebral arterioles to activation of potassium channels and examine potential mechanisms, which contribute to altered responses of cerebral arterioles during activation of potassium channels. Our hypothesis is that nicotine alters dilatation of cerebral arterioles in response to activation of potassium channels. In summary, studies proposed in this application will be the first comprehensive attempt to examine the effects of nicotine on cellular pathways, which govern reactivity of cerebral arterioles. Our studies will provide valuable insights into mechanisms by which nicotine may contribute to cerebral microvascular dysfunction, including stroke, observed in cigarette smokers and users of tobacco products. In addition, results of these studies may provide insights regarding possible therapeutic approaches for the treatment of nicotine-induced vascular dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NITRIC OXIDE AND CARDIAC REMODELING FOLLOWING INFARCTION Principal Investigator & Institution: Sun, Yao; Medicine; University of Tennessee Health Sci Ctr Memphis, Tn 38163 Timing: Fiscal Year 2002; Project Start 10-JUL-2001; Project End 31-MAY-2004
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Nitric Oxide
Summary: (provided by applicant): The overall objective of this proposal is to explore the mechanisms for antifibrotic role of nitric oxide on myocardial remodeling following infarction. The hypothesis to be tested is that nitric oxide regulates myofibroblasts (myoFb) apoptosis/growth, collagen turnover, and transforming growth factor (TGF)beta1 expression in the infarcted heart, thus protecting the heart from ongoing collagen accumulation. Extensive myocardial fibrosis is a characteristic feature in the failing heart with previous myocardial infarction (MI). Locally generated factors serve as chemical mediators by either promoting or suppressing cardiac fibrosis. A discordant balance in reciprocal regulation accounts for progressive structural remodeling of the myocardium. An emerging body of evidence implicates nitric oxide as an inhibitory regulator of cardiac fibrosis. The pathway by which nitric oxide regulates such cardiac remodeling remains uncertain, MyoFb, phenotypically transformed fibroblast-like cells, are central for cardiac extracellular matrix remodeling and create a dynamic microenvironment for collagen turnover in the infarcted heart. By using a mouse model of MI and inducible nitric oxide synthase gene knockout mice together with cultured myoFb obtained from infarcted heart, the following specific aims will be fulfilled. Aim 1: to determine whether nitric oxide regulates myoFb growth/survival and activity in the infarcted heart by characterizing its influence on myoFb apoptosis and regulatory genes, myoFb replication and phenotype change. Aim 2: to detect whether nitric oxide is involved in collagen turnover by detecting its potential role in metalloproteinase-1 (MMP-1) synthesis, MMP-1 activation, tissue-derived MMP inhibitors expression, and cardiac collagen synthesis. Aim 3: to determine whether nitric oxide modulated TGF-beta1 expression and activity at sites of cardiac fibrosis by investigating its effect on TGF-beta1 synthesis, activation and receptor expression. Findings derived from the proposed studies should advance our understanding on pathogenesis and management cardiac remodeling by fibrous tissue, which will provide the opportunity for pharmacologic interventions that limit collagen deposition in the heart with MI and improve cardiac function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NITRIC OXIDE AND DROSOPHILA DEVELOPMENT Principal Investigator & Institution: Enikolopov, Grigori N.; Associate Professor; Cold Spring Harbor Laboratory 1 Bungtown Road Cold Spring Harbor, Ny 11724 Timing: Fiscal Year 2002; Project Start 05-AUG-1999; Project End 31-MAY-2004 Summary: The overall goal of this project is to understand the function of nitric oxide (NO) in organism development. NO is a diffusible multifunctional second messenger implicated in numerous physiological functions in animals. Recently NO has emerged as an important factor in cell proliferation, cell differentiation, and animal development. Our studies have shown that NO acts as an antiproliferative agent during organism development, regulating the balance between cell proliferation and differentiation, and, ultimately, controlling the shape and size of tissues and organs in the developing Drosophila. This proposal will test the hypothesis that NO is a general regulator of cell proliferation and differentiation during organism development and morphogenesis. We will combine genetic and molecular approaches to study the mechanisms of NO action. We will search for mutations in the dNOS locus. Such mutations will provide a starting point to develop specific genetic lesions in dNOS gene and to perform screens for genetic partners of dNOS. We will characterize the molecular organization of the isolated NO synthase (NOS) genes involved in Drosophila development, and we will search for other NOS gene(s) in Drosophila genome. We will elucidate the biological functions of the developmentally regulated isoforms which are capable of inhibiting
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NOS activity, and we will search for other genes that interact with NOS. Recently, we have demonstrated that NO interacts with the retinoblastoma pathway to control eye development in Drosophila, and here we propose to study genetic and molecular interactions between NOS and the components of the cell cycle machinery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NITRIC OXIDE AND SMOOTH MUSCLE CELL PROLIFERATION Principal Investigator & Institution: Sarkar, Rajabrata; Northern California Institute Res & Educ 4150 Clement Street (151-Nc) San Francisco, Ca 941211545 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-JUL-2005 Summary: My goal is to be an academic vascular surgeon who has an independent research laboratory and teaches vascular surgery in a university setting. My long-term research interest, including my Ph.D. studies, has been inhibition of vascular smooth muscle Cell proliferation by nitric oxide, a process clinically relevant to vascular surgery. Proliferation of smooth muscle cells is critical to the development of both atherosclerosis and post- surgical disorders such as restenosis and vein graft failure. In this proposal l will use a variety of molecular approaches, including dominant negative mutants and anti sense constructs, as well as analysis of kinase and cyclin activity, to define the intracellular mechanisms involved in the antiproliferative effect of nitric oxide. The Specific Aims are: 1) To examine the role of cyclic necleotides and cyclic necleotide-dependent kinases in mediating the anti-proliferative effects of nitric oxide, 2) To determine the effect of nitric oxide on expression of the cell cycle- dependent proto-oncogenes (e.g. fos, myc, myb) and the potential role of inhibition of protooncogene expression in growth inhibition by nitric oxide, 3) To determine the mechanism of induction of the cyclin- dependent kinase inhibitor p21 by nitric oxide and the importance of p21 in mediating growth arrest by nitric oxide. The effects of modulation of these intracellular pathways will be evaluated in cultured smooth muscle cells treated with exogenous nitric oxide. These investigations under the guidance of my sponsors, coupled with the courses, seminars and collaborations in this Research Career Award, will substantially broaden my scientific experience and allow me to approach future problems in vascular biology with a wide array of fundamental experimental techniques. Definition of these mechanisms is important to understanding both the physiologic inhibition of pathologic smooth muscle cell proliferation by endothelium and potential new therapeutic strategies for proliferative vascular disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NITRIC OXIDE CONTROL OF CGRP IN TRIGEMINAL NEURONS Principal Investigator & Institution: Durham, Paul L.; Biology; Southwest Missouri State University 901 S National St Springfield, Mo 65802 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): The objective of the proposed research is to understand the mechanisms by which nitric oxide (NO) regulates calcitonin generelated peptide (CGRP) gene expression in trigeminal neurons. Serum levels of CGRP are elevated in alt forms of vascular headaches, including migraine. The neuropeptide CGRP is known to play a critical role in the underlying pathology of migraine due to its ability to regulate cerebral blood flow, mediate neurogenic inflammation, and relay nociceptive information to the CNS. Another agent implicated in migraine pathology is nitric oxide (NO). Glyceryl trinitrate, an exogenous NO donor, triggers migraine
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attacks, while blockade of NO synthesis aborts acute migraine attacks. The cerebrovascular affect of NO is thought to be mediated by the local release of neuropeptides from trigeminal neurons. In this proposal, I will test the hypothesis that NO directly stimulates CGRP gene expression and determine whether serotonergic antimigraine drugs can repress the effect of NO. Studies proposed in the first specific aim will determine the effect of NO alone or in combination with other inflammatory mediators on CGRP release from trigeminal neurons and whether the anti-migraine drug sumatriptan can repress this effect. The second aim will focus on identifying the basal and NO-responsive regulatory sites in the CGRP promoter. Primary trigeminal ganglia cultures will be transiently transfected with CGRP-luciferase reporter DNA and reporter activity measured. The effect of sumatriptan on basal and NO-stimulated CGRP promoter activity will be determined. The third aim will elucidate the pathways involved in NO signaling in trigeminal neurons. Initially, specific cyclase and kinase inhibitors and activators will be used to identify the major pathway(s) involved in regulating the synthesis and release of CGRP. Further studies of individual pathways will utilize phosphospecific antibodies and signaling pathway detection kits. The effect of sumatriptan on NO-activated pathways will be determined. The overall goal of these studies is to gain insight into basal and NO regulation of CGRP gene expression in trigeminal neurons that may lead to the development of novel therapeutic strategies for migraine and other diseases involving neurogenic inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GINGIVALIS
NITRIC
OXIDE
DEFENSE
AGAINST
PORPHYROMONAS
Principal Investigator & Institution: Gyurko, Robert; Periodontology & Oral Biology; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006 Summary: (provided by applicant): Periodontal disease, the leading cause of tooth loss in the adult population, is an inflammatory disease which is triggered by bacteria, but it is thought that periodontal tissue damage is primarily inflicted by the host's own defense reaction. Nitric oxide (NO) is a multifunctional molecule present in periodontal tissues, which can be toxic to bacteria as well as to cells of the periodontal tissue. NO is released in response to Porphyromonas gingivalis (P. gingivalis) infection, a bacterium which is clinically and experimentally associated with periodontal disease. We propose experiments to elucidate the role of NO in the defense against P. gingivalis infection. In preliminary studies we have compared P. gingivalis-induced periodontal bone loss in normal mice and in mutant mice which do not produce NO in response to bacteria (iNOS KO mice). We found that iNOS KO mice are resistant to P. gingivalis induced bone loss. To investigate the mechanisms by which NO participates in antimicrobial defense, the role of NO in inflammatory reaction is evaluated in an implant chamber model of P. gingivalis infection. We study the interaction of NO with other antibacterial molecules, such as superoxide, by testing mutant mice deficient in NO, superoxide, or both NO and superoxide. To assess the importance of NO in regulating bone destruction, isolated bone tissue from normal and iNOS KO mice is tested for a series of signaling molecules which are known to cause bone loss. The role of NO in bone development at various ages of normal and iNOS KO mice is also tested. Robert Gyurko, DDS, PhD is currently conducting research on the role of NO in cardiovascular diseases at the Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA. He is applying for the NIDCR Scholar Development and Faculty Transition
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Award to pursue scientific career as an independent investigator at Boston University School of Dental Medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NITRIC OXIDE EFFECTS ON BRONCHOPULMONARY DYSPLASIA Principal Investigator & Institution: Bland, Richard D.; Professor of Pediatrics; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Bronchopulmonary dysplasia (BPD) often complicates prolonged mechanical ventilation after premature birth. Defining the mechanisms that cause BPD and developing a safe, effective treatment strategy are the ultimate objectives of this project. To study the pathogenesis of BPD and to test various therapeutic interventions, we developed a preterm lamb model that mimics the clinical and pathological findings of this disease. The underlying hypothesis is that early postnatal inflammation of the immature lung exposed to prolonged, repetitive stretch with 02enriched gas leads to oxidant and protease induced lung injury that can be inhibited or prevented by early and continuous postnatal delivery of inhaled nitric oxide (iNO), the response to which may be enhanced by antenatal steroid treatment. The proposal has 3 specific aims: (i) to compare immediate vs delayed (7d) postnatal delivery of continuous, low-dose iNO (and the relevant control, no iNO) in chronically ventilated preterm lambs; (ii) to determine if antenatal steroid treatment will modify the response to immediate or delayed iNO; and (iii) to determine if iNO will inhibit lung inflammation and thereby facilitate postnatal adaptation of the pulmonary circulation and respiratory tract, leading to improved respiratory gas exchange. This project complements the clinical trial of iNO in preterm infants with respiratory failure. Serial specimens of bronchial secretions, lung lavage fluid and lung lymph will allow assessment of inflammation in evolving BPD. The research plan includes physiological, biochemical, histological and molecular techniques to define mechanisms underlying abnormalities in the lung circulation (persistent elevation of vascular resistance, edema from increased vascular filtration pressure, loss of the pulmonary vasodilator response to iNO, increased arterial smooth muscle, reduced numbers of microvessels and less capillary surface density, decreased expression of endothelial nitric oxide synthase and soluble guanylate cyclase); respiratory tract (increased expiratory resistance, proliferation of bronchiolar smooth muscle, reduced numbers of alveoli); and lung interstitium (increased lung tropoelastin expression and disordered elastin accumulation) that characterize the lamb model of BPD. Collaborative studies with other SCOR projects that focus on surfactant proteins and function (I), vascular endothelial growth factor and its receptors (II), inflammatory mediators (III), and mitogens that influence smooth muscle proliferation and connective tissue elements (IV) will provide new insight on mechanisms of lung dysfunction and dysplasia in BPD and the impact of iNO and antenatal steroids on these abnormalities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NITRIC MECHANISMS
OXIDE
INDUCED
CELL
INJURY--MOLECULAR
Principal Investigator & Institution: Spitz, Douglas R.; Associate Professor; Radiology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-JUL-1994; Project End 31-JAN-2004
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Nitric Oxide
Summary: The goal of this proposal is to determine how disruption of thiol metabolism by reactive nitrogen species (RNS) derived from nitric oxide (NO.) contributes to activation of oxidation/reduction (redox) sensitive signal transduction pathways leading to the induction of cytotoxic as well as cytoprotective responses. This goal was chosen on the basis of data gathered in the first funding period and data from the literature showing that NO. altered thiol status, redox sensitive kinase activation and the activation of redox sensitive transcription factors (AP-1 and NF-kappaB) leading to the induction of both cytoprotective as well as cytotoxic responses. The proposed experiments will determine how RNS derived from NO.: 1) alter intracellular soluble thiol pools (i.e., glutathione, cysteine, gamma-glutamylcysteine) as well as thiol metabolizing enzymes (i.e., gamma-glutamylcysteine synthetase) in fibroblasts and endothelial cells; 2) alter activity or levels of thiol containing proteins (ie., thioredoxin, thioredoxin reductase) known to transmit redox signals from soluble thiols to transcription factors (ie., AP-1 and NF-kappaB); 3) contribute to the activation of redox sensitive kinases (ie., mitogen activated protein kinases) thought to be involved with AP-1 and NF-kappaB activation; 4) effect the activation of redox sensitive transcription factors (ie., AP-1 and NF-kappaB) and genes thought to be regulated by AP- 1 and NFkappaB (ie., gamma-glutamylcysteine synthetase). Finally, the experiments will determine the relative contribution of nitric oxide- induced alterations in thiol metabolism, signal transduction and transcription factor activation to biological responses seen in endothelial cells, HAl hamster fibroblasts, and nitric oxide resistant variants derived from HAl. A rigorous interdisciplinary approach using cell biology, biochemistry, molecular biology, and analytical chemistry will be used to pursue these Aims. Pharmacological agents (ie., N- acetylcysteine, and inhibitors of kinases, protease, and thioredoxin reductase) as well as molecular manipulations (ie., antisense, dominant negative, dominant positive transfections) will be used to probe causal relationships between NO-induced alterations in thiols and signal transduction pathways, and biological outcomes seen following exposure to RNS. The long term goal is identification of basic mechanisms by which RNS after biological outcomes during oxidative stress. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NITRIC OXIDE PRODUCTION AND REACTIONS IN THE LUNG Principal Investigator & Institution: Erzurum, Serpil C.; Professor; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Primary pulmonary hypertension (PPH) is a fatal disease of unclear etiology, characterized by progressive increase in pulmonary artery pressure. The long term goal of this research is to determine the role of NO, oxidants and NO-oxidant chemical reaction products in pulmonary hypertension. Our preliminary data provide clear evidence that NO and NO reaction products (N03, S-nitrosothiols) are lower in lungs of PPH than healthy controls. We propose that the low levels of NO and its reaction products in PPH are due to decreased NO synthesis and increased NO consumption by reactions with oxidant species, leading to alternative reaction endproducts. We show that NO reaction products are strongly correlated in an inverse relationship to pulmonary artery pressures in PPH. Theoretical modeling and simulation of our data suggest that progression and mortality in PPH will be predicted by NO reaction products. These data indicate a possible role for NO and oxidants in the pathogenesis of PPH. We will test our hypotheses with 4 aims. First, we will extend our preliminary findings and obtain longitudinal data on pulmonary artery pressures, cardiac output
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and lung diffusion capacity in 30 PPH patients. The values of these factors at specific time points will be modeled as linear functions of the corresponding levels of NO and NO reaction products to test our hypothesis that NO reaction products are predictive of progression of PPH. Second, low NO levels in PPH may result from decreased nitric oxide synthase (NOS) levels or activity. NOS expression for all 3 isoforms will be quantitated and localized in PPH lungs in comparison to controls. NOS activity will be measured and posttranslational mechanisms regulating activity evaluated. Third, low NO in PPH may also result from increased consumption. We propose that oxidative consumption of NO is increased in PPH due to alterations in the reducing-oxidizing (redox) environment of the lung. Since oxidative status of the lung cannot be assessed directly, we will test this hypothesis by measures of (i) nitrotyrosine formation; (ii) Nuclear Factor kappaB, a transcription factor activated in inflammation through oxidant mechanisms; and (iii) antioxidant levels. Finally, the concept that NO consumption through NO-oxidant reactions is dependent upon the redox environment will be tested in an in vitro cell culture system. Together, these experiments will define the mechanisms regulating NO levels and reactions in the lung, and provide a comprehensive picture regarding the role of NO and NO reaction products in PPH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NITRIC OXIDE REGULATION OF ADRENAL STEROIDOGENESIS Principal Investigator & Institution: Campbell, William B.; Associate Professor; Pharmacology and Toxicology; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Vascular endothelial cells (ECs) release a number of biologically-active mediators (PGI2, nitric oxide (NO) and endothelin) that act on adjacent smooth muscle cells to influence vascular tone. In the adrenal cortex, as adrenal arteries get smaller and divide into capillaries and sinusoids, the smooth muscle layer is lost and the abluminal side of the EC comes in close anatomical contact with the steroidogenic cells. Thus, in the capillaries of the adrenal cortex, these mediators may influence the function of the adjacent steroidogenic cells. We have focused our studies on the role of endothelial-derived NO on steroidogenesis. We found that the NO donors inhibit angiotensin II (All)-stimulated aldosterone release. The inhibition by NO is not mediated by cyclic GMP but by NO binding to the cytochrome P450 enzymes involved in aldosterone biosynthesis. We were unable to detect NO synthesis, NO synthase (NOS) activity or NOS protein in ZG cells. However, adrenal capillary ECs contain NOS and release NO. We wilt test the hypothesis that ECs, which are in close anatomical proximity to ZG cells in the adrenal cortex, release NO and regulate or modulate aldosterone release. The proposed studies will investigate the effects of exogenous, endogenous and endothelial-derived NO on aldosterone release. These studies will be conducted in vitro in cultured bovine ZG cells and adrenal capillary ECs. Also, studies will be performed in the perfused rat adrenal gland and in vivo in anesthetized rats. The hypothesis will be tested by addressing four specific aims: (1) We will characterize the effect of exogenous NO on aldosterone release in cultured bovine ZG cells. The effect of the NO donor, deta-nonoate, will be tested on aldosterone release under conditions that vary the oxygen concentration. Additional studies will determine the biosynthetic step inhibited by NO and the effect of chronic NO treatment on aldosterone production and steroidogenic enzymes. (2) Since ZG cells do not have NOS, we will determine the effect of endogenous NO by conferring NOS activity on ZG cells by transducing the cells with an adenovirus containing NOS. (3) We will characterize the influence of endothelial-
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derived NO on ZG cell aldosterone release. Using co-incubation of ECs and ZG cells, we will determine the effect of agonists on the release of NO from ECs and the action of this NO on ZG cell aldosterone release. (4) We will determine the role of endothelial NO in regulating steroidogenesis and adrenal blood flow in the in situ perfused adrenal gland and in vivo in anesthetized rats. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NITRIC OXIDE REGULATION OF COMPENSATORY LUNG GROWTH Principal Investigator & Institution: Laubach, Victor E.; Assistant Professor; Surgery; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: Pneumonectomy (removal of a whole lung) is a life-saving procedure in patients who cannot otherwise be cured; but it carries considerable morbidity and mortality. While pneumonectomy results in rapid growth of the remaining lung, the stimuli and molecular mechanisms of this compensatory lung growth (CLG) remain unknown. Understanding these mechanisms will answer important questions concerning CLG and organ regeneration. Thus the long-term objectives of this proposal are to understand the molecular mediators that trigger and regulate CLG. Nitric oxide (NO) is an important regulator of CLG, and is known to mediate the angiogenic and mitogenic properties of key growth factors in endothelial cells and type II alveolar cells. Thus this proposal will test the overall hypothesis that NO is a key mediator of CLG through the modulation of angiogenesis and type II cell proliferation. To test this hypothesis, knockout mice deficient in endothelial NO synthase (eNOS), inducible NOS (iNOS), and both eNOS/iNOS will be used to study NO-mediated mechanisms of postpneumonectomy CLG. Specific Aim 1 will test the hypothesis that NO is required for CLG by modulating angiogenesis and type II cell proliferation and differentiation. Angiogenesis and type II cell proliferation and differentiation will be measured in the NOS-deficient mice. Specific Aim 2 will test the hypothesis that NO is essential to CLG by modulating expression of specific proliferation factors in the lung. Expression of cytokines, NOS, growth factors and their receptors will be measured. Augmentation of CLG will be tested by administration of exogenous growth factors, and use of inhaled NO will determine the times during which NO is critical to CLG. Specific Aim 3 will test the hypothesis that a mechanism of NO- regulated CLG is via the cGMP signaling pathway and the MAPK cascade. Activation of cGMP-dependent kinase I and MAPK kinase will be determined, and CLG will be measured in mice after the inhibition of cGMP-dependent kinase I using a selective pharmacologic inhibitor. Identification of the molecular mediators in regenerative lung growth will not only advance the field of lung biology and transplantation, but will permit the advancement of future therapies for lung injury and end-stage lung disease through the stimulation and control of lung growth and regeneration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NITRIC OXIDE REGULATORY SYSTEM IN THE PENIS Principal Investigator & Institution: Burnett, Arthur L.; Associate Professor; Urology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 16-APR-1998; Project End 31-MAR-2003 Summary: (adapted from the application) It is currently accepted that the mechanism of vascular and trabecular smooth muscle relaxation in the penis required for penile
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erection depends upon nitric oxide. This novel biochemical mediator is well understood to be synthesized and released from nerve terminals within the erectile tissue of the penis. Some evidence also exists for its release from the endothelial component of the erectile tissue. As nitric oxide exerts such a significant role in the physiology of the penis, it would be pertinent to also understand the control mechanisms effecting its release and action in this organ. It is entirely conceivable that nitric oxide operates much like other mediators which are neither released constantly or unchangeably but are precisely regulated by modulatory substances. Regulation of the nitric oxide signal transduction pathway in the penis may significantly affect erectile tissue function and dysfunction. An improved understanding of the regulatory basis for nitric oxide effects in the penis would be expected to advance the biochemical and pharmacological approaches to promote erectile tissue function and dysfunction. An improved understanding of the regulatory basis for nitric oxide effects in the penis would be expected to advance the biochemical and pharmacologic approaches to promote erectile integrity and to minimize structural and functional damage involving the erectile tissue of the penis. Such an advance is welcomed in view of the established 10-20 percent rate of erectile dysfunction present in the American male population. This research proposal centers on two primary objectives, the regulatory basis for nitric oxide in the physiology of the penis and that possibly influencing penile pathophysiology. Specific aims are: (1) to examine the effects of selective an combined nitric oxide synthase isoform deletions on penile erections in genetically altered mutant mice and determine whether compensatory mechanisms develop which preserve erectile function in these mice; (2) to investigate the effects of stimulation and inhibition of neural and humoral factors commonly associated with erectile function and dysfunction on the maintenance of penile erections in mutant mice with selecting and combined deletions of nitric oxide synthase isoforms; and (3) to evaluate neurotrophic mechanisms that may result in physiologic upregulation of nitric oxide synthase in the penis applying neurotrophin delivery to experiments paradigms of erectile dysfunction. The experimental strategies employed by this proposal prominently feature a mutant mouse paradigm in which nitric oxide synthase genes are genetically disrupted. Consequences of this model on erectile function at baseline and following perturbations such as androgen withdrawal, neurotransmitter stimulation, neurotrophin exposure, and diabetogenesis will be studied using immunoblot analysis to confirm nitric oxide synthase expressions, immunohistochemistry to confirm nitric oxide synthase localizations, nitric oxide synthase assay to confirm nitric oxide synthase activity, and both physiologic erection and isometric tension studies of isolated erectile tissue to determine the effects of erectile function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NITRIC OXIDE TOLERANCE IN SMOOTH MUSCLE Principal Investigator & Institution: Perkins, William J.; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: Nitric oxide (NO) is widely used by surgeons, anesthesiologists and critical care physicians managing critically-ill patients (e.g., inhaled NO for treatment of pulmonary hypertension and nitrovasodilators for decreasing afterload and for improving myocardial perfusion). Tolerance to these NO-based therapies occurs clinically and the extent to which this NO-induced NO hyporesponsiveness is due to decreased activity in the vascular smooth muscle NO-cGMP-cGK signaling system is unknown. The objective of this proposal is to determine the mechanisms by which
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Nitric Oxide
chronic exposure to NO affects this signaling system in vascular smooth muscle. Two broad categories of mechanism for the development of chronic NO-induced NO hyporesponsiveness involving the vascular smooth muscle NO- cGMP-cGK signaling system are possible: 1) changes in [cGMP]i regulation and 2) reductions in the sensitivity to cGMP (cGMP sensitivity). To explore these mechanisms, we will utilize a cultured pulmonary artery preparation (PA) which permits experiments in fully functional, differentiated vascular smooth muscle cells. This cultured vessel preparation makes it possible to directly relate chronic NO-induced changes in the vascular smooth muscle NO-cGMP-cGK signaling system to chronic NO-induced decreases in NO responsiveness. Chronic NO exposure will be achieved using both NO-donors, and endogenously-derived NO following nitric oxide synthase gene transfer. Greater insight into the factors responsible for chronic NO-induced NO hyporesponsiveness will aid in the development of future NO-based therapeutic strategies. This is of particular relevance in the pulmonary circulation, in which inhaled NO is administered as a therapy for pulmonary hypertension, yet a large fraction of these patients are unresponsive to the NO. Methods used in the proposed studies include isometric force measurements, RT-PCR to isolate mRNA for all soluble guanylyl cyclase subunits (sGC) and cGMP-dependent protein kinase (cGK) isoforms, quantitative RT-PCR and immunoblotting to measure expression of each, and sGC and cGK enzyme activity measurement. We will use a combination of pharmacological probes and novel antisense oligomers to determine the mechanism by which chronic NO treatment decreases the expression and activity of sGC subunits and cGK isoforms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NITRIC OXIDE TRANSPORT MECHANISMS: MODEL AND EXPERIMENTS Principal Investigator & Institution: Jaron, Dov; Director; School of Biomedical Engineering, Science & Health Systems; Drexel University 3201 Arch Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The general goal of the proposed research is to improve our understanding of the complex interaction between nitric oxide (NO), hemoglobin, oxygen, carbon dioxide, and thiols in the blood and tissue In recent years, many hypotheses have been suggested regarding the production and transport of NO in the blood and various factors that may affect these processes However, disagreement still exists over the true mechanisms of action and transport of NO. Several specific questions remain (1) How do the complex interactions of intracellular calcium, oxygen, shear stress, and thiol levels affect the amount of NO produced by the endothelium and delivered to tissue? (2) Do nitrosothiols or nitrosylhemoglobin (SNO-I-Ib) act as a facilitated carrier mechanism by storing NO and transporting it to areas where it is needed? (3) Can mathematical modeling assist in determining the most probable transport mechanisms for NO? The proposed research seeks to answer these questions using a combination of in vitro and in vivo experimental studies and mathematical modeling Experimental studies have been designed to provide vital information for the mathematical modeling and will be used to test model validity and evaluate hypothesized mechanisms of NO transport In vitro studies will be conducted in a parallel-plate flow chamber using rat endothelial cells. Nitric oxide release will be stimulated using neurohumoral mediators and measured under basal conditions. Additional conditions, including altered oxygen and carbon dioxide levels, various levels of shear stress and addition of thiols will be imposed. In vivo studies will be
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conducted in the arterioles and venules of the rat mesentery. NO levels will be measured under normal physiological conditions, during hypoxia and hypercapnia and under altered thiol, shear stress and hematocrit levels. The effects of these interventions on NO production, transport, and distribution will be measured, incorporated into the mathematical model, and used to test its validity under various ranges of conditions. The mathematical model will simulate the production, mass transport, feedback regulation, and biochemical mechanisms of action of NO in the microcirculation and tissue. Quantitative data obtained from the validated model will be used to predict parameters that cannot be measured in vivo, analyze the hypotheses and further the understanding of NO production and transport mechanisms, and used to shape future experimental studies. Understanding NO transport mechanisms is important clinically since altered NO regulation has been implicated in pathophysiological conditions Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NO& EPITHELIAL REPAIR IN CRYPTOSPORIDIOSIS Principal Investigator & Institution: Gookin, Jody L.; Anatomy/Physiological Scis Rad; North Carolina State University Raleigh 2230 Stinson Drive Raleigh, Nc 27695 Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 31-DEC-2006 Summary: The Research Proposal: The long-term goal of these laboratories are to better understand the cellular mechanisms of diarrhea and tissue injury, define the integrated mechanisms of mucosal defense and repair in infectious enteritis, and identify rational approaches to nutritional and pharmacologic enhancement of epithelial repair. Our preliminary studies showed that inducible nitric oxide synthase is expressed intensely by damaged enterocytes after acute mucosal bile salt injury. Exogenous L-arginine promotes epithelial repair after the injury; an effect that depends upon NO synthesis. The present studies hypothesize that iNOS is a key mediator of epithelial defense and repair in Cryptosporidium infection by hastening elimination of infected enterocytes and restitution. We will use a well-characterized experimental model of neonatal porcine cryptosporidiosis and migration studies of porcine jejunal enterocytes to examine the role of NOS in epithelial injury and restitution at both the cellular and whole tissue level and in the presence and absence of inflammatory mediators. The Candidate is a veterinarian who has completed a residency in Internal Medicine and is a board certified Diplomate of the American College of Veterinary Internal Medicine. The candidate has also completed a Ph.D. in Physiology with a minor in Biotechnology. The dissertation examined the role of L-arginine and prostaglandins in restoration of mucosal barrier function after acute mucosal bile salt injury. As a veterinary internist and gastrointestinal physiologist, the candidate is committed to a career in academia pursuing basic research, with a lesser commitment to clinical service and teaching. The Environment: The sponsor and co-sponsors of this proposal each can provide unique contributions to the proposed research and professional development of the candidate. The laboratories in which the candidate is engaged are capable of providing the room, equipment, animal handling facilities, and support staff necessary for completion of this proposal. The laboratories are contained within the College of Veterinary Medicine (NCSU) and School of Medicine (UNC) which provides intensive interdisciplinary training and support through the Core Center for Gastrointestinal Biology and Disease, Biotechnology Program, seminars, and journal clubs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Nitric Oxide
Project Title: NO ROLE IN VASCULAR PROTECTION BY POLYPHENOLS & ALCOHOL Principal Investigator & Institution: Parks, Dale A.; Professor; Anesthesiology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: The interaction of dietary components, such as the polyphenols and alcohol, on chronic diseases, particularly those of the cardiovascular system, is only recently emerging. This is a key area since considerable epidemiological evidence indicates that consumption of moderate levels of alcoholic beverages, particularly red wine, decreases both the incidence of cardiovascular disease and the mortality associated with myocardial infarction. Molecular mechanisms of this cardiovascular protection remain uncertain but appear to involve complex interactions of these components with cells in the vascular wall. The main attribute of the polyphenols that have been forwarded to explain these protective effects has been their antioxidant properties. Data forming the foundation of this proposal indicate an interesting elaboration of the hypothesis that polyphenols act as antioxidants, particularly in conjunction with ethanol. It is proposed that transcriptional regulation of the concentration and activity of critical vascular protective enzymes makes a major contribution to the enhanced cardiovascular protective effects and is more pronounced in combination with ethanol. The main effect of the enhanced endogenous cytoprotective enzymes is to increase the bioavailability of nitric oxide (NO). Preliminary data shows that dietary polyphenols and alcohol (1) enhance NO-dependent vascular function (2) increase expression of nitric oxide synthases (NOS) mRNA in the vasculature; (3) induce protein expression of both iNOS and eNOS isoforms in the vasculature; (4) induce vascular superoxide dismutases (SOD); and (5) that increased bioavail- ability of NO may be responsible for the cardiovascular protection. These data have led to the hypothesis that "moderate alcohol or dietary polyphenols will increased NO bioavailability and play a pivotal role in conferring vascular protection". This hypothesis will be tested by completion of the following Specific Aims: (1) induction of NOS by dietary polyphenols and moderate alcohol increases bioavailability of NO and results in vascular protection, (2) induction of SOD and a consequent decrease in superoxide (O2-.) by dietary polyphenols and moderate alcohol increases the bioavailability of NO and results in vascular protection, and (3) polyphenol supplementation results in vascular protection due to both increased bioavailability of NO and a consequent decreased susceptibility to pro-inflammatory oxidants. The completion of these specific aims will provide insight into the mechanisms that lead to increased NO and role that these NO-dependent mechanisms play in the cardiovascular protection associated with polyphenols and alcohol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SHRINKAGE
NO-INDUCED
NEUROTOXICITY
AND
APOPTOTIC
CELL
Principal Investigator & Institution: Bossy-Wetzel, Ella R.; Burnham Institute 10901 N Torrey Pines Rd La Jolla, Ca 920371005 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2006 Summary: (provided by applicant): Excessive stimulation of glutamate receptors of the NMDA sub-type result in the activation of nitric oxide synthase (NOS), the generation of nitric oxide (NO), and neuronal cell death. The apoptotic signaling pathway by which NO exerts its neurotoxic effects remains poorly understood. Events such as protein nitrosylation, mitochondrial dysfunction and activation of stress-activated p38 mitogen
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activated protein (MAP) kinase have been proposed to act as downstream effectors of NO-induced neurotoxicity. Affected neurons are thought to die by apoptosis, a form of cell death that involves the activation of cell death proteases, known as caspases. However, caspase inhibition often only delays neuronal cell death. Thus cell death determining events, upstream of casr ase activation, are likely to contribute to the commitment to cell death. Cell shrinkage is a universal event of all apoptotic cell death and involves the efflux of intracellular K+ ions. The molecular mechanism that drives K+ efflux during apoptosis is unclear. The purpose of this project will be to explore the possibility whether activation of outward voltage-gated K+ channels and subsequent cell shrinkage and mitochondrial injury via a pathway mediated by free Zn+ may constitute early events that commit neurons irreversibly to NO-induced neurotoxicity. To pursue these goals, primary cerebrocortical neurons will be analyzed using approaches such as time-lapse deconvolution microscopy, whole cell patch-clamp recording, transient transfections, biochemistry, and cell-free systems of apoptosis with isolated mitochondria. Among the specific questions that will be addressed in this project are: (1) Does NO provoke K+ efflux, enhancement of voltage-gated K+ channels, and apoptotic cell shrinkage? (2) Does stress-activated p38 MAP kinase regulate the activity of voltage-gated potassium channels and cell shrinkage? (3) Does NO provoke Zn2+ release from metallothionein (MT) which in turn results in mitochondrial damage, generation of reactive oxygen species, and p38 MAP kinase phosphorylation? Because NO plays an important role in a wide range of neurodegenerative diseases including stroke, Parkinson's disease, Alzheimer's disease, multiple sclerosis, epilepsy, and AIDS dementia, results obtained from this project could provide broad implications for the development of new therapeutic drugs to mitigate or even prevent neuronal cell loss during neurodegeneration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OBESITY, NITRIC OXIDE, OXIDATIVE STRESS, NA SENSITIVITY Principal Investigator & Institution: Flack, John M.; Professor; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: We propose a 39-week clinical study in healthy, normotensive, overweight (BMI equal to or more than 25 kg/m[2]) African American men and women aged 45 years and older that, after an initial screening and eligibility period (4 weeks), will be conducted in three phases. Phase 1 (9 weeks) begins the isocaloric 100 mmol dietary sodium diet phase. After the initial 3 weeks, a six-week period of 100 mmol/d sodium supplementation will be administered to determine salt sensitivity. Phase 2 (8 weeks) will maintain the 100 mmol sodium dietary intake and will additionally add a weight loss component to attain weight loss of about 1.5 - 2 pounds/week. Phase 3 (18 weeks) will consist of a two-period crossover trial consisting of randomization to the treatment sequence of dietary sodium supplementation of 100 mmol/d (6 weeks) followed by placebo (6 weeks) or vice versa. A 6-week placebo washout period will separate the two active periods. The 100 mmol sodium/weight loss diet from phase 2 will be maintained during this treatment phase. The difference in BP between the end of the sodium and placebo periods will determine salt sensitivty after weight loss. The overarching study hypothesis is that obesity-related salt sensitivity is attributable, in large degree, to oxidative-stress mediated reductions in nitric oxide [NO] availability. The destruction of NO is linked to obesity-related elevations of non-esterified fatty acids, leptin, and reninangiotensin-aldosterone system activity - all of which are known to increase oxidative stress. Genetic variation in the angiotensin converting enzyme, specifically
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Nitric Oxide
homozygosity for the insertion [I] polymorphism, will predict higher levels of salt sensitivity, oxidative stress, and lesser NO production. Environmental stressors interact with obesity to augment salt sensitivity. We further hypothesize that the degree of reversibility of salt sensitivity will closely parallel weight loss-induced reductions in oxidative stress. The primary specific aim of the study is to determine the main and interactive effects of stressors, obesity, and genetic variation of the ACE and endothelial nitric oxide synthase (eNOS) genotypes on oxidative stress and salt sensitivity and, after weight loss, to re-examine these effects as well as to link changes in oxidative stress to persistence of salt sensitivity between study phases 2 and 3. This study will provide important new insights into the pathophysiology of salt sensitivity in African Americans who are at high risk for development of hypertension and related cardiovascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OXIDANT INDUCED VASCULAR CELL PROLIFERATION AND APOPTOSIS Principal Investigator & Institution: Kalyanaraman, Balaraman; Professor/Director; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Long-term goal: The long-term goal of Project 5 is to unravel the free radical mechanisms by which reactive oxygen and nitrogen species (ROS/RNS) induce proliferation and apoptosis of vascular smooth muscle cell (VSMC) and endothelial cells (EC). Hypothesis: The general hypothesis to be tested is that (i) nitric oxide (NO) prevents lipid hydroperoxide- and oxidized low-density lipoprotein(oxLDL)-mediated apoptosis and proliferation in vascular cells by scavenging the potentially damaging peroxyl radical and (ii) the nitrogenic and apoptotic effects of ROS are regulated by cellular iron. Specific Aims: First, we will define the proliferative and apoptotic effects of specific oxidants (H2O2, lipid hydroperoxide, aldehydes and peroxynitrite) in VSMC/EC and determine the inhibitory effects of well-defined cell- permeable antioxidant mimetics, redox-metal chelators, and NO donors. Antioxidant mechanisms (radical scavenging and induction of anti- apoptotic proteins) will be investigated. Intracellular levels and sources of superoxide anion will be determined. Next, we will extend these studies to oxLDL, which is more pathophysiologically relevant. Finally, we will determine how ROS and oxLDL-mediated cellular effects are controlled by tetrahydrobiopterin (BH4), an indispensable co-factor in the biosynthesis of NO from endothelial nitric oxide synthase (eNOS) and how BH4 regulates superoxide and NO formation from eNOS. Methods: We will use endothelial cell lines (BAEC and HUVEC), rat aortic and cerebral arterial smooth muscle cells, and catalase-transfected VSMC and EC. OxLDL formed by treating LDL with several biologically-relevant oxidants will be used. Apoptosis will be detected by several methods including DNA fragmentation, TUNEL analysis, propidium iodide staining, caspase-3 activity, mitochondrial cytochrome c release, Bcl-2 and Bax activity. Superoxide levels will be determined by spin-trapping, aconitase activation/inactivation, fluorescence and chemiluminescence techniques. Significance: The abnormal proliferation of VSMC is implicated in various diseases (e.g.,hypercholesterolemia, atherosclerosis, hypertension). Oxidant-induced endothelial apoptosis may be crucial to the development of vascular diseases which are also characterized by tetrahydrobiopterin deficiency. Novelty: Defining the basic mechanisms by which oxidants and antioxidants selectively perturb and restore endothelial and smooth muscle cell function may provide a better understanding of the antioxidant therapy in vascular diseases.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEPTIDE REGULATION OF THE CHOROID PLEXUS-CSF SYSTEM Principal Investigator & Institution: Johanson, Conrad E.; Professor; Rhode Island Hospital (Providence, Ri) Providence, Ri 029034923 Timing: Fiscal Year 2002; Project Start 20-AUG-1999; Project End 31-JUL-2004 Summary: Choroid plexus (CP) has a great impact on the neuronal extracellular fluid environment. Choroid epithelial cells secrete cerebrospinal fluid (CSF) as well as peptides that modulate brain development, fluid balance and repair following injury and disease. Various growth factors and neuropeptides synthesized in CP are secreted into CSF, thereby exerting endocrine-like effects on target cells in brain as well as local effects on CP. Thus, CP is both a TARGET and a SOURCE for peptides. The renewal projects focus on regulation of the CP-CSF system by peptides, specifically basic fibroblast growth factor (FGF-2) and arginine vasopressin (AVP). The main questions to be answered are: what functions of CP are regulated by FGF-2 and AVP, and how is the release of these peptides from CP to CSF controlled? Both FGF-2 and AVP have been widely implicated in CNS fluid homeostasis, and they are intimately associated with nitric oxide synthase (NOS) which generates nitric oxide (NO). The general working hypothesis is that FGF-2 and AVP, with actions mediated in part by NO, act in concert to reduce choroidal fluid turnover into CSF. Using acute and chronic experimentation in vivo with Sprague- Dawley rats, we will investigate how FGF-2 and AVP alter CP blood flow, CSF-forming capacity and epithelial ultrastructure. Moreover, the rat CP in vitro and the pig CP epithelium monolayer cell cultures will be utilized to analyze mechanisms of peptide effects on cellular organelles, ion transport, and fluid formation. Consequently, the three CP models, investigated with several methodologies, will enable a broad-spectrum analysis of how FGF-2, AVP, NO and other agent interact to regulate CP secretion. Elucidating the ability of FGF-2 and AVP to alter CSF dynamics will provide a larger picture of neuro-endocrine modulation of CNS fluids. Enhanced expression of FGF-2 and AVP in the CP-CSF system following ischemia and hydrocephalus suggests that peptides help to stabilize extracellular fluid volume and composition post-injury. Our long-term goal is to delineate the multifunctional roles of CP in brain fluid homeostasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEROXYNITRITE AND SOD IN MOTOR NEURON APOPTOSIS Principal Investigator & Institution: Estevez, Alvaro G.; Assistant Professor; Physiology and Biophysics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2006 Summary: (From the Applicant's Abstract): Our long-term goal is to understand how mutations to SOD can increase oxidative stress and cause the death of motor neurons in amyotrophic lateral sclerosis (ALS). We have shown that endogenous formation of the peroxynitrite by the diffusion-limited reaction between superoxide and nitric oxide induces apoptosis in cultured embryonic rat motor neurons deprived of trophic support. Both inhibitors of nitric oxide synthesis as well as Cu, Zn superoxide dismutase (SOD) delivered intracellularly with liposomes protect motor neurons from apoptosis. These data indicate that the interaction between nitric oxide and superoxide has a role in motor neuron apoptosis. Mutations to SOD are implicated in the selective degeneration of motor neurons in ALS and expression of ALS-SOD mutants in transgenic mice
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Nitric Oxide
produces motor neuron disease. A common phenotype among the ALS-SOD mutations so far investigated is to decrease the affinity for zinc. We have shown that zinc-deficient SOD is both less efficient at scavenging superoxide and a better catalyst of tyrosine nitration. Furthermore, the copper in zinc-deficient SOD can act as a non-specific oneelectron oxidase, robbing electrons from antioxidants like ascorbate and glutathione that can be transferred to oxygen to produce superoxide. In the presence of NO, zincdeficient SOD can catalyze the formation of peroxynitrite. In the previous cycle of funding, we have shown that zinc-deficient SOD induces apoptosis in motor neurons by a nitric oxide-dependent mechanism. For the renewal, our first aim is to further investigate the mechanisms by which zinc-deficient SODs can kill cultured motor neurons and to determine what can protect motor neurons from this toxicity. Our second aim is to characterize the source or sources of superoxide induced in motor neurons by trophic factor is to characterize the source or sources of superoxide induced in motor neurons by trophic factor withdrawal. Our third aim is to test the role of tyrosine nitration by peroxynitrite in the death of motor neurons induced by either trophic factor deprivation or by zinc-deficient SOD. Completion of the specific aims will provide a mechanistic basis for explaining how motor neurons are particularly vulnerable to SOD mutations and establish a link between sporadic and familial SODs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PO2 MODULATION OF NO AND ET1 IN PULMONARY HYPERTENSION Principal Investigator & Institution: Fagan, Karen A.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: Pulmonary hypertension (PHT), both primary and secondary, leads to significant morbidity and mortality with few acceptable therapeutic options. While there are well known associated disease states with primary PHT (collagen vascular diseases, anorexigen exposure, idiopathic) and secondary PHT (COPD, congenital heart disease) the initial injury leading to vasoconstriction, vascular remodeling, and increased pulmonary vascular resistance is unknown. Derangements in endogenous vasodilators and vasoconstrictors (NO and ET-1 respectively) have been implicated in the hypertensive pulmonary circulation in experimental models of PHT as well as in the human disease. Our laboratory is interested in the role of endogenously derived nitric oxide (NO) from eNOS (endothelial derived nitric oxide synthase), endothelin-1 (ET-1), and the effect of hypoxia on the development of PHT. Specifically, using mice congenitally deficient in eNOS, alterations in activity of ET-1 and the effect of physiologic levels of hypoxia on the development of PHT are actively being studied. We hypothesize that eNOS deficiency imparts an increased sensitivity to hypoxia leading to the development of PHT under mild, physiologic hypoxia as seen in Denver, CO and in many disease states associates with PHT. Further, we hypothesize that there is significant interactions, or cross-talk, between NO and ET-1 in vivo such that NO acts, in part, to downregulate the expression and activity of ET-1. We will present preliminary data using isolated perfused mouse lung preparations demonstrating increased pulmonary vasoreactivity to hypoxia in eNOS deficient mice. We will also report the development of PHT in eNOS knock-out mice at mild hypoxia (Denver's altitude) compared to controls, which is attenuated by conditions equivalent to sea level. Preliminary data suggesting an increase in expression of ET-1 in eNOS deficient vs. control mice will also be presented. Specifically, we will address the questions: 1) does NO modulate pulmonary vascular tone in a PO2- dependent manner and 2) does NO
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act, in part, to oppose the expression and activity of ET-1. We will utilize ex vivo and in vivo measurements of pulmonary vasoreactivity and PHT under normoxic (sea level), mild, physiologic hypoxic (as seen in Denver, CO), and severe hypoxic conditions to determine the consequences of eNOS deficiency. By using transgenic mice, we will avoid the problems inherent using pharmacologic antagonists of NOS isoforms. Additionally, we will use well established techniques in our laboratory to study the interaction of NO and the expression and activity of ET-1 in vivo. Improved understanding of these endogenous vasoregulatory substances, their interactions with one another, and the effect of modest hypoxia in vivo are the major goals of this proposal and may lead to new therapeutic options. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PREGNANCY, HYPOXIA AND TRANSCRIPTIONAL REGULATION OF NO Principal Investigator & Institution: White, Margueritte M.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAR-2003 Summary: (Adapted from applicant's abstract) Dr. Margueritte White is an Assistant Professor of Medicine who has completed a joint clinical and research fellow-ship in Maternal Fetal Medicine through the Department of Obstetrics and Gynecology and the Cardiovascular Pulmonary Research Laboratory (CVP) at the University of Colorado. She is presently the recipient of the MIRS award which has supported her work in the CVP for the past 2 years and which ends in March 1998. She has recently completed a full year of graduate level courses required for Ph.D. candidates in the Molecular Biology Program (Advanced Molecular Biology, Molecular Genetics, Cell Biology and Molecular Virology). Through her fellowship to date, she has worked under the mentorship of Dr. Lorna Moore in CVP, Professor of Medicine, who is nationally and internationally recognized for her human and animal studies on the effects of high altitude on maternal vascular adjustments to pregnancy. This collaboration has resulted in two first author peer-reviewed publications, one manuscript in preparation, and four abstracts presented at national meetings. In addition, Dr. White has contributed to and been co-author on additional publications and abstracts emanating from this work (biographical sketch). Dr. White's research has focused on the role of nitric oxide in altering vascular reactivity during pregnancy under normoxic and chronically hypoxic conditions. She is extending her studies, thus far performed in guinea pig isolated vessel rings, to a cellular level in order to investigate molecular mechanisms by which pregnancy and chronic hypoxia influence transcriptional regulation of the endothelial nitric oxide synthase gene. Towards that end, in addition to completing graduate courses in molecular biology, she has established a collaborative and mentoring relationship with Dr. Benamin Perryman, Professor of Medicine with joint appointments in the Department of Cell and Structural Biology and the interdepartmental Molecular Biology Program. This collaboration has resulted in a recent abstract presentation at a national meeting. Dr. White will carry out the proposed studies under the direct supervision of Drs. Lorna Moore and Ben Perryman in whose laboratories there is considerable expertise in studying vascular biology and mechanisms of gene regulation, respectively. Dr. White's project brings together expertise from two nationally recognized centers of excellence in both research and training, the Cardiovascular Pulmonary Lab and the Molecular Biology Program both in adjoining buildings within the School of Medicine. The strength of Dr. White's proposal lies in her application of
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state of the art techniques in molecular biology to explore questions of physiologic importance regarding maternal vascular adjustments to pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS
REACTIVE
SPECIES
IN
VASCULAR
DISEASE-INJURY
Principal Investigator & Institution: Ischiropoulos, Harry; Associate Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 05-SEP-1997; Project End 31-MAR-2006 Summary: (provided by applicant): Experiments in this application will examine the molecular mechanisms responsible for the modulation of cellular metabolism and resistance to oxidants by endogenous nitric oxide (NO). Published data indicated that NO either directly mainly by reversible S-nitrosylation of critical cysteine residues or by elevating cGMP levels modulates the adaptive responses that render cells resistant to oxidative stress and apoptosis. However, the majority of the cellular models rely upon the deliver of NO by NO donors or by the induction of the inducible nitric oxide synthase (NOS). To study the contribution of NO generated by the low output endothelial NOS in the cellular protection against oxidants, we utilized ECV3O4 cells transfected with endothelial NOS. The transfected cells generated sufficient NO to induce elevation of cGMP in smooth muscle cells in an L-NAME inhabitable manner. Using this well-defined model preliminary data revealed that NO regulates the steady state of ATP, the flux of glucose by the glycolytic and pentose phosphate pathways and respiration. Moreover, this dynamic regulation of metabolism and mitochondrial bioenergetics was associated with an increased resistance to H2O2 exposure. Exposure to H2O2 at 50-100 pM induced a delayed cell death (18 hours after exposure) to nearly 50 percent of ECV3O4 but less than 20 percent in the ECV3O4-eNOS cells. Inhibition of NO production ameliorated the protective effect and restored the steady state levels of ATP and glucose fluxes. Preliminary data using human pulmonary artery endothelial cells confirmed the NO-dependent protection against H202 induced delayed cell death. These preliminary data together with scarce published data on the ability of NO to regulate metabolism suggest a previous unrecognized function of NO that may causally relate to adaptation against oxidative stress. We propose that the generation of low levels of NO by eNOS is sufficient to dynamically regulate cellular glucose metabolism and respiration providing a primary and previously unrecognized molecular mechanism for the NO-induced protection against oxidative stress. To examine these hypotheses we propose the following specific aims: (1) define the molecular mechanism(s) of nitric oxide-mediated regulation of cellular metabolism; (2) investigate the causal association between nitric oxide-dependent alterations in metabolism with the adaptation to oxidative stress; and (3) examine if endogenous nitric oxide regulation of mitochondrial respiration and mitochondrial function is responsible for the protection against oxidative stresses. Experiments in the first aim are focused on the allosteric, covalent and other regulatory functions of NO in critical enzymes that catalyze essential and irreversible steps in the glycolytic pathway and TCA cycle. The second aim will utilize biochemical, pharmacological and molecular approaches to provide evidence for the potential causal relationship between NO-mediated regulation of metabolism and resistance to oxidative stress. The third aim examines the importance of NO-regulated mitochondrial respiration and function in protecting cells from oxidant exposures and typical inducers of apoptosis. Overall the proposed experiments will evaluate in a systematic manner the critical role of endogenously generated NO as a mediator of cellular metabolism and respiration that enables cells to resist oxidative stress.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REDOX PROPERTIES OF HEME-OXYGENASE IN NO SYNTHASES Principal Investigator & Institution: Bayachou, Mekki; Chemistry; Cleveland State University E 24Th & Euclid Ave Cleveland, Oh 44115 Timing: Fiscal Year 2003; Project Start 06-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Nitric oxide (NO) is undeniably one of the most important biological signaling species discovered in the recent two decades. Age-old as it seems, nitric oxide only recently emerged as a key player involved in control mechanisms of cardiovascular activities, in neurotransmission, and as potent weapon in antibacterial and antiviral action of macrophages. NO is synthesized in vivo from the amino acid L-arginine by a class of enzymes known as Nitric Oxide Synthases (NOSs) requiring a P450-heme, a biopterin cofactor and molecular oxygen in its oxygenase domain. Although the biochemistry of these enzymes has been the focus of vigorous investigations in the last decade, a lot is yet to be learned about their molecular functioning, and especially their post-translational regulation; understanding the details of these processes may open avenues for potential NOS targeted therapies. In this regard, we propose a direct-electrochemical study to investigate mechanisms of electron transfer to, and oxygen activation by nitric oxide synthases. We aim to develop fast protocols to study the effect of the cofactor tetrahydrobiopterin on the electronic properties of the heme as well as on oxygen activation in the NOS catalysis. Similarly, we want to use direct-electrochemistry to measure the effect of substrate arginine and NOS-inhibitors, especially endogenous methylarginines, on redox properties of the heme-oxygenase in NOS. To this end, we use immobilized NOS-oxygenase domain (NOSoxy) in thin films on electrodes to perform fast and direct electrochemistry (i.e. without mediators). We synergistically use computational methodologies to complement and guide our experimental endeavors. Specific aims of our proposed study are: 1) Measure thermodynamic redox potentials and kinetics of charge transfer to iron-heme in NOSoxys by direct electrochemistry and quantify the effects of binding of substrate L-arginine, cofactor biopterin, and NOS-inhibitors (such as endogenous methylarginines). 2) Compare direct electrochemical behavior of different isoforms (i.e. neuronal NOS: nNOS, inducible NOS: iNOS, etc.), as well as wild-type NOSoxys versus mutants, and correlate experimental results on oxygen activation and catalysis to computational findings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF ANGIOTENSIN PEPTIDE RECEPTORS Principal Investigator & Institution: Diz, Debra I.; Professor; Wake Forest University 2240 Reynolda Rd Winston-Salem, Nc 27106 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: Ang-(1-7) activates the vasodilator systems which oppose the hypertensive At1-mediated actions of Ang II. We propose three aims to investigate the potential mechanisms for the actions of Ang-(1-7). Aim 1: A novel non-At1, non-AT2 receptor [AT(1-7)] is responsible for the hemodynamic and vascular actions of Ang-(1-7). 125I[Sar/1-Thr/8]Ang II binding, in the presence of blocking concentrations of AT1 and AT2 receptor antagonists, demonstrated a novel Ang-(1-7) receptive site sit mesenteric artery and aorta of SHR treated with a combination of lisinopril/losartan. The binding site displayed a pharmacological profile with agonists and antagonists that previously characterized in endothelial cells. We will now determine whether this receptor is
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unique to the vasculature or exhibits a more widespread distribution (kidney, heart and brain) using receptor binding techniques. Aim 2: Ang-(1-7) actions blocked by At1 or AT2 receptor antagonists are not attributable to classical AT1 or AT2 receptors. In addition to the actions of Ang-(1- 7) at the novel non-AT1 non-AT2 AT(1-7) receptor, several actions of Ang-(1-7) are similar to Ang II or are blocked by AT1 or AT2 receptor antagonists. Ang-(1-7) generally displays low affinity for typical AT1 or AT2 receptors and is not associated with vasoconstrictor, pressor or drinking responses. Thus, we propose that isoforms of AT1 or AT2 receptors are responsible for the actions of Ang-(17) that are blocked by AT1 or AT2 receptor antagonists. We will use receptor knockout mice to show that the Ang-(1-7) actions or binding sites inhibited by AT1 or AT2 receptor antagonists do not persist in these receptor knockout animals. We will also characterize the protein forms of At1 and AT2 receptors known to exist in various tissues for differences in pharmacology toward Ang-(1-7) and [D-Ala/7]-Ang-(1-7). Aim 3: Ang-(1-7) counteracts the actions of Ang II at the AT1 receptor by desensitization and/or down-regulation of the AT1 receptor via homologous (through prostaglandins or nitric oxide) mechanisms. Acute and chronic exposure to elevated Ang-(1-7) decreases AT1 receptors and AT1 receptor-mediated responses in brain, kidney and cells in cultured. Prostaglandins causes heterologous down-regulation of other receptors and decrease in AT1 receptor mRNA with nitric oxide are reported. Alternatively, Ang(1-7) acts as a weak agonist at the AT1 receptor, in a process similar to homologous receptor regulation. Preliminary studies in CHO-AT/1A cells indicated a direct effect of Ang-(1-7) on the AT/1A receptor, consistent with agonist-induced homologous downregulation. We will use in vivo and in vitro models to determine the effects of acute and long-term treatments with Ang-(1-7) on AT1 receptor affinity and density and AT1 receptor mRNA by RT-PCR in the presence or absence of cyclooxygenase or nitric oxide synthase blockade. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF EARLY EMBRYO DEVELOPMENT BY NITRIC OXIDE Principal Investigator & Institution: Huet-Hudson, Yvette M.; Associate Professor; Biology; University of North Carolina Charlotte Office of Research Services Charlotte, Nc 282230001 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): A significant number of potential pregnancies are lost during the periimplantation stages of embryo development. It has been estimated by the Commission on Life Sciences of the National Research Council that more than 200,000 infants born each year in this country have abnormalities that arise during embryonic development. Other infants have markedly low birth weights which may result in death or disability later in postnatal life. A large portion of these abnormalities may result from alterations of normal embryonic development. Our studies have indicated that nitric oxide (NO) is required for preimplantation embryo development. In addition, exposure to estrogen, which induced implantation, increases the production of NO 10 fold in dormant blastocysts. However, little is known about the affect of NO on gene expression in periimplantation embryos. The purpose of the proposed experiments is to elucidate the integrated mechanisms regulated by NO in early embryonic development and initiation of implantation. This will be accomplished by conducting the following experiments: (a) Compare the localization of expression of the nitric oxide synthase (NOS) genes in embryos on days 1-4 of pregnancy (preimplantation). Results will indicate if induction of more than one NOS gene is
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required for NO production and if there is differential expression of these genes during preimplantation embryo; (b) Determine the nature of signaling cascades generated by NO in the embryo on days 1-4 of pregnancy. Specifically we will examine the effect, time course and cell specificity of cell cycle genes including: early immediate genes: clos, c-jun and e-myc (mRNA and protein), cyclins (D,E, A and B) and retinoblastoma gene in response to NO. Results will determine if NO is acting through the activation of immediate early genes to genes regulating the cell cycle: (c) Determine if the inhibition of NO production alters expression of cell-cycle checkpoint genes. Determine the effect of inhibition of NO on the time course and cell specificity of levels of the cell-cycle checkpoint genes ATM, ATR, MAD and BUB in embryos on days 1-4 of pregnancy. Results will indicate if inhibition of NO stops normal mitotic division by altering expression of checkpoint genes. The proposed study will establish the status of NO production in the embryo and its effects on embryonic gene expression will generate important and meaningful information regarding normal and abnormal reproductive functions. Furthermore, this information should have implications in human fertility treatments, as a tool to select healthier IVF-derived embryos with increased probability for successful pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF MYELOPEROXIDASE CATALYSIS BY NITRIC OXIDE Principal Investigator & Institution: Abu-Soud, Husam M.; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 15-JUL-2001; Project End 31-OCT-2002 Summary: Myeloperoxidase (MPO) is abundant hemoprotein present in neutrophils and monocytes which plays an essential role in immune surveillance and host defense mechanisms. It also is implicated in the pathogenesis of atherosclerosis and other inflammatory disorders. Upon phagocyte activation, MPO is secreted into both the extracellular milieu and the phagolysosome where it uses hydrogen peroxide (H2O2) produced during a respiratory burst as co-substrate. Activated intermediates, Compounds I and II, are sequentially formed which generate cytotoxic oxidants and diffusible radical species. Despite the potential significance of MPO to both human health and disease, little is known about the factors that influence MPO catalytic activity and function. In this proposal we focus on the potential role of nitric oxide (NO, nitrogen monoxide) and physiological reductants like ascorbate (Vitamin C) in the regulation of MPO activity, conformation and function. MPO and inducible nitric oxide synthase (NOS) are both stored and secreted in primary granules of activated leukocytes, and NO is known to react with the iron center of hemoproteins at near diffusion-controlled rates. However, the potential interactions between NO and the distal heme moiety of MPO are essentially unexplored. Similarly, ascorbate and other physiological reductants function in regulation the redox state of tissues. However, their role in modulating MPO catalysis through heme reduction has not been explored. The overall goal of this proposal is to identify the biochemical mechanisms through which NO and physiological reductants like ascorbate modulate MPO catalytic activity, conformation and function. We will examine the role of NO in modulating MPO activity and function and develop a comprehensive kinetic model for the interaction of nitrogen oxides with MPO. In parallel, we will examine the potential role of peroxidases in serving as a catalytic sink for NO, modulating its bioavailability and function. We will test the hypothesis that MPO-nitrosyl complexes serve as a novel mechanism for catalyzing formation of nitrosothiol adducts both in vitro and in vivo. Finally, we will
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explore the role of physiological reductants in reducing MPO-Fe(III) to the inactive form MPO- Fe(II), as well as characterize the role of heme reduction on MPO structure and function. Studies of MPO catalytic mechanisms and function are essential to a more fundamental understanding of the factors which govern MPO-dependent processes in human health and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RELATIVE HYPERTENSION
ARGININE
DEFICIENCY
IN
PULMONARY
Principal Investigator & Institution: Badesch, David B.; Professor, Pulmonary Critical Care Medic; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: Pulmonary hypertension (PH) affects patients of all ages, both sexes (with a predilection toward young females), is highly lethal, and frequently requires complicated, invasive, and expensive therapy. Abundant evidence supports the broad importance of nitric oxide (NO) in the maintenance of normal vascular function, and more recently of vascular structure. Evidence in a wide array of vascular disorders also suggests that availability of L-arginine, the sole substrate for NO generation, limits NO generation. Under such circumstances NO production may be enhanced by administration of exogenous arginine. These considerations could be of direct and potentially practical importance in the pathophysiology and treatment of PH, but have not been extensively evaluated. Accordingly, this proposal tests the hypothesis that patients with PH have a chronic relative deficiency of NO synthase substrate (arginine). Thus increased generation of NO in response to increased shear stress and flow would be limited by substrate availability. We further hypothesize that chronic supplementation with L-arginine or protection of NO from oxidant degradation, would augment NO activity, ameliorating pulmonary vascular injury and structural remodeling, with consequent clinical improvement in PH as measured by exercise capacity and cardiopulmonary hemodynamics. This work could define simple, inexpensive, low risk measures which might contribute to the treatment of PH. The specific aims are to determine whether: 1. NO activity (NOx, citrulline) is increased in patients with various forms of PH (PPH and SPH). 2. Levels of L-arginine (nitric oxide synthase substrate) are reduced in patients with various forms of PH. 3. Treatment of PPH with prostacyclin increases NO activity and/or decreases NOS substrate (arginine) levels. 4. L-arginine levels can be augmented in patients with PPH by chronic L-arginine supplementation, or by the administration of antioxidant vitamins. 5. Raising L-arginine levels in patients with PPH results in augmentation of NO activity (NOx, citrulline), short- term biologic effect as assessed by improvement in measures endothelial cell function, and long-term biologic effect as assessed by improvement in the 6-minute walk test and cardiopulmonary hemodynamics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RENIN-ANGIOTENSIN AND FIBRINOLYSIS INTERACTION IN HUMANS Principal Investigator & Institution: Brown, Nancy J.; Associate Professor of Medicine and Phar; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 18-AUG-1998; Project End 31-JUL-2006
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Summary: (provided by applicant): Activation of the renin-angiotensin-aldosterone system (RAAS) has been identified as a risk factor for the development of ischemic heart disease, whereas pharmacological interruption of the RAAS with angiotensinconverting enzyme (ACE) inhibitors reduces the development of atherosclerosis in animal models and in patients with coronary artery disease. Although multiple mechanisms may contribute to this association between the RAAS and atherosclerotic events, we have focused on the effects of the RAAS on the plasminogen activator system, which serves as one of the major endogenous defense mechanisms against intravascular thrombosis and plays a critical role in vascular and tissue remodeling. Our group and others have shown that both angiotensin (Ang) II and nitric oxide synthase inhibition stimulate plasminogen activator inhibitor (PAI-1) expression, whereas bradykinin stimulates nitric oxide production and tissue-type plasminogen activator (tPA) release. Furthermore, we have shown in patients post-MI, in healthy subjects on a low-salt diet, in normotensive post-menopausal women, and in hypertensive, insulinresistant subjects that ACE inhibition decreases plasma PAI-1 levels and favorably affects fibrinolytic balance. The central hypothesis of the mechanistic studies presented in this proposal is that bradykinin mediates both of the desirable effects of ACE inhibition on vascular fibrinolytic balance by lowering PAI-1 through a nitric oxidedependent mechanism and by increasing t-PA through a nitric oxide-independent pathway. In Specific Aim 1, we will determine the effect of a specific bradykinin receptor antagonist on the hemodynamic and fibrinolytic responses to chronic ACE inhibition in patients with essential hypertension. In Specific Aim 2, we will use pharmacologic tools that increase (L-arginine) or decrease (L-NAME) the availability of nitric oxide to test the hypothesis that nitric oxide contributes to the favorable effects of ACE inhibition on PAI-1 in humans. In both of these Specific Aims we will examine the interactive effect of a common 4G/5G polymorphism in the PAI-1 promoter on the contributions of bradykinin and nitric oxide to the fibrinolytic response to ACE inhibition. In Specific Aim 3, we will test the hypothesis that bradykinin stimulates t-PA release through a ouabain-sensitive pathway, a non-nitric oxide-dependent pathway. It is anticipated that these studies will generate critical new information regarding the mechanisms through which the RAA and kallikrein-kinin systems regulate vascular fibrinolytic function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE NEUROTOXICITY
OF
INFLAMMATION
IN
MANGANESE-INDUCED
Principal Investigator & Institution: Filipov, Nikolay M.; Assistant Professor; Ctr for Environmental Hlth Sci; Mississippi State University P. O. Box 6156 Mississippi State, Ms 39762 Timing: Fiscal Year 2002; Project Start 27-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant) Studies suggest that environmental contaminants, include manganese (Mn), may contribute to Idiopathic Parkinson?s Disease (IPD), but the etiology of this disease still remains elusive. Two major sources of Mn pollution in the United States arise from the reintroduction of the fuel additive methylcyclopentadienyl manganese tricarbonyl and the widespread use of Mncontaining fungicides (maneb). Recently, the investigators obtained evidence that Mn, a neurotokicant causing Parkinson?s Disease-like symptoms, increases proinflammatory cytokines and nitric oxide production by activated microglia in vitro. These findings suggest that (i) inflammation plays a role in Mn-induced neurotoxicity, and (ii) Mn exposure may be a contributing factor (via enhanced production of inflammatory
52
Nitric Oxide
mediators) to IPD. The research proposed here will explore these possibilities utilizing both in vitro and in vivo approaches. Additional studies will begin to delineate the mechanism(s) by, which Mn enhances the inflammatory response in the brain. It is hypothesized that exposure to Mn, enhances activation of microglia which are disproportionately distributed in the brain and as a result, over-production of proinflammatory cytokines and nitric oxide occurs with the final outcome being selective neuronal loss in the basal ganglia. Furthermore, exposure to Mn in the context of an inflammatory stimulus would potentiate the dopaminergic neuronal damage in the 1-methyl-4-phenyl-1,2,3,4- tetrahydropyridline (MPTP) mouse model of PD. Microglial cell line (N9), as well as primary microglia, will be used to determine whether Mn speciation plays a role in the increased inflammatory response. Microglial (N9)dopaminergic (PC 12) cell line co-cultures, as well as mesencephalic primary cultures will be used in vitro studies and the effects of Mn in the presence of a microglial activator (endotoxin, LPS) on neuronal cell death will be assessed. Additionally, Mn influence on the sensitivity of the dopaminergic neurons to MPTP under the same in vitro conditions will be evaluated. C57BL/6 (MPTP-sensitive) and CD-1 (MPTPresistant) mice will be used for in vivo studies and animals will be treated similarly to the cell cultures in the in vitro studies. After short (14 days) exposure to Mn, some animals will be challenged with MPTP, and the degree of basal ganglia damage, as well as microglial activation will be assessed. Successful completion of the proposed research will help revealing the role of inflammation in Mn neurotoxicity and, more importantly, establish a mechanism by which environmental contaminants may contribute to the etiology of IPD. The long-term goal of the proposed studies is to understand the role of microglia and environmental contaminants in neurodegenerative diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF NITRIC OXIDE IN FERTILIZATION Principal Investigator & Institution: Epel, David; Professor of Biological Sciences; Biological Sciences; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: (adapted from the applicant's abstract): The goal of this study is to determine the roles of nitric oxide (NO) and its possible relationship with the intracellular Ca2+ transients in the processes of oocyte activation and cell cycle. The possible role of NO in regulating the egg's ion channels (as part of polyspermy block) and sperm physiology (such as motility and the acrosome reaction) will also be investigated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ROLE OF NITRIC OXIDE IN SUBARACHNOID HEMORRHAGE (SAH) Principal Investigator & Institution: Bederson, Joshua B.; Neurosurgery; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Acute ischemic brain injury associated with Subarachnoid hemorrhage (SAH) is the most important determinant of outcome after SAH, but its mechanisms are poorly understood and effective treatments do not exist. The goal of this study is to characterize alterations in cerebral Nitric oxide (NO) levels and NO synthase (NOS) pathways after SAH and to determine their contribution to SAH-induced acute cerebral ischemic injury. Three primary hypotheses will be tested: 1) SAH is accompanied by acute triphasic alterations in the NO/NOS pathway that cause
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ischemic neuronal injury. 2) CBF changes and neuronal apoptosis can be used to study participation of NO in ischemic injury after SAH 3) Participation of NO in ischemic neuronal injury after SAH can be pharmacologically manipulated to decrease ischemic damage. In this proposal cerebral NO levels will be determined and activity and protein levels of NOS isozymes, endothelial (eNOS), neuronal (nNOS) and inducible (iNOS), will be studied after experimental SAH. The influence of NO levels on CBF and apoptosis in each putative phase of SAH will be examined. NO donors and NOS inhibitors will be administered to study the phase-dependent modulation of NO and NOS activity and expression on markers of cerebral ischemia. The experimental design will focus on three major questions: 1) What are the time dependent alterations in cerebral NO levels and their relation to NOS expression and activity during the first 72 hours after SAH? 2) Can changes in CBF and neuronal apoptosis be used as pathophysiological end points to study involvement of NO in ischemic injury after SAH? and 3) Can pharmacological modulation of cerebral NO levels and NOS expression and activity be used to decrease the intensity of ischemic neuronal injury after SAH? This study will increase our understanding of acute SAH induced cerebral ischemia and aid in the development of pharmacological treatments designed to prevent this ischemic injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF REACTIVE OXYGEN SPECIES IN FLOW-MEDIATED VASODILATION Principal Investigator & Institution: Gutterman, David D.; Professor; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Laminar shear stress is an important stimulus for vasodilation. In many species the mechanism involves endothelial release of nitric oxide. In humans with coronary artery disease (CAD), we have determined that endothelial derived hyperpolarization factor (EDHF) formed by cytochrome P450 mediates flow-induced dilation, possibly to compensate for loss of nitric oxide (NO). Shear stress has also been shown to induce changes in the vascular redox state. Flow-dependent release of superoxide, which is dismutated to H2O2., is observed in conduit arteries and endothelial cells in culture. Production of reactive oxygen species (ROS) has traditionally been considered a pathological response that leads to impaired vasomotor function. However, ROS may plan an important role in the physiological regulation of vessel function. Recent data suggests that H2O2 is an EDHF. Since cytochrome P450, a key enzymatic pathway in the formation of EDHF, also generates ROS, we hypothesize in Aim 1 that H2O2 mediates flow-induced dilation in human coronary arterioles. The signaling pathway transducing shear stress to NO release has been characterized and involves activation of tyrosine kinases linked to integrins and focal adhesions, heterotrimeric G-proteins, and phospholipases. Whether these cell processes are also involved in shear- mediated release of ROS is not known. Furthermore the endothelial oxidant enzyme systems responsible for generating ROS are incompletely understood. These critical features of shear-induced redox changes will be examined. In Aim 2, we shall determine which key enzyme systems including cytochrome P450, nitric oxide synthase, and NADPH oxidase are responsible for shear-induced generation of ROS. In Aim 3 we shall determine the intracellular signaling pathways producing ROS, focusing on the role of tyrosine kinases, phospholipases, and G-proteins. The effects of inhibiting endothelial function on ROS production will be examined. These questions will be examined in isolated human coronary arterioles prepared for in vitro measurement of
54
Nitric Oxide
flow-induced dilation, smooth muscle hyperpolarization, and fluorescence as well as ESR detection of ROS. Our model system is well-suited for studying ROS-mediated flow- induced vasomotor responses since these vessels demonstrate flow- mediated vasodilation (FMD), release superoxide in response to flow, and do not produce vasoactive levels of NO in response to shear. NO may interfere with ROS activity by converting superoxide to peroxynitrite, producing direct vasomotor responses, and by inhibiting cytochrome P450. The proposed experiments are designed to provide novel mechanistic insight into pathophysiological regulation of the human coronary microcirculation. The results should improve our understanding of the shear-mediated events leading to release of ROS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF URIC ACID IN HYPERTENSION AND RENAL DISEASE Principal Investigator & Institution: Johnson, Richard; Professor; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2006 Summary: (provided by applicant): The presence of an elevated serum uric acid is strongly associated with hypertension and renal disease. Despite the association and the ease with which to treat this condition, it remains unknown if the elevated uric acid has a pathogenic role in cardiovascular disease or whether it simply represents a 'marker' for other associated risk factors. Epidemiological studies have been unable to resolve this issue, and experimental studies have been thwarted by the absence of an animal model of mild hyperuricemia and by a paucity of cell culture studies. In preliminary data we have developed a model of mild hyperuricemia in rats and have found that they develop hypertension after several weeks through a crystal independent mechanism in which an afferent arteriolopathy develops in association with alterations in the renin angiotensin, cyclooxygenase-2 and nitric oxide pathways in the kidney. Mild hyperuricemia also results in interstitial renal disease, and hyperuricemia exacerbates renal injury in two different animal models. Our central hypothesis is that hyperuricemia induces hypertension and renal disease acutely by stimulating COX-2 in vascular smooth muscle cells and in the macula densa, which subsequently stimulates renin production, inhibits macula densa nitric oxide synthase, and raises blood pressure. Hyperuricemia also causes a primary afferent arteriolopathy that we hypothesize is mediated by local PDGF expression, and we postulate that once the arteriolopathy is established that salt-sensitive hypertension will persist even if the uric acid levels are corrected. In aim 1 we will examine the role of COX2 in our model, and will examine the kinetics of its expression and the effect of inhibition of COX2 on the alterations in renin, nitric oxide synthase, blood pressure and renal lesions. In aim 2 we will study the mechanism by which uric acid induces the arteriolopathy in our rats, and we will concentrate on the role of PDGF; furthermore, we will determine if the arteriolopathy provides a mechanism by which hypertension will be self-sustained despite correction of the hyperuricemia. In aim 3 we will initiate studies of the cellular mechanism by which uric acid stimulates PDGF and COX2 in cultured vascular smooth muscle cells and macula densa cells, with emphasis on the role of the recently cloned urate channel and on the MAP kinase cascade. Given that there are over 20 million individuals with hyperuricemia in the United States, and that 25-50% of all hypertensive individuals are hyperuricemic, we believe that studies examining the role of hyperuricemia in hypertension and cardiovascular disease are strongly indicated. We believe that the preliminary data, coupled with the studies proposed, provide the first insights into a potential pathogenic mechanism by which uric acid induces hypertension
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and renal disease in rats, and may well provide important insights into the role of hyperuricemia in hypertension, cardiovascular and renal disease in man. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLES OF NITRIC OXIDE AND OXYGEN IN OCULAR MELANOMA Principal Investigator & Institution: Braun, Rodney D.; Anatomy and Cell Biology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-FEB-1998; Project End 31-JAN-2004 Summary: (Adapted from applicant's abstract): Choroidal melanoma is the most common primary ocular cancer among the adult population. It is an important disease, because treatment may destroy vision in the affected eye and the tumor can metastasize. Its treatment is very controversial and is currently the subject of a major NEI clinical trial. Enucleation is a common treatment, but there has only been recent emphasis to develop eye-sparing therapies. Unfortunately, these newer treatments have been only marginally successful in eradicating the tumor while sparing vision. The ultimate goal should be to improve therapy so that safer, more efficacious treatments can be applied sooner in the course of the disease. The ability to treat sooner and more aggressively may ultimately enhance patient survival. Some eye-sparing therapies (e.g., radiation therapy, photodynamic therapy, and immunotherapy) are dependent on oxygen, yet virtually nothing is known about the physiology of this tumor, including mechanisms for blood flow control. In other areas of cancer research, there has been recent interest in the modulation of nitric oxide (NO) to modify tumor blood flow and oxygenation to improve treatment. One major drawback of these strategies, however, is that NO modulators must typically be given systemically, and side effects may limit their clinical application. Since choroidal melanomas are often accessible to treatment using an episcleral approach, the utilization of compounds associated with NO to locally manipulate the microenvironment of this tumor is especially appealing, since systemic treatment can be avoided. The purpose of the proposed study is to test hypotheses relating to the effects of NO on blood flow and oxygenation in human choroidal melanoma growing in the choroid of the athymic rat. The hypotheses to be tested are that (1) NO synthetase (NOS) is expressed in human choroidal melanoma parenchyma and/or vasculature, (2) NO plays a role in regulating microvascular blood flow in human choroidal melanoma and (3) human choroidal melanoma in vivo has areas in which the oxygen tension is low (hypoxia) and the oxygenation of the tumor is dependent on NO availability. The results of these studies could lead to development and testing of new therapies for choroidal melanoma, based upon selective, local delivery of agents which modulate NO availability and modify tumor blood oxygenation, thereby enhancing the effectiveness of treatments directed toward salvage of the affected eye. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SCOR IN PATHOBIOLOGY OF LUNG DEVELOPMENT Principal Investigator & Institution: Ballard, Philip L.; Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-SEP-1996; Project End 31-JUL-2006 Summary: (Applicant's Abstract) This renewal SCOR program continues basic and clinical studies to address molecular mechanisms of lung development as well as the pathogenesis and prevention of bronchopulmonary dysplasia (BPD). This disease continues to be a major cause of morbidity and mortality in premature infants even in
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Nitric Oxide
the era of antenatal corticosteroid treatment and surfactant replacement. The overall hypothesis of the SCOR program is that BPD is the result of injury and abnormal repair in an immature lung, and that basic studies related to processes of normal lung development, the inflammatory response, and effects of inhaled nitric oxide will provide important information regarding the pathogenesis and prevention of BPD. The SCOR involves 18 investigators from the Schools of Medicine and Dental Medicine at the University of Pennsylvania plus three investigators from the School of Medicine at the University of Utah, and consists of five basic science projects, each with a clinical component, and three Cores. The goals of the basic science projects are to investigate differentiation of alveolar type II cells and the roles of the hydrophobic surfactant proteins (Project 0001), signaling mechanisms in endothelial cell differentiation and vascular development (Project 0005), molecular events in the cellular inflammatory response after lung injury (Project 0006), and the role and regulation of key growth factors in lung development and the fibroproliferative response (Project 0004). These projects use lung tissue and cells, rats and transgenic mice as experimental models. The Tissue Culture Core provides cultured lung tissue and cells and maintains a repository of fetal and postnatal human lung tissue. An off-site basic science project utilizes a unique premature lamb model of BPD to investigate effects and mechanisms of inhaled nitric oxide on development of lung disease (Project 0007). The clinical focus of the program is the pathogenesis of BPD and prevention by inhaled nitric oxide. The Clinical Core enrolls premature infants in SCOR protocols and collects extensive clinical data and samples for studies by the basic science projects. This patient population includes infants participating in a NIH-funded multicenter clinical trial of inhaled nitric oxide to prevent BPD. The Director of the SCOR is an experienced investigator in lung development and the participating investigators include both senior researchers and well trained, promising younger investigators, each with specific expertise in their respective areas of study. The program is highly interactive with close collaborations between projects and with the clinical component. The renewal SCOR represents a multidisciplinary, highly integrated, and thematic translational research program related to the pathogenesis and prevention of BPD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SHOCK & ISCHEMIA: TISSUE FACTOR CONTROL BY NITRIC OXIDE Principal Investigator & Institution: Muluk, Satish C.; Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: The applicant seeks to become a superb clinician-scientist. After graduating summa cum laude from college and medical school, he trained in surgery at the Massachusetts General Hospital. He undertook a 2-yr research fellowship at the NIH, and despite having substantial clinical duties, he has continued high-quality basic research over the last 4 1/2 years at the University of Pittsburgh. To develop his research career, he seeks more time commitment to basic research, something that would be made possible by the K08 award. The research environment provided by the surgery department is unsurpassed, offering opportunities to learn and use advanced research techniques. The lab here has a distinguished history of NIH grants and it has trained several successful surgeon-scientists. This proposal stems from the applicant's broad goal of understanding the problem of thrombosis. Although the etiology of thrombosis is multifactorial, one molecule that is of undisputed importance is tissue factor (TF). We offer the novel hypothesis that nitric oxide (NO) is an important
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regulator of TF. There are good reasons to examine NO as a TF regulator. NO has diverse effects and there is significant overlap between the signaling systems affected by NO and those known to affect TF. A primary target for both is the vascular system. TF reduction by NO would be consistent with NO's vascular homeostasis function. However, when induced in large amounts, NO is deleterious in many biologic settings. TF is a cause of organ damage in many of these same settings. Preliminary work suggests that NO upregulates TF in vascular smooth muscle cells (SMC) and endothelial cells (EC). Also, we have found that NO may be needed for the TF upregulation normally seen during reperfusion after ischemia. We hypothesize that NO upregulates TF, and that this upregulation is biologically relevant. Aim 1: To determine the mechanisms by which NO enhances TF expression in vascular SMC and EC. We will study EC and SMC in cell and organ culture to accomplish this aim. Aim 2: To determine the significance of NO regulation of TF in reperfusion after shock and ischemia. We will study TF regulation by NO, using mice deficient in inducible nitric oxide synthase, the enzyme that synthesizes induced NO. Aim 3: To determine the significance of NO regulation of TF in atherosclerotic plaques. We will study transgenic mice prone to develop atherosclerosis, so we can determine whether NO-regulates TF in atheromas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: S-NITROSYLATION OF A -ADRENERGIC RECEPTORS INTHE LUNG Principal Investigator & Institution: Grayck, Eva N.; Pediatrics; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 03-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): This application is designed to enable the principal investigator to develop as an independent physician-scientist in the field of pulmonary vascular biology. Under the co-mentorship of two established investigators, Dr. Jonathan Stamler and Dr. Robert Lefkowitz, the P.I. will gain new expertise in the study of alpha-adrenergic receptor function in the pulmonary vasculature and substantially strengthen her level of expertise in NO biochemistry and protein modification by Snitrosylation. Preliminary data show that pulmonary vasoconstriction by a-adrenergic agonists is attenuated by the endothelial- derived relaxing factor, nitric oxide (NO). NO (or molecules derived from it) is known to regulate protein function by chemical modifications of cysteine residues, i.e. Snitrosylation. The specific aims test the hypothesis that NO regulates pulmonary vascular tone by chemically modifying alpha1Beta-adrenergic receptors in pulmonary vascular smooth muscle. Aim 1) Determine which components of (alpha1-adrenergic receptor signaling are modified by NO to antagonize vasoconstriction. Aim 2) Determine whether NO S-nitrosylates the (alpha1-adrenergic receptor or other targets detected in Aim 1, and identify the cysteines involved. Aim 3) Investigate the role and mechanisms of constitutive and inducible nitric oxide synthase isoforms in the regulation of a1-adrenergic function in vitro and in vivo. Experiments will be performed in HEK293 transfected with alpha1beta-adrenergic receptor (Aims 1 and 2), cultured rat pulmonary vascular cells and PA rings (Aim 3). This proposal will also establish whether the effects of NO are specific for the (alpha1adrenergic receptor or represent a general mechanism for NO to regulate G-protein coupled receptor signaling. Understanding the factors that regulate pulmonary vascular function will lead to rational development of new therapies for lung diseases that affect the pulmonary blood vessels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Nitric Oxide
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Project Title: PRODUCTION
STEROIDS
/VASCULAR
REACTIVITY
/NITRIC
Principal Investigator & Institution: Keller-Wood, Maureen Pharmacodynamics; University of Florida Gainesville, Fl 32611
E.;
OXIDE Professor;
Timing: Fiscal Year 2002; Project Start 06-APR-2001; Project End 31-MAR-2004 Summary: (Adapted from applicant's description): The overall goal of these studies is to test the hypothesis that there is an interaction between increased secretion of adrenal corticosteroids and increased secretion of estrogen during pregnancy which is necessary for normal blood pressure control in the peripartal period. Studies in pregnant, hypocorticoid ewes and clinical experience in pregnant women with hypoadrenocorticism suggest that normal blood pressure control in late pregnancy requires increased adrenal secretion. Insufficient supply of cortisol results in rapid and profound hypotension, with increased morbidity and mortality in both mother and fetus. The experiments in this proposal will directly test the hypothesis that a decrease in cortisol at a time of increased estrogen results in a greater decrease in vascular reactivity to phenylephrine and that this correlates with increased production of nitric oxide production in one or more sites in the body. Four groups of ewes will be studied: adrenalectomized, ovariectomized ewes, adrenalectomized ovariectomized ewes treated with estradiol, adrenal- intact ovariectomized ewes, and adrenal-intact ovariectomized ewes treated with estradiol. All adrenalectomized ewes will be treated with aldosterone and cortisol for one week following surgery, and then the adrenal steroid infusions will be stopped to produce the hypoadrenal state. Animals will be studied at a time point (8 hours) in which the adrenalectomized estrogen treated animals are hypotensive, but the adrenalectomized ewes without estradiol treatment are not overtly hypotensive. Experiments will test vascular reactivity in response to phenylephrine in all 4 groups of ewes to test the hypothesis that estrogen administration decreases vascular reactivity in adrenalectomized ewes. Experiments will also determine plasma levels of nitrates and nitrites and the ability of infusion of L-NAME, an inhibitor of nitric oxide synthase (NOS), to increase vascular reactivity in adrenalectomized ewes with estradiol treatment. Experiments will also test the concentrations of cGMP, and levels of iNOS, eNOS, and nNOS protein measured by Western analysis and mRNA by RT-PCR in aorta, uterine artery, mesenteric artery, renal artery, renal interlobular artery, renal medulla and cortex, and skeletal muscle, taken from animals in the same 4 experimental groups. These experiments will determine if absence of cortisol results in increased NOS in one or more of these sites. Samples of tissue will also be examined by immunohistochemistry to more precisely identify the cell populations containing iNOS, eNOS or nNOS in these ewes. These experiments will therefore describe which isoform(s), and in which cells, NOS is altered by cortisol withdrawal, either alone or in combination with increased estrogen. This information will form the basis of future experiments to determine the mechanism of the interaction of estrogen and cortisol in control of NO and regulation of blood pressure during pregnancy. These studies will therefore add to our understanding of normal blood pressure control during pregnancy, and of the pathophysiology of hypoadrenocorticism at term. These studies will also to our understanding of the counterbalancing effects of increased cortisol and increased estrogens in control of normal blood pressure in normal pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRATEGIES TO LIMIT DEFIBRILLATION AND REPERFUSION INJUR Principal Investigator & Institution: Kerber, Richard E.; Professor of Medicine; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-JUL-1995; Project End 31-MAY-2004 Summary: Nitric oxide plays a major role in oxygen-derived free radical generation in defibrillation and reperfusion injury; nitric oxide reacts with the superoxide radical to form peroxynitrite, which is toxic in itself and also forms further strongly oxidizing species resembling the hydroxyl radical. By limiting nitric oxide availability, nitric oxide synthase inhibitors may limit this process and ameliorate defibrillation/ reperfusion toxicity. Magnesium also has a role to play: it can also limit oxygen-derived free radical generation via its actions as a "physiologic calcium antagonist", which include limiting the formation and release of endothelial-derived nitric oxide. The combination of NO synthase inhibitors and magnesium may be particularly effective. We will emphasize the direct detection of ascorbate radical to examine a series of testable hypotheses. Our overall hypotheses that the nitric oxide/superoxide/peroxynitrite pathway is a major source of free radicals that contribute to both defibrillation and reperfusion injury. Modulation of nitric oxide will alter bury from defibrillation and ischemia-reperfusion. The specific, testable hypotheses are: 1) Nitric oxide synthase inhibitors, by limiting the NO available to react with superoxide (forming peroxynitrite), reduce free radical generation and thereby ameliorate defibrillation and reperfusion injury. This preserves left ventricular function after defibrillation and/or reperfusion (i.e., less "stunning"). 2) Conversely, NO donors (SIN-1), by providing more NO substrate to react with superoxide and form toxic peroxynitrite, will increase free radical generation after defibrillation and/or reperfusion, worsening left ventricular function. 3) Magnesium, which we have already shown to reduce free radical generation in reperfusion injury, will be similarly cardioprotective in ameliorating defibrillation injury, reducing radical generation and deserving ventricular function. 4) The combination of nitric oxide synthase inhibitors and magnesium, which alter two different mechanisms/pathways to limit free radical generation, will be especially cardioprotective, ameliorating defibrillation and reperfusion injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURAL METALLOBIOCHEMISTRY OF NITRIC OXIDE SYNTHASES Principal Investigator & Institution: Getzoff, Elizabeth D.; Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 15-AUG-1997; Project End 31-MAR-2006 Summary: (provided by applicant) The overall Project goal is to understand how nitric oxide synthase (NOS) isozymes regulate the synthesis of nitric oxide (NO) and thereby its dual biological activities as (i) a diffusible messenger for neurotransmission, longterm potentiation, platelet aggregation and blood pressure regulation, and (ii) a cytotoxic agent for defense against tumor cells and parasites. The inducible (iNOS), endothelial (eNOS), and neuronal (nNOS) isoforms achieve their key functions via an intriguing calcium-regulated electron-transfer mechanism and a unique assembly of at least five cofactors. Each subunit of the NOS dimer has two modules joined by a calmodulin-binding (CaM) hinge region: 1) an oxygenase domain (NOSox) with heme, tetrahydrobiopterin (H4B), and L-Arg binding sites forming the catalytic center for NO
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production, plus a single structural Zn site at the dimer interface, and 2) a reductase module (NOSred) with NADPH, FAD, and FMN sites supplying electrons to the heme. Systematic characterizations of all three isozymes and individual NOSox, CaM-binding, and NOSred components will address the complex structural biochemistry underlying NOS activity, isozyme specificity, and regulation. Coupled Stuehr, Tamner, and Getzoff group efforts will insure efficient application of unified structure-function studies. Biochemical and mutational characterizations by the Stuehr group will proceed in concert with coupled experimental crystallographic, solution scattering and electron microscopic results plus computational structural analyses by the Getzoff and Tamner groups. As an integrated whole, this project will provide the basis to develop and test hypotheses, and to thereby bridge the growing gap between huge increases in detailed NOS structural and biochemical data and in-depth comprehension of NOS activities. This work focuses on defining conserved and variable isozyme features responsible for 1) catalytic activity and regulation of NOSox, 2) ligand binding to NOSox isozymes, 3) structure and activity of NOSred, and 4) domain interactions in assembled NOS. Designed NOS mutants will be used to experimentally test emerging principles for NOS structure and function. This coordinated structural biochemistry cycle aims to provide a molecular understanding of the activity, inhibition, and regulation of NOS isozymes relevant to important aspects of their biology. These results will furthermore build the essential framework for a unified understanding of NOS relevant to the design of structure-based inhibitors as desirable chemical tools for studying NOS function and as therapeutic agents for stroke, septic shock, and inflammatory damage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SUBSTANCE P, NO & MICROGLIA IN CNS INFLAMMATION Principal Investigator & Institution: Nathan, Barnett R.; Neurology; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-MAY-2004 Summary: In the next 5 years I plan to study in vitro and in vivo the interactions of microglia, macrophages, substance P and nitric oxide as well as the effect of these substances on mitochondrial function. Substance P (SP) has effects as a pain mediator in the spinal cord and has vasoactive properties. It also plays a significant role in the pathogenesis of neurogenic inflammation, being released from peripheral nerve terminals and causing precapillary vasodilatation, postcapillary plasma extravasation and histamine release. Nitric oxide (NO) is known to play a role in bacterial meningitis and also has immunomodulatory and vasoactive properties. Peripheral blood macrophages and central nervous system (CNS) microglia share similar immunogenic properties and may be derived from the same cell line. Microglia are suspected to play a role in the pathophysiology of a wide variety of inflammatory CNS diseases and the mediators for this microglial induced injury may be modulators such as substance P and nitric oxide. The underlying hypothesis which provides the framework for all of the proposed studies is that substance P (SP), nitric oxide(NO) and microglia play a central role in the pathophysiology of bacterial meningitis (BM) and other acute CNS inflammatory conditions. The overall goal of this application is to investigate the effects of SP and NO on macrophage and microglia functions in in vitro and in vivo systems. This overall goal will be approached by addressing the following specific hypotheses. Hypothesis 1: Substance P plays a central role in bacterial meningitis, both through its direct immunomodulatory effects and through its effects on nitric oxide. In stimulated phagocytic cells there is an upregulation of preprotachykinin and SP receptor message. Hypothesis 2: Nitric oxide plays a central role in the pathophysiology of bacterial
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meningitis. There is upregulation of inducible nitric oxide synthase (iNOS) message resulting in increased production of NO. SP modulates iNOS via inhibition of iNOS message. Hypothesis 3: Both the resident and transient phagocytic cells in the CNS (microglia and macrophages) participate in the pathophysiology of bacterial meningitis. SP and NO modulate their effects in CNS inflammation via these cells. Hypothesis 4: The ultimate site for the effects of SP and NO may be the mitochondrial respiratory chain enzymes of these phagocytic cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNAPTIC REGULATION OF NITRIC OXIDE Principal Investigator & Institution: Bredt, David S.; Professor; Physiology; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-FEB-1997; Project End 31-JAN-2006 Summary: Endogenous nitric oxide (NO) mediates diverse functions in neuronal transmission and plasticity. In addition to its actions as a physiological mediator, NO also participates in neurotoxic brain injury, including stroke and certain neurodegenerative processes. NO synthase (NOS) is a calmodulin dependent enzyme that is regulated by the steep gradients of Ca2+ encountered in the vicinity of open Ca2+ channels. In brain NOS is functionally coupled to Ca2+ influx through N-methyl-Dglutamate (NMDA) type glutamate receptors, whereas other Ca2+ pools are poorly linked to NOS. A fundamental understanding of NO actions in brain requires identification of the functional connection of NNOS with NMDA receptors. In an effort to address this important question, this laboratory has initiated a program of cell biological studies of NOS disposition in brain. This work demonstrates that the subcellular localization of NNOS is mediated by an unusual bivalent PDZ protein motif. This NNOS PDZ domain contains a conserved binding pocket that associates with the C-termini of certain proteins including CAPON and phosphofructokinase. On the other hand, an extended "P-finger" of the NNOS PDZ domain binds to PSD-95 and PSD-93, postsynaptic density proteins that mediate synaptic clustering of NMDA receptors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TETRAHYDROBIOPTERIN: REGULATOR OF ENDOTHELIAL FUNCTION Principal Investigator & Institution: Katusic, Zvonimir S.; Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-DEC-1994; Project End 31-MAR-2005 Summary: (Verbatim from the application): Cardiovascular diseases, including atherosclerosis, remain a leading cause of death and disability in the United States. Nitric oxide is a key regulator of vascular tone, platelet aggregation, white blood cell adhesion, and smooth muscle cell proliferation. Nitric oxide has also been recognized as a critical mediator of angiogenesis. Endothelial dysfunction due to decreased production of nitric oxide is an early event believed to play a major role in initiation and progression of atherosclerosis. Tetrahydrobiopterin (BH4) is an essential cofactor needed for enzymatic activity of nitric oxide synthase. BH4 plays a key role in the control of endothelial nitric oxide production. The general hypothesis of this proposal is that during development of atherosclerosis, up-regulation of BH4 biosynthesis is an adaptive response designed to preserve biosynthesis of nitric oxide and protect the vascular wall from oxidative stress. To test this hypothesis we propose studies with the following specific aims: (1) determine the effects of oxidative stress on vascular BH4
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metabolism, (2) characterize the relationship between BH4 metabolism and endothelial dysfunction in arteries exposed to hypercholesterolemia in vivo, and (3) analyze the role of superoxide anion in BH4 metabolism and endothelial dysfunction in murine models of atherosclerosis. Apolipoprotein E (ApoE)-deficient mice and low-density lipoprotein (LDL) receptor-deficient mice develop spontaneous hypercholesterolemia and atherosclerosis with many features that are characteristic of lesions in humans. Preliminary findings indicate that endothelial dysfunction, as reflected in impaired endothelium-dependent relaxations, is present in murine models of atherosclerosis. The exact mechanism responsible for endothelial dysfunction induced by hypercholesterolemia is not understood. Initial analysis performed on isolated aorta of ApoE-deficient mice indicated that increased production of superoxide anions in the vascular wall plays a major role in inactivation of endothelial nitric oxide. However, the effects of superoxide anions and oxidative stress on BH4 metabolism have not been studied. To characterize the role of superoxide anion in BH4 metabolism and endothelial dysfunction, arteries from superoxide dismutase (SOD) transgenic mice and SODdeficient mice will be studied. Overexpression of SOD in ApoE-deficient mice will be used to protect BH4 from superoxide anion-induced oxidative stress and rescue endothelial dysfunction. Double knockout ApoE-SOD-deficient mice will be created to determine whether increased production of superoxide anion accelerates oxidation of BH4 and impairment of endothelium-dependent relaxation. It is anticipated that the results of the proposed experiments will provide novel and important information concerning the effect of oxidative stress on vascular BH4 metabolism and the pathogenesis of atherosclerosis. This information may help to develop new therapeutic interventions designed to prevent endothelial dysfunction and progression of atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF NITRIC OXIDE IN CHOLESTEROL HOMEOSTASIS Principal Investigator & Institution: Ihrig, Melanie M.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant) Cholesterol homeostasis is maintained by balancing intestinal absorption, endogenous biosynthesis, hepatic uptake and biliary secretion of cholesterol and bile acids. Recently, there has been a renewed interest in the role of intestinal cholesterol absorption in cholesterol homeostasis. A number of studies have assessed the effect of reduced small bowel transit time on cholesterol absorption, and each found a significant correlation between transit time, cholesterol absorption and serum cholesterol concentration. We have demonstrated that mice with a targeted mutation in the inducible nitric oxide synthase (iNOS) gene have elevated serum cholesterol levels. Each of three unique isoforms of NOS is expressed in different cell types and under different conditions throughout the gastrointestinal tract. There is considerable evidence that nitric oxide (NO) produced in the gastrointestinal tract influences enteric myoelectrical activity, coordinates peristalsis and ultimately affects intestinal transit time. Nitric oxide acts as an inhibitory neurotransmitter, and as a vasodilator in the intestinal tract. Additionally, enteric pathogens, and the experimental administration of lipopolysaccharide (LPS), elicit excessive production of NO through transcriptional upregulation of iNOS. Thus, NO concentrations in the intestinal tract wax and wane depending on the immediate circumstances. A plausible explanation for the increased serum cholesterol levels observed in the iNOS-deficient mice, then, is delayed small bowel transit time, brought on by perturbation of the regulation and
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coordination of intestinal motility. Aberrant cholesterol homeostasis is a risk factor for both atherosclerosis and cholesterol gallstone formation. In addition to hypercholesterolemia, we observed aortic atheromas in the iNOS-deficient mice. Prolonged intestinal transit time augments formation of cholesterol gallstones, and if prolonged intestinal transit time is the underlying cause of hypercholesterolemia in iNOS-deficient mice, the manifestation of atherosclerosis and cholelithiasis may well be linked. The proposed studies will explore these possibilities in iNOS-deficient mice under various experimental conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TLR'S, NITRIC OXIDE AND CHRONIC LUNG DISEASE Principal Investigator & Institution: Truog, William E.; Professor; Children's Mercy Hosp (Kansas City, Mo) 2401 Gillham Rd Kansas City, Mo 64108 Timing: Fiscal Year 2002; Project Start 10-FEB-2002; Project End 31-JAN-2006 Summary: (provided by applicant): This application is submitted in response to RFA Hl00-012: Ancillary Studies in Lung Disease Trials. The parent trial to which this application is linked, (U01-HL62514), is testing the hypothesis that low dose inhaled nitric oxide, administered to infants 500 to 1250 g birth weight, will produce an increase in survival without chronic lung disease (CLD) from 50 percent to 61 percent at 36 week post menstrual age. The parent study is a blinded, placebo controlled, three week trial of decreasing dose nitric oxide or placebo beginning between 7 and 21 days of age. Part of the rationale supporting the parent trial is that nitric oxide may moderate pulmonary inflammation, a crucial precursor of full-blown CLD. Although the parent trial includes measurements of tracheal aspirate interleukin 1B and interleukin-8, it cannot investigate mechanisms of, nor initiation, propagation, or persistence of, pulmonary inflammation. Our proposed study will examine the role of two members of the family of transmembrane receptors, Toll-like receptors (TLRs), found on leukocytes and other cells and upregulated in response to endotoxin and to other stimuli. These substances transduce the signal propagating inflammatory mediator production. We will quantitate protein expression and mRNA expression of TLR-2, and TLR-4 from leukocytes obtained from serial tracheal aspirate samples. We will perform these serial studies in a subset of enrolled patients who will mirror the parent clinical trial sample in terms of ethnicity, gender, and severity of underlying disease. Our specific aims are to determine if upregulation of TLR-2 and/or TLR-4 antedates development of CLD of prematurity and to determine if there is a significant correlation with severity of CLD. We will determine if the mechanism of improved outcome with NO administration occurs in association with NO-associated suppression of upregulation of TLR, a possibility for which we have supportive pilot data. Even if the parent study cannot reject the null hypothesis that nitric oxide will have no benefit in this disease, this mechanistic study will provide important new information about natural history of CLD and about crucial mechanisms of early pulmonary inflammation. Its results may also open up intriguing pathways for treatments aimed at selective diminution of pulmonary inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: XANTHINE OXIDASE MODULATION OF CELL OXIDANT PRODUCTION Principal Investigator & Institution: Tarpey, Margaret M.; Associate Professor; Anesthesiology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294
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Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: (Adapted from the Applicant's Abstract): The endothelium serves as a critical component in the maintenance of vascular homeostasis. Alterations in endothelial cell production of oxidants contribute to defective vascular function and are implicated in the pathogenesis of diverse vascular diseases. However, the tissue sources of enhanced vascular cell oxidant production and the sites of oxidant action have not been determined with certainty. Recently, recognition of a) elevated plasma levels of circulating xanthine oxidase activity in diverse disease processes (sepsis, hypercholesterolemia, post- liver transplantation) and b) the ability of xanthine oxidase to specifically bind to endothelium with resultant increases in intracellular xanthine oxidase activity provide potential mechanism(s) by which non-endothelial cell-derived xanthine oxidase could contribute to endothelial oxidant production. While enhanced production of superoxide can diminish nitric oxide bioavailability by virtue of its reaction with nitric oxide and thus, concomitantly yield secondary oxidants, the potential for superoxide and other cellular oxidants to directly modify the activity of endothelial nitric oxide synthase has not been fully explored. From this foundation of understanding, it is hypothesized that increases in cell-associated xanthine oxidase modulate endothelial-dependent vascular function. To address this hypothesis, the following Specific Aims will be pursued: 1) Characterize vascular cell interactions with circulating xanthine oxidase. The kinetics of cell binding and uptake of circulating xanthine oxidase/dehydrogenase will be determined. In addition, xanthine oxidase circulating and ultimate tissue distribution will be defined in vivo. 2) Explore the impact of elevated xanthine oxidase-derived products (reactive species, uric acid) on expression and activity of endothelial nitric oxide synthase. The effects of xanthine oxidase on transcription and translation of endothelial nitric oxide synthase will be ascertained as well. The vascular functional consequences of increased xanthine oxidase activity will also be determined. Upon successful completion of the proposed aims, a) the contribution of xanthine oxidase to endothelial cell oxidant production will be better defined, b) detailed mechanistic information will be available regarding the presence, reactions and regulation of specific oxidative pathways that modulate endothelial nitric oxide synthase expression and activity and c) new insight will be gained for prospectively devising mechanism-directed pharmacologic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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 “nitric oxide” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for nitric oxide in the PubMed Central database: 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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[beta]-Chemokines Enhance Parasite Uptake and Promote Nitric Oxide-Dependent Microbiostatic Activity in Murine Inflammatory Macrophages Infected with Trypanosoma cruzi. by Aliberti JC, Machado FS, Souto JT, Campanelli AP, Teixeira MM, Gazzinelli RT, Silva JS.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96814
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1,25-Dihydroxyvitamin D3 Induces Nitric Oxide Synthase and Suppresses Growth of Mycobacterium tuberculosis in a Human Macrophage-Like Cell Line. by Rockett KA, Brookes R, Udalova I, Vidal V, Hill AV, Kwiatkowski D.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108664
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A biochemical rationale for the discrete behavior of nitroxyl and nitric oxide in the cardiovascular system. by Miranda KM, Paolocci N, Katori T, Thomas DD, Ford E, Bartberger MD, Espey MG, Kass DA, Feelisch M, Fukuto JM, Wink DA.; 2003 Aug 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=170895
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A Commercial Preparation of Catalase Inhibits Nitric Oxide Production by Activated Murine Macrophages: Role of Arginase. by Tian Y, Xing Y, Magliozzo R, Yu K, Bloom BR, Chan J.; 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97521
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A dichotomous role for nitric oxide during acute Toxoplasma gondii infection in mice. by Khan IA, Schwartzman JD, Matsuura T, Kasper LH.; 1997 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28414
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A Dirofilaria immitis Polyprotein Up-Regulates Nitric Oxide Production. by Tezuka H, Imai S, Tsukidate S, Fujita K.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128244
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A mechanism of paraquat toxicity involving nitric oxide synthase. by Day BJ, Patel M, Calavetta L, Chang LY, Stamler JS.; 1999 Oct 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23088
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A molecular basis for nitric oxide sensing by soluble guanylate cyclase. by Zhao Y, Brandish PE, Ballou DP, Marletta MA.; 1999 Dec 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24720
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A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP. by Lev-Ram V, Wong ST, Storm DR, Tsien RY.; 2002 Jun 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123077
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A new role for an old enzyme: Nitrate reductase-mediated nitric oxide generation is required for abscisic acid-induced stomatal closure in Arabidopsis thaliana. by Desikan R, Griffiths R, Hancock J, Neill S.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138608
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A role for nitric oxide in hydroxyurea-mediated fetal hemoglobin induction. by King SB.; 2003 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151883
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A Role for Nitric Oxide in Muscle Repair: Nitric Oxide --mediated Activation of Muscle Satellite Cells. by Anderson JE.; 2000 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14889
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A Tumor Necrosis Factor Mimetic Peptide Activates a Murine Macrophage Cell Line To Inhibit Mycobacterial Growth in a Nitric Oxide-Dependent Fashion. by Britton WJ, Meadows N, Rathjen DA, Roach DR, Briscoe H.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108172
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Activation of Nuclear Factor [kappa]B and Induction of Inducible Nitric Oxide Synthase by Ureaplasma urealyticum in Macrophages. by Li YH, Yan ZQ, Jensen JS, Tullus K, Brauner A.; 2000 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97819
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Activation of the Phosphatidylinositol 3-Kinase/Protein Kinase Akt Pathway Mediates Nitric Oxide-Induced Endothelial Cell Migration and Angiogenesis. by Kawasaki K, Smith RS Jr, Hsieh CM, Sun J, Chao J, Liao JK.; 2003 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166338
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Acute hemodynamic effects of inhaled nitric oxide, dobutamine and a combination of the two in patients with mild to moderate secondary pulmonary hypertension. by Vizza CD, Rocca GD, Roma DA, Iacoboni C, Pierconti F, Venuta F, Rendina E, Schmid G, Pietropaoli P, Fedele F.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96124
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Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. by McMillan K, Adler M, Auld DS, Baldwin JJ, Blasko E, Browne LJ, Chelsky D, Davey D, Dolle RE, Eagen KA, Erickson S, Feldman RI, Glaser CB, Mallari C, Morrissey MM, Ohlmeyer MH, Pan G, Parkinson JF, Phillips GB, Polokoff MA, Sigal NH, Vergona R, Whitlow M, Young TA, Devlin JJ.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26464
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Altered regulation of inducible nitric oxide synthase expression in macrophages from senescent mice. by Chen LC, Pace JL, Russell SW, Morrison DC.; 1996 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174369
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Amyloid [beta]-peptide stimulates nitric oxide production in astrocytes through an NF[kappa]B-dependent mechanism. by Akama KT, Albanese C, Pestell RG, Van Eldik LJ.; 1998 May 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20459
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Analysis of the role of the nnrR gene product in the response of Rhodobacter sphaeroides 2.4.1 to exogenous nitric oxide. by Kwiatkowski AV, Laratta WP, Toffanin A, Shapleigh JP.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=179441
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Ancient origins of nitric oxide signaling in biological systems. by Durner J, Gow AJ, Stamler JS, Glazebrook J.; 1999 Dec 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33950
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Antitubercular therapy decreases nitric oxide production in HIV/TB coinfected patients. by Wanchu A, Bhatnagar A, Khullar M, Sud A, Bambery P, Singh S.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=119853
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Ascorbic acid acts as an inhibitory transmitter in the hypothalamus to inhibit stimulated luteinizing hormone-releasing hormone release by scavenging nitric oxide. by Karanth S, Yu WH, Walczewska A, Mastronardi C, McCann SM.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26532
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Atrial natriuretic peptide infusion and nitric oxide inhalation in patients with acute respiratory distress syndrome. by Bindels AJ, van der Hoeven JG, Groeneveld PH, Frolich M, Meinders AE.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31579
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Augmentation of Nitric Oxide Production by Gamma Interferon in a Mouse Vascular Endothelial Cell Line and Its Modulation by Tumor Necrosis Factor Alpha and Lipopolysaccharide. by Morikawa A, Koide N, Kato Y, Sugiyama T, Chakravortty D, Yoshida T, Yokochi T.; 2000 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97701
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Babesia bovis-Stimulated Macrophages Express Interleukin-1[beta], Interleukin-12, Tumor Necrosis Factor Alpha, and Nitric Oxide and Inhibit Parasite Replication In Vitro. by Shoda LK, Palmer GH, Florin-Christensen J, Florin-Christensen M, Godson DL, Brown WC.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101760
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Bcl-2 and Bcl-XL Block Thapsigargin-Induced Nitric Oxide Generation, c-Jun NH2Terminal Kinase Activity, and Apoptosis. by Srivastava RK, Sollott SJ, Khan L, Hansford R, Lakatta EG, Longo DL.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84418
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Blood Mononuclear Cell Nitric Oxide Production and Plasma Cytokine Levels in Healthy Gabonese Children with Prior Mild or Severe Malaria. by Perkins DJ, Kremsner PG, Schmid D, Misukonis MA, Kelly MA, Weinberg JB.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96841
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Both the Fas Ligand and Inducible Nitric Oxide Synthase Are Needed for Control of Parasite Replication within Lesions in Mice Infected with Leishmania major whereas the Contribution of Tumor Necrosis Factor Is Minimal. by Chakour R, Guler R, Bugnon M, Allenbach C, Garcia I, Mauel J, Louis J, Tacchini-Cottier F.; 2003 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=187307
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Calmodulin-dependent endothelium-derived relaxing factor/nitric oxide synthase activity is present in the particulate and cytosolic fractions of bovine aortic endothelial cells. by Forstermann U, Pollock JS, Schmidt HH, Heller M, Murad F.; 1991 Mar 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=51110
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Carbon monoxide and nitric oxide as coneurotransmitters in the enteric nervous system: Evidence from genomic deletion of biosynthetic enzymes. by Xue L, Farrugia G, Miller SM, Ferris CD, Snyder SH, Szurszewski JH.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26525
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Catalytic consumption of nitric oxide by 12 /15- lipoxygenase: Inhibition of monocyte soluble guanylate cyclase activation. by Coffey MJ, Natarajan R, Chumley PH, Coles B, Thimmalapura PR, Nowell M, Kuhn H, Lewis MJ, Freeman BA, O'Donnell VB.; 2001 Jul 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=35458
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Central Role for Interleukin-4 in Regulating Nitric Oxide-Mediated Inhibition of TCell Proliferation and Gamma Interferon Production in Schistosomiasis. by Patton EA, La Flamme AC, Pedras-Vasoncelos JA, Pearce EJ.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127598
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Changes in the Antioxidant Systems as Part of the Signaling Pathway Responsible for the Programmed Cell Death Activated by Nitric Oxide and Reactive Oxygen Species in Tobacco Bright-Yellow 2 Cells. by de Pinto MC, Tommasi F, De Gara L.; 2002 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166599
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Characterization of the norB Gene, Encoding Nitric Oxide Reductase, in the Nondenitrifying Cyanobacterium Synechocystis sp. Strain PCC6803. by Busch A, Friedrich B, Cramm R.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126718
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Characterization of the Stable L-Arginine-Derived Relaxing Factor Released from Cytokine-Stimulated Vascular Smooth Muscle Cells as an NG-Hydroxy-L-ArginineNitric Oxide Adduct. by Hecker M, Boese M, Schini-Kerth VB, Mulsch A, Busse R.; 1995 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42006
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Chemical nature of nitric oxide storage forms in rat vascular tissue. by Rodriguez J, Maloney RE, Rassaf T, Bryan NS, Feelisch M.; 2003 Jan 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140970
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Chlamydial Infection in Inducible Nitric Oxide Synthase Knockout Mice. by Igietseme JU, Perry LL, Ananaba GA, Uriri IM, Ojior OO, Kumar SN, Caldwell HD.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108050
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Clearance of Shigella flexneri Infection Occurs through a Nitric Oxide-Independent Mechanism. by Way SS, Goldberg MB.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108306
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Cloning, expression, and characterization of a nitric oxide synthase protein from Deinococcus radiodurans. by Adak S, Bilwes AM, Panda K, Hosfield D, Aulak KS, McDonald JF, Tainer JA, Getzoff ED, Crane BR, Stuehr DJ.; 2002 Jan 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117522
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Cyclophosphamide Decreases Nitrotyrosine Formation and Inhibits Nitric Oxide Production by Alveolar Macrophages in Mycoplasmosis. by Hickman-Davis JM, Lindsey JR, Matalon S.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98775
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Cytochrome c[prime prime or minute] from Rhodobacter capsulatus Confers Increased Resistance to Nitric Oxide. by Cross R, Aish J, Paston SJ, Poole RK, Moir JW.; 2000 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=94437
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Cytokine Responses to Group B Streptococci Induce Nitric Oxide Production in Respiratory Epithelial Cells. by Goodrum KJ, Poulson-Dunlap J.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127614
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Cytostatic and cytotoxic effects of activated macrophages and nitric oxide donors on Brugia malayi. by Thomas GR, McCrossan M, Selkirk ME.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175385
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Decreased Antipyrine Clearance following Endotoxin Administration: In Vivo Evidence of the Role of Nitric Oxide. by Kitaichi K, Wang L, Takagi K, Iwase M, Shibata E, Nadai M, Takagi K, Hasegawa T.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89545
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Defective Nitric Oxide Effector Functions Lead to Extreme Susceptibility of Trypanosoma cruzi-Infected Mice Deficient in Gamma Interferon Receptor or Inducible Nitric Oxide Synthase. by Holscher C, Kohler G, Muller U, Mossmann H, Schaub GA, Brombacher F.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108035
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Development and mechanism of a specific supersensitivity to nitrovasodilators after inhibition of vascular nitric oxide synthesis in vivo. by Moncada S, Rees DD, Schulz R, Palmer RM.; 1991 Mar 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=51190
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Different mechanisms underlying the stimulation of KCa channels by nitric oxide and carbon monoxide. by Wu L, Cao K, Lu Y, Wang R.; 2002 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151105
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Different responses of astrocytes and neurons to nitric oxide: The role of glycolytically generated ATP in astrocyte protection. by Almeida A, Almeida J, Bolanos JP, Moncada S.; 2001 Dec 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=65023
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Differential Interleukin-8 and Nitric Oxide Production in Epithelial Cells Induced by Mucosally Invasive and Noninvasive Trypanosoma cruzi Trypomastigotes. by Eickhoff CS, Eckmann L, Hoft DF.; 2003 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=187333
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Diffusion of nitric oxide can facilitate cerebellar learning: A simulation study. by Schweighofer N, Ferriol G.; 2000 Sep 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27081
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Direct inhibition by nitric oxide of the transcriptional ferric uptake regulation protein via nitrosylation of the iron. by D'Autreaux B, Touati D, Bersch B, Latour JM, MichaudSoret I.; 2002 Dec 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139193
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Direct measurement of nitric oxide generation from nitric oxide synthase. by Xia Y, Zweier JL.; 1997 Nov 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25093
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Direct nitric oxide signal transduction via nitrosylation of iron-sulfur centers in the SoxR transcription activator. by Ding H, Demple B.; 2000 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25796
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DNA Damage and Mutation in Human Cells Exposed to Nitric Oxide in vitro. by Nguyen T, Brunson D, Crespi CL, Penman BW, Wishnok JS, Tannenbaum SR.; 1992 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48797
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DNA from Protozoan Parasites Babesia bovis, Trypanosoma cruzi, and T. brucei Is Mitogenic for B Lymphocytes and Stimulates Macrophage Expression of Interleukin12, Tumor Necrosis Factor Alpha, and Nitric Oxide. by Shoda LK, Kegerreis KA, Suarez CE, Roditi I, Corral RS, Bertot GM, Norimine J, Brown WC.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98143
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Does Nitric Oxide Play a Critical Role in Viral Infections? by Reiss CS, Komatsu T.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109964
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Down-regulation of iron regulatory protein 1 gene expression by nitric oxide. by Oliveira L, Drapier JC.; 2000 Jun 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18655
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Effect of Mycobacterium tuberculosis-Specific 10-Kilodalton Antigen on Macrophage Release of Tumor Necrosis Factor Alpha and Nitric Oxide. by Trajkovic V, Singh G, Singh B, Singh S, Sharma P.; 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=132989
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Effect of Nitric Oxide on Poliovirus Infection of Two Human Cell Lines. by LopezGuerrero JA, Carrasco L.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109559
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Effects of gamma interferon and nitric oxide on the interaction of Mycobacterium avium subsp. paratuberculosis with bovine monocytes. by Zhao B, Collins MT, Czuprynski CJ.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175213
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Effects of in vivo adventitial expression of recombinant endothelial nitric oxide synthase gene in cerebral arteries. by Chen AF, Jiang SW, Crotty TB, Tsutsui M, Smith LA, O'Brien T, Katusic ZS.; 1997 Nov 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25041
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Effects of nifedipine, metronidazole, and nitric oxide donors on spore germination and cell culture infection of the microsporidia Encephalitozoon hellem and Encephalitozoon intestinalis. by He Q, Leitch GJ, Visvesvara GS, Wallace S.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163079
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Effects of Nitric Oxide on Pseudomonas aeruginosa Infection of Epithelial Cells from a Human Respiratory Cell Line Derived from a Patient with Cystic Fibrosis. by Darling KE, Evans TJ.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153226
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Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice. by Napoli C, Cirino G, Del Soldato P, Sorrentino R, Sica V, Condorelli M, Pinto A, Ignarro LJ.; 2001 Feb 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30230
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Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis. by Napoli C, Aldini G, Wallace JL, de Nigris F, Maffei R, Abete P, Bonaduce D, Condorelli G, Rengo F, Sica V, D'Armiento FP, Mignogna C, de Rosa G, Condorelli M, Lerman LO, Ignarro LJ.; 2002 Feb 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122252
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Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice. by Jones SP, Greer JJ, van Haperen R, Duncker DJ, de Crom R, Lefer DJ.; 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153651
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Endotoxin-induced desensitization of mouse macrophages is mediated in part by nitric oxide production. by Fahmi H, Charon D, Mondange M, Chaby R.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173236
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Enzymatic Removal of Nitric Oxide Catalyzed by Cytochrome c[prime prime or minute] in Rhodobacter capsulatus. by Cross R, Lloyd D, Poole RK, Moir JW.; 2001 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95204
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Evidence for in vivo transport of bioactive nitric oxide in human plasma. by Rassaf T, Preik M, Kleinbongard P, Lauer T, Heiss C, Strauer BE, Feelisch M, Kelm M.; 2002 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150967
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Evidence of Autocrine Modulation of Macrophage Nitric Oxide Synthase by [alpha]Melanocyte-Stimulating Hormone. by Star RA, Rajora N, Huang J, Stock RC, Catania A, Lipton JM.; 1995 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41277
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Expression and Bactericidal Activity of Nitric Oxide Synthase in Brucella suisInfected Murine Macrophages. by Gross A, Spiesser S, Terraza A, Rouot B, Caron E, Dornand J.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108054
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Flavohemoglobin Hmp Protects Salmonella enterica Serovar Typhimurium from Nitric Oxide-Related Killing by Human Macrophages. by Stevanin TM, Poole RK, Demoncheaux EA, Read RC.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128135
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Focusing of nitric oxide mediated nitrosation and oxidative nitrosylation as a consequence of reaction with superoxide. by Espey MG, Thomas DD, Miranda KM, Wink DA.; 2002 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123221
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Functional interaction of endothelial nitric oxide synthase with a voltage-dependent anion channel. by Sun J, Liao JK.; 2002 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130594
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Functionally differentiating two neuronal nitric oxide synthase isoforms through antisense mapping: Evidence for opposing NO actions on morphine analgesia and tolerance. by Kolesnikov YA, Pan YX, Babey AM, Jain S, Wilson R, Pasternak GW.; 1997 Jul 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21584
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Gamma Interferon Modulates CD95 (Fas) and CD95 Ligand (Fas-L) Expression and Nitric Oxide-Induced Apoptosis during the Acute Phase of Trypanosoma cruzi Infection: a Possible Role in Immune Response Control. by Martins GA, Vieira LQ, Cunha FQ, Silva JS.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96666
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Gamma Interferon Treatment of Patients with Chronic Granulomatous Disease Is Associated with Augmented Production of Nitric Oxide by Polymorphonuclear Neutrophils. by Ahlin A, Larfars G, Elinder G, Palmblad J, Gyllenhammar H.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=103734
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Gamma interferon-induced nitric oxide production reduces Chlamydia trachomatis infectivity in McCoy cells. by Mayer J, Woods ML, Vavrin Z, Hibbs JB Jr.; 1993 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302755
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Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. by Radomski MW, Palmer RM, Moncada S.; 1990 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=55311
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Gonococcal Nitric Oxide Reductase Is Encoded by a Single Gene, norB, Which Is Required for Anaerobic Growth and Is Induced by Nitric Oxide. by Householder TC, Fozo EM, Cardinale JA, Clark VL.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101784
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Group B streptococcus-induced nitric oxide production in murine macrophages is CR3 (CD11b/CD18) dependent. by Goodrum KJ, McCormick LL, Schneider B.; 1994 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302933
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Growth Hormone-Releasing Factor Increases Somatostatin Release and mRNA Levels in the Rat Periventricular Nucleus via Nitric Oxide by Activation of Guanylate Cyclase. by Aguila MC.; 1994 Jan 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43033
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Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: A strategy for bacterial survival. by Gobert AP, McGee DJ, Akhtar M, Mendz GL, Newton JC, Cheng Y, Mobley HL, Wilson KT.; 2001 Nov 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61129
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Heterologous NNR-Mediated Nitric Oxide Signaling in Escherichia coli. by Hutchings MI, Shearer N, Wastell S, van Spanning RJ, Spiro S.; 2000 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=94790
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High Levels of Inducible Nitric Oxide Synthase mRNA Are Associated with Increased Monocyte Counts in Blood and Have a Beneficial Role in Plasmodium falciparum Malaria. by Chiwakata CB, Hemmer CJ, Dietrich M.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97148
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Host Response to Infection: the Role of CpG DNA in Induction of Cyclooxygenase 2 and Nitric Oxide Synthase 2 in Murine Macrophages. by Ghosh DK, Misukonis MA, Reich C, Pisetsky DS, Weinberg JB.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98865
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Human CD46 Enhances Nitric Oxide Production in Mouse Macrophages in Response to Measles Virus Infection in the Presence of Gamma Interferon: Dependence on the CD46 Cytoplasmic Domains. by Hirano A, Yang Z, Katayama Y, Korte-Sarfaty J, Wong TC.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112520
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Human Receptor for Measles Virus (CD46) Enhances Nitric Oxide Production and Restricts Virus Replication in Mouse Macrophages by Modulating Production of Alpha/Beta Interferon. by Katayama Y, Hirano A, Wong TC.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111459
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Hydroxyurea induces fetal hemoglobin by the nitric oxide --dependent activation of soluble guanylyl cyclase. by Cokic VP, Smith RD, Beleslin-Cokic BB, Njoroge JM, Miller JL, Gladwin MT, Schechter AN.; 2003 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151872
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Hypotension and inflammatory cytokine gene expression triggered by factor Xa -nitric oxide signaling. by Papapetropoulos A, Piccardoni P, Cirino G, Bucci M, Sorrentino R, Cicala C, Johnson K, Zachariou V, Sessa WC, Altieri DC.; 1998 Apr 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22560
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Identification of a neuronal nitric oxide synthase in isolated cardiac mitochondria using electrochemical detection. by Kanai AJ, Pearce LL, Clemens PR, Birder LA, VanBibber MM, Choi SY, de Groat WC, Peterson J.; 2001 Nov 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61179
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In Vivo Blockage of Nitric Oxide with Aminoguanidine Inhibits Immunosuppression Induced by an Attenuated Strain of Salmonella typhimurium, Potentiates Salmonella Infection, and Inhibits Macrophage and Polymorphonuclear Leukocyte Influx into the Spleen. by MacFarlane AS, Schwacha MG, Eisenstein TK.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96401
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In Vivo Formation of Electron Paramagnetic Resonance-Detectable Nitric Oxide and of Nitrotyrosine Is Not Impaired during Murine Leishmaniasis. by Giorgio S, Linares E, Ischiropoulos H, Von Zuben FJ, Yamada A, Augusto O.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113503
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Inducible nitric oxide synthase expression inhibition by adenovirus E1A. by Cao W, Bao C, Lowenstein CJ.; 2003 Jun 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164663
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Induction of Gamma Interferon and Nitric Oxide by Truncated Pneumolysin That Lacks Pore-Forming Activity. by Baba H, Kawamura I, Kohda C, Nomura T, Ito Y, Kimoto T, Watanabe I, Ichiyama S, Mitsuyama M.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127632
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Induction of Inducible Nitric Oxide Synthase-NO[center dot] by Lipoarabinomannan of Mycobacterium tuberculosis Is Mediated by MEK1-ERK, MKK7-JNK, and NF[kappa]B Signaling Pathways. by Chan ED, Morris KR, Belisle JT, Hill P, Remigio LK, Brennan PJ, Riches DW.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98123
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Induction of platelet formation from megakaryocytoid cells by nitric oxide. by Battinelli E, Willoughby SR, Foxall T, Valeri CR, Loscalzo J.; 2001 Dec 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64703
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Induction of ResDE-Dependent Gene Expression in Bacillus subtilis in Response to Nitric Oxide and Nitrosative Stress. by Nakano MM.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=134876
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Inhibition of Anaerobic Phosphate Release by Nitric Oxide in Activated Sludge. by Van Niel EW, Appeldoorn KJ, Zehnder AJ, Kortstee GJ.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106794
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Inhibition of Caspase 3 Abrogates Lipopolysaccharide-Induced Nitric Oxide Production by Preventing Activation of NF-[kappa]B and c-Jun NH2-Terminal Kinase/Stress-Activated Protein Kinase in RAW 264.7 Murine Macrophage Cells. by Chakravortty D, Kato Y, Sugiyama T, Koide N, Mu MM, Yoshida T, Yokochi T.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98022
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Inhibition of Influenza Virus Replication by Nitric Oxide. by Rimmelzwaan GF, Baars MM, de Lijster P, Fouchier RA, Osterhaus AD.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112914
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Inhibition of Leukocyte Rolling by Nitric Oxide during Sepsis Leads to Reduced Migration of Active Microbicidal Neutrophils. by Benjamim CF, Silva JS, Fortes ZB, Oliveira MA, Ferreira SH, Cunha FQ.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128083
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Inhibition of mitochondrial protein synthesis results in increased endothelial cell susceptibility to nitric oxide-induced apoptosis. by Ramachandran A, Moellering DR, Ceaser E, Shiva S, Xu J, Darley-Usmar V.; 2002 May 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124456
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Inhibition of mitochondrial respiration by endogenous nitric oxide: A critical step in Fas signaling. by Beltran B, Quintero M, Garcia-Zaragoza E, O'Connor E, Esplugues JV, Moncada S.; 2002 Jun 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124394
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Inhibition of NF-[kappa]B DNA binding and nitric oxide induction in human T cells and lung adenocarcinoma cells by selenite treatment. by Kim IY, Stadtman TC.; 1997 Nov 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24236
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Inhibitory Activity of Constitutive Nitric Oxide on the Expression of Alpha/Beta Interferon Genes in Murine Peritoneal Macrophages. by Guillemard E, Varano B, Belardelli F, Quero AM, Gessani S.; 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104258
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Inhibitory effect of nitric oxide on the replication of a murine retrovirus in vitro and in vivo. by Akarid K, Sinet M, Desforges B, Gougerot-Pocidalo MA.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=189619
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Inhibitory Effects of Nitric Oxide and Gamma Interferon on In Vitro and In Vivo Replication of Marek's Disease Virus. by Xing Z, Schat KA.; 2000 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111870
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Innate Immunity to Amebic Liver Abscess Is Dependent on Gamma Interferon and Nitric Oxide in a Murine Model of Disease. by Seydel KB, Smith SJ, Stanley SL Jr.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97149
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Interleukin-12 (IL-12) Enhancement of the Cellular Immune Response against Human Immunodeficiency Virus Type 1 Env Antigen in a DNA Prime/Vaccinia Virus Boost Vaccine Regimen Is Time and Dose Dependent: Suppressive Effects of IL-12 Boost Are Mediated by Nitric Oxide. by Gherardi MM, Ramirez JC, Esteban M.; 2000 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112133
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Intracellular Release of Nitric Oxide by NCX 972, an NO-Releasing Metronidazole, Enhances In Vitro Killing of Entamoeba histolytica. by Sannella A, Gradoni L, Persichini T, Ongini E, Venturini G, Colasanti M.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161880
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Intravascular flow decreases erythrocyte consumption of nitric oxide. by Liao JC, W. Hein T, Vaughn MW, Huang KT, Kuo L.; 1999 Jul 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17589
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Inverse Relationship between Severity of Experimental Pyelonephritis and Nitric Oxide Production in C3H/HeJ Mice. by Nowicki B, Singhal J, Fang L, Nowicki S, Yallampalli C.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115987
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Investigation of Role of Nitric Oxide in Protection from Bordetella pertussis Respiratory Challenge. by Canthaboo C, Xing D, Wei XQ, Corbel MJ.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127720
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l-Arginine Availability Modulates Local Nitric Oxide Production and Parasite Killing in Experimental Trypanosomiasis. by Gobert AP, Daulouede S, Lepoivre M, Boucher JL, Bouteille B, Buguet A, Cespuglio R, Veyret B, Vincendeau P.; 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98402
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l-Arginine-dependent suppression of apoptosis in Trypanosoma cruzi: Contribution of the nitric oxide and polyamine pathways. by Piacenza L, Peluffo G, Radi R.; 2001 Jun 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34663
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Leukotriene B4 Induces Nitric Oxide Synthesis in Trypanosoma cruzi-Infected Murine Macrophages and Mediates Resistance to Infection. by Talvani A, Machado FS, Santana GC, Klein A, Barcelos L, Silva JS, Teixeira MM.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128190
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Lipopolysaccharides of Brucella abortus and Brucella melitensis Induce Nitric Oxide Synthesis in Rat Peritoneal Macrophages. by Lopez-Urrutia L, Alonso A, Nieto ML, Bayon Y, Orduna A, Sanchez Crespo M.; 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97342
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Macrophages resistant to endogenously generated nitric oxide-mediated apoptosis are hypersensitive to exogenously added nitric oxide donors: Dichotomous apoptotic response independent of caspase 3 and reversal by the mitogen-activated protein kinase kinase (MEK) inhibitor PD 098059. by Mohr S, McCormick TS, Lapetina EG.; 1998 Apr 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20210
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Mechanism of nitric oxide-dependent killing of Mycobacterium bovis BCG in human alveolar macrophages. by Nozaki Y, Hasegawa Y, Ichiyama S, Nakashima I, Shimokata K.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175518
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Metallothionein Protects Against the Cytotoxic and DNA-Damaging Effects of Nitric Oxide. by Schwarz MA, Lazo JS, Yalowich JC, Allen WP, Whitmore M, Bergonia HA, Tzeng E, Billiar TR, Robbins PD, Lancaster JR Jr, Pitt BR.; 1995 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41962
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Mice Lacking Inducible Nitric Oxide Synthase Demonstrate Impaired Killing of Porphyromonas gingivalis. by Gyurko R, Boustany G, Huang PL, Kantarci A, Van Dyke TE, Genco CA, Gibson III FC.; 2003 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=187326
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Microtubule dysfunction by posttranslational nitrotyrosination of [alpha]-tubulin: A nitric oxide-dependent mechanism of cellular injury. by Eiserich JP, Estevez AG, Bamberg TV, Ye YZ, Chumley PH, Beckman JS, Freeman BA.; 1999 May 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26887
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Microtubule-disrupting agents inhibit nitric oxide production in murine peritoneal macrophages stimulated with lipopolysaccharide or paclitaxel (Taxol). by Kirikae T, Kirikae F, Oghiso Y, Nakano M.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174233
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Modulation of Inducible Nitric Oxide Synthase Expression by the Attaching and Effacing Bacterial Pathogen Citrobacter rodentium in Infected Mice. by Vallance BA, Deng W, De Grado M, Chan C, Jacobson K, Finlay BB.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130393
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Modulation of nitric oxide bioavailability by erythrocytes. by Huang KT, Han TH, Hyduke DR, Vaughn MW, Van Herle H, Hein TW, Zhang C, Kuo L, Liao JC.; 2001 Sep 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58805
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Murine Macrophages Use Oxygen- and Nitric Oxide-Dependent Mechanisms To Synthesize S-Nitroso-Albumin and To Kill Extracellular Trypanosomes. by Gobert AP, Semballa S, Daulouede S, Lesthelle S, Taxile M, Veyret B, Vincendeau P.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108487
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Mycobacteriocidal Action of Exogenous Nitric Oxide. by Long R, Light B, Talbot JA.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89090
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Necessity and sufficiency of beta interferon for nitric oxide production in mouse peritoneal macrophages. by Zhang X, Alley EW, Russell SW, Morrison DC.; 1994 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=186064
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Neuronal (type I) nitric oxide synthase regulates nuclear factor[kappa]B activity and immunologic (type II) nitric oxide synthase expression. by Togashi H, Sasaki M, Frohman E, Taira E, Ratan RR, Dawson TM, Dawson VL.; 1997 Mar 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20148
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Neuronal Differentiation and Protection from Nitric Oxide-Induced Apoptosis Require c-Jun-Dependent Expression of NCAM140. by Feng Z, Li L, Ng PY, Porter AG.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133958
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NF-[kappa]B and AP-1 Activation by Nitric Oxide Attenuated Apoptotic Cell Death in RAW 264.7 Macrophages. by von Knethen A, Callsen D, Brune B.; 1999 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25174
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Nitric Oxide Acts as an Antioxidant and Delays Programmed Cell Death in Barley Aleurone Layers. by Beligni MV, Fath A, Bethke PC, Lamattina L, Jones RL.; 2002 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166752
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Nitric Oxide and Another Potent Vasodilator are Formed from NG-Hydroxy- LArginine by Cultured Endothelial Cells. by Zembowicz A, Hecker M, Macarthur H, Sessa WC, Vane JR.; 1991 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53096
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Nitric Oxide and Apoptosis Induced in Peyer's Patches by Attenuated Strains of Salmonella enterica Serovar Enteritidis. by Cerquetti MC, Goren NB, Ropolo AJ, Grasso D, Giacomodonato MN, Vaccaro MI.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127727
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Nitric oxide and salicylic acid signaling in plant defense. by Klessig DF, Durner J, Noad R, Navarre DA, Wendehenne D, Kumar D, Zhou JM, Shah J, Zhang S, Kachroo P, Trifa Y, Pontier D, Lam E, Silva H.; 2000 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34022
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Nitric oxide and thiol redox regulation of Janus kinase activity. by Duhe RJ, Evans GA, Erwin RA, Kirken RA, Cox GW, Farrar WL.; 1998 Jan 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18148
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Nitric oxide binding at the mononuclear active site of reduced Pyrococcus furiosus superoxide reductase. by Clay MD, Cosper CA, Jenney FE Jr, Adams MW, Johnson MK.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153001
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Nitric oxide contributes to induction of innate immune responses to gram-negative bacteria in Drosophila. by Foley E, O'Farrell PH.; 2003 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=195964
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Nitric oxide down-regulates brain-derived neurotrophic factor secretion in cultured hippocampal neurons. by Canossa M, Giordano E, Cappello S, Guarnieri C, Ferri S.; 2002 Mar 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122510
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Nitric oxide for the evaluation and treatment of pulmonary hypertension in congenital heart disease. by Kovalchin JP, Mott AR, Rosen KL, Feltes TF.; 1997; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325473
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Nitric Oxide Improves Internal Iron Availability in Plants. by Graziano M, Beligni MV, Lamattina L.; 2002 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166696
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Nitric oxide in plant immunity. by Hausladen A, Stamler JS.; 1998 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33884
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Nitric Oxide Increases the Decay of Matrix Metalloproteinase 9 mRNA by Inhibiting the Expression of mRNA-Stabilizing Factor HuR. by Akool ES, Kleinert H, Hamada FM, Abdelwahab MH, Forstermann U, Pfeilschifter J, Eberhardt W.; 2003 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=162218
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Nitric Oxide Induces Stomatal Closure and Enhances the Adaptive Plant Responses against Drought Stress. by Mata CG, Lamattina L.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116475
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Nitric oxide induction by pertussis toxin in mouse spleen cells via gamma interferon. by Sakurai S, Kamachi K, Konda T, Miyajima N, Kohase M, Yamamoto S.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173919
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Nitric Oxide Inhibits Coxiella burnetii Replication and Parasitophorous Vacuole Maturation. by Howe D, Barrows LF, Lindstrom NM, Heinzen RA.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128226
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Nitric oxide inhibits H2O2-induced transferrin receptor-dependent apoptosis in endothelial cells: Role of ubiquitin-proteasome pathway. by Kotamraju S, Tampo Y, Keszler A, Chitambar CR, Joseph J, Haas AL, Kalyanaraman B.; 2003 Sep 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=196859
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Nitric Oxide Inhibits Hypothalamic Luteinizing Hormone-Releasing Hormone Release by Releasing [gamma]-Aminobutyric Acid. by Seilicovich A, Duvilanski BH, Pisera D, Theas S, Gimeno M, Rettori V, McCann SM.; 1995 Apr 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42178
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Nitric Oxide Inhibits Rhinovirus-Induced Cytokine Production and Viral Replication in a Human Respiratory Epithelial Cell Line. by Sanders SP, Siekierski ES, Porter JD, Richards SM, Proud D.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124563
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Nitric oxide inhibits tumor necrosis factor-[alpha]-induced apoptosis by reducing the generation of ceramide. by De Nadai C, Sestili P, Cantoni O, Lievremont JP, Sciorati C, Barsacchi R, Moncada S, Meldolesi J, Clementi E.; 2000 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25854
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Nitric Oxide Is a Signal for NNR-Mediated Transcription Activation in Paracoccus denitrificans. by Van Spanning RJ, Houben E, Reijnders WN, Spiro S, Westerhoff HV, Saunders N.; 1999 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93909
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Nitric oxide is consumed, rather than conserved, by reaction with oxyhemoglobin under physiological conditions. by Joshi MS, Ferguson TB Jr, Han TH, Hyduke DR, Liao JC, Rassaf T, Bryan N, Feelisch M, Lancaster JR Jr.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124916
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Nitric oxide is involved in control of Trypanosoma cruzi-induced parasitemia and directly kills the parasite in vitro. by Vespa GN, Cunha FQ, Silva JS.; 1994 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303244
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Nitric Oxide is Produced by Cowdria ruminantium-Infected Bovine Pulmonary Endothelial Cells In Vitro and Is Stimulated by Gamma Interferon. by Mutunga M, Preston PM, Sumption KJ.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108171
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Nitric Oxide Is Protective in Listeric Meningoencephalitis of Rats. by Remer KA, Jungi TW, Fatzer R, Tauber MG, Leib SL.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98473
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Nitric oxide is required for effective innate immunity against Klebsiella pneumoniae. by Tsai WC, Strieter RM, Zisman DA, Wilkowski JM, Bucknell KA, Chen GH, Standiford TJ.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175233
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Nitric oxide leads to prized NObility: background to the work of Ferid Murad. by Scott-Burden T.; 1999; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325589
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Nitric Oxide Limits the Expansion of Antigen-Specific T Cells in Mice Infected with the Microfilariae of Brugia pahangi. by O'Connor RA, Devaney E.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130375
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Nitric oxide mediates N-methyl-d-aspartate receptor-induced activation of p21ras. by Yun HY, Gonzalez-Zulueta M, Dawson VL, Dawson TM.; 1998 May 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20455
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Nitric Oxide Metabolism in Neisseria meningitidis. by Anjum MF, Stevanin TM, Read RC, Moir JW.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135047
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Nitric Oxide Modulates the Activity of Tobacco Aconitase. by Navarre DA, Wendehenne D, Durner J, Noad R, Klessig DF.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58894
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Nitric Oxide Negatively Modulates Wound Signaling in Tomato Plants. by OrozcoCardenas ML, Ryan CA.; 2002 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166580
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Nitric oxide negatively regulates c-Jun N-terminal kinase/stress-activated protein kinase by means of S-nitrosylation. by Park HS, Huh SH, Kim MS, Lee SH, Choi EJ.; 2000 Dec 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18927
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Nitric oxide negatively regulates mammalian adult neurogenesis. by Packer MA, Stasiv Y, Benraiss A, Chmielnicki E, Grinberg A, Westphal H, Goldman SA, Enikolopov G.; 2003 Aug 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=170958
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Nitric Oxide Partially Controls Coxiella burnetii Phase II Infection in Mouse Primary Macrophages. by Zamboni DS, Rabinovitch M.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=148841
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Nitric Oxide Participation in the Fungicidal Mechanism of Gamma InterferonActivated Murine Macrophages against Paracoccidioides brasiliensis Conidia. by Gonzalez A, de Gregori W, Velez D, Restrepo A, Cano LE.; 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97457
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Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase. by Shiva S, Brookes PS, Patel RP, Anderson PG, Darley-Usmar VM.; 2001 Jun 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34648
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Nitric oxide preferentially induces type 1 T cell differentiation by selectively upregulating IL-12 receptor [beta]2 expression via cGMP. by Niedbala W, Wei XQ, Campbell C, Thomson D, Komai-Koma M, Liew FY.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138586
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Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin. by Ruschitzka FT, Wenger RH, Stallmach T, Quaschning T, de Wit C, Wagner K, Labugger R, Kelm M, Noll G, Rulicke T, Shaw S, Lindberg RL, Rodenwaldt B, Lutz H, Bauer C, Luscher TF, Gassmann M.; 2000 Oct 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17248
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Nitric Oxide Production and Mononuclear Cell Nitric Oxide Synthase Activity in Malaria-Tolerant Papuan Adults. by Boutlis CS, Tjitra E, Maniboey H, Misukonis MA, Saunders JR, Suprianto S, Weinberg JB, Anstey NM.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161965
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Nitric oxide production does not directly increase macrophage candidacidal activity. by Vazquez-Torres A, Jones-Carson J, Balish E.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173125
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Nitric oxide reaction with red blood cells and hemoglobin under heterogeneous conditions. by Han TH, Hyduke DR, Vaughn MW, Fukuto JM, Liao JC.; 2002 May 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124345
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Nitric Oxide Reacts with Intracellular Glutathione and Activates the Hexose Monophosphate Shunt in Human Neutrophils: Evidence for S-Nitrosoglutathione as a Bioactive Intermediary. by Clancy RM, Levartovsky D, Leszczynska-Piziak J, Yegudin J, Abramson SB.; 1994 Apr 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43645
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Nitric oxide regulates K+ and Cl- channels in guard cells through a subset of abscisic acid-evoked signaling pathways. by Garcia-Mata C, Gay R, Sokolovski S, Hills A, Lamattina L, Blatt MR.; 2003 Sep 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=196936
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Nitric Oxide Regulates Vascular Cell Adhesion Molecule 1 Gene Expression and Redox-Sensitive Transcriptional Events in Human Vascular Endothelial Cells. by Khan BV, Harrison DG, Olbrych MT, Alexander RW, Medford RM.; 1996 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38604
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Nitric Oxide Signaling and Transcriptional Control of Denitrification Genes in Pseudomonas stutzeri. by Vollack KU, Zumft WG.; 2001 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95168
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Nitric Oxide Synthase Generates Superoxide and Nitric Oxide in Arginine-Depleted Cells Leading to Peroxynitrite-Mediated Cellular Injury. by Xia Y, Dawson VL, Dawson TM, Snyder SH, Zweier JL.; 1996 Jun 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39102
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Nitric oxide synthase in cardiac sarcoplasmic reticulum. by Xu KY, Huso DL, Dawson TM, Bredt DS, Becker LC.; 1999 Jan 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15192
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Nitric Oxide Synthesis Enhances Human Immunodeficiency Virus Replication in Primary Human Macrophages. by Blond D, Raoul H, Le Grand R, Dormont D.; 2000 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102085
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Nitric Oxide, cGMP, and Hormone Regulation of Active Sodium Transport. by McKee M, Scavone C, Nathanson JA.; 1994 Dec 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45375
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Nitric oxide: a pro-inflammatory mediator in lung disease? by Vliet AV, Eiserich JP, Cross CE.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59543
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Nitric oxide-induced apoptosis in pancreatic [beta] cells is mediated by the endoplasmic reticulum stress pathway. by Oyadomari S, Takeda K, Takiguchi M, Gotoh T, Matsumoto M, Wada I, Akira S, Araki E, Mori M.; 2001 Sep 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58562
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Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. by Hofseth LJ, Saito S, Hussain SP, Espey MG, Miranda KM, Araki Y, Jhappan C, Higashimoto Y, He P, Linke SP, Quezado MM, Zurer I, Rotter V, Wink DA, Appella E, Harris CC.; 2003 Jan 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140909
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Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): Potential role of cyclin D1. by Pervin S, Singh R, Chaudhuri G.; 2001 Mar 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30696
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Nitric oxide-induced damage to mtDNA and its subsequent repair. by Grishko VI, Druzhyna N, LeDoux SP, Wilson GL.; 1999 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=148736
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Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53. by Li CQ, Trudel LJ, Wogan GN.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124920
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Nitric Oxide-Induced Homologous Recombination in Escherichia coli Is Promoted by DNA Glycosylases. by Spek EJ, Vuong LN, Matsuguchi T, Marinus MG, Engelward BP.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135131
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Nitric Oxide-Induced p53 Accumulation and Regulation of Inducible Nitric Oxide Synthase Expression by Wild-Type p53. by Forrester K, Ambs S, Lupold SE, Kapust RB, Spillare EA, Weinberg WC, Felley-Bosco E, Wang XW, Geller DA, Tzeng E, Billiar TR, Harris CC.; 1996 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39816
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Nitric oxide-induced suspended animation promotes survival during hypoxia. by Teodoro RO, O'Farrell PH.; 2003 Feb 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140754
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Nitric Oxide-Mediated Inhibition of the Ability of Rickettsia prowazekii To Infect Mouse Fibroblasts and Mouse Macrophagelike Cells. by Turco J, Liu H, Gottlieb SF, Winkler HH.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107941
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Nitric Oxide-Mediated Proteasome-Dependent Oligonucleosomal DNA Fragmentation in Leishmania amazonensis Amastigotes. by Holzmuller P, Sereno D, Cavaleyra M, Mangot I, Daulouede S, Vincendeau P, Lemesre JL.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128075
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Nitric oxide-related species inhibit evoked neurotransmission but enhance spontaneous miniature synaptic currents in central neuronal cultures. by Pan ZH, Segal MM, Lipton SA.; 1996 Dec 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26420
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Nitrolinoleate, a nitric oxide-derived mediator of cell function: Synthesis, characterization, and vasomotor activity. by Lim DG, Sweeney S, Bloodsworth A, White CR, Chumley PH, Krishna NR, Schopfer F, O'Donnell VB, Eiserich JP, Freeman BA.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138544
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Nitroxyl and its anion in aqueous solutions: Spin states, protic equilibria, and reactivities toward oxygen and nitric oxide. by Shafirovich V, Lymar SV.; 2002 May 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124232
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Non-heme iron protein: A potential target of nitric oxide in acute cardiac allograft rejection. by Pieper GM, Halligan NL, Hilton G, Konorev EA, Felix CC, Roza AM, Adams MB, Griffith OW.; 2003 Mar 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152257
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NOSTRIN: A protein modulating nitric oxide release and subcellular distribution of endothelial nitric oxide synthase. by Zimmermann K, Opitz N, Dedio J, Renne C, Muller-Esterl W, Oess S.; 2002 Dec 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139423
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Novel repair activities of AlkA (3-methyladenine DNA glycosylase II) and endonuclease VIII for xanthine and oxanine, guanine lesions induced by nitric oxide and nitrous acid. by Terato H, Masaoka A, Asagoshi K, Honsho A, Ohyama Y, Suzuki T, Yamada M, Makino K, Yamamoto K, Ide H.; 2002 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137176
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On the activation of soluble guanylyl cyclase by nitric oxide. by Bellamy TC, Wood J, Garthwaite J.; 2002 Jan 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117590
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Opposite effects of nitric oxide and nitroxyl on postischemic myocardial injury. by Ma XL, Gao F, Liu GL, Lopez BL, Christopher TA, Fukuto JM, Wink DA, Feelisch M.; 1999 Dec 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24485
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Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP. by MacIntyre I, Zaidi M, Alam AS, Datta HK, Moonga BS, Lidbury PS, Hecker M, Vane JR.; 1991 Apr 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=51355
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Outer surface lipoproteins of Borrelia burgdorferi stimulate nitric oxide production by the cytokine-inducible pathway. by Ma Y, Seiler KP, Tai KF, Yang L, Woods M, Weis JJ.; 1994 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303016
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Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. by Ozaki M, Kawashima S, Yamashita T, Hirase T, Namiki M, Inoue N, Hirata KI, Yasui H, Sakurai H, Yoshida Y, Masada M, Yokoyama M.; 2002 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151086
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Oxidation of Nitric Oxide in Aqueous Solution to Nitrite but not Nitrate: Comparison with Enzymatically Formed Nitric Oxide From L-Arginine. by Ignarro LJ, Fukuto JM, Griscavage JM, Rogers NE, Byrns RE.; 1993 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47296
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Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease. by Aslan M, Ryan TM, Adler B, Townes TM, Parks DA, Thompson JA, Tousson A, Gladwin MT, Patel RP, Tarpey MM, Batinic-Haberle I, White CR, Freeman BA.; 2001 Dec 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=65009
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Peroxynitrite contributes to the candidacidal activity of nitric oxide-producing macrophages. by Vazquez-Torres A, Jones-Carson J, Balish E.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174197
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Peroxynitrite, the coupling product of nitric oxide and superoxide, activates prostaglandin biosynthesis. by Landino LM, Crews BC, Timmons MD, Morrow JD, Marnett LJ.; 1996 Dec 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26357
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Phagocyte NADPH Oxidase, but Not Inducible Nitric Oxide Synthase, Is Essential for Early Control of Burkholderia cepacia and Chromobacterium violaceum Infection in Mice. by Segal BH, Ding L, Holland SM.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=143145
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Pharmacological and immunohistochemical evidence for a functional nitric oxide synthase system in rat peritoneal eosinophils. by Zanardo RC, Costa E, Ferreira HH, Antunes E, Martins AR, Murad F, De Nucci G.; 1997 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28441
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Phlebotomus papatasi Saliva Inhibits Protein Phosphatase Activity and Nitric Oxide Production by Murine Macrophages. by Waitumbi J, Warburg A.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108085
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Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action. by Lauer T, Preik M, Rassaf T, Strauer BE, Deussen A, Feelisch M, Kelm M.; 2001 Oct 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60136
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Platelet-Activating Factor Induces Nitric Oxide Synthesis in Trypanosoma cruziInfected Macrophages and Mediates Resistance to Parasite Infection in Mice. by Aliberti JC, Machado FS, Gazzinelli RT, Teixeira MM, Silva JS.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96586
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Pneumolysin, a Protein Toxin of Streptococcus pneumoniae, Induces Nitric Oxide Production from Macrophages. by Braun JS, Novak R, Gao G, Murray PJ, Shenep JL.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96649
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Poly(ADP-ribosyl)ation basally activated by DNA strand breaks reflects glutamate -nitric oxide neurotransmission. by Pieper AA, Blackshaw S, Clements EE, Brat DJ, Krug DK, White AJ, Pinto-Garcia P, Favit A, Conover JR, Snyder SH, Verma A.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26524
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Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. by Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun CO, Buerk DG, Huang PL, Jain RK.; 2001 Feb 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30185
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Prevention of Encephalomyocarditis Virus-Induced Diabetes in Mice by Inhibition of the Tyrosine Kinase Signalling Pathway and Subsequent Suppression of Nitric Oxide Production in Macrophages. by Hirasawa K, Jun HS, Han HS, Zhang ML, Hollenberg MD, Yoon JW.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112874
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Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: Implications for the treatment of multiple sclerosis. by Hooper DC, Bagasra O, Marini JC, Zborek A, Ohnishi ST, Kean R, Champion JM, Sarker AB, Bobroski L, Farber JL, Akaike T, Maeda H, Koprowski H.; 1997 Mar 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20122
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Production and Consumption of Nitric Oxide by Three Methanotrophic Bacteria. by Ren T, Roy R, Knowles R.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=92235
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Protective Role of Nitric Oxide in Staphylococcus aureus Infection in Mice. by Sasaki S, Miura T, Nishikawa S, Yamada K, Hirasue M, Nakane A.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108010
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Quantifying Translocation of Listeria monocytogenes in Rats by Using Urinary Nitric Oxide-Derived Metabolites. by Sprong RC, Hulstein MF, van der Meer R.; 2000 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=92459
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Rapid desensitization of the nitric oxide receptor, soluble guanylyl cyclase, underlies diversity of cellular cGMP responses. by Bellamy TC, Wood J, Goodwin DA, Garthwaite J.; 2000 Mar 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16032
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Reactive oxygen species and nitric oxide mediate plasticity of neuronal calcium signaling. by Yermolaieva O, Brot N, Weissbach H, Heinemann SH, Hoshi T.; 2000 Jan 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26683
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Reaping of nitric oxide by sickle cell disease. by Lancaster JR Jr.; 2002 Jan 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117341
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Recombinational Repair Is Critical for Survival of Escherichia coli Exposed to Nitric Oxide. by Spek EJ, Wright TL, Stitt MS, Taghizadeh NR, Tannenbaum SR, Marinus MG, Engelward BP.; 2001 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=94858
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Reduced Levels of Nitric Oxide Metabolites in Cerebrospinal Fluid Are Associated with Equine Protozoal Myeloencephalitis. by Njoku CJ, Saville WJ, Reed SM, Oglesbee MJ, Rajala-Schultz PJ, Stich RW.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=119978
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Regulation of Human Immunodeficiency Virus Type 1 Replication in Human T Lymphocytes by Nitric Oxide. by Jimenez JL, Gonzalez-Nicolas J, Alvarez S, Fresno M, Munoz-Fernandez MA.; 2001 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=114219
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Regulation of staphylococcal enterotoxin B-elicited nitric oxide production by endothelial cells. by LeClaire RD, Kell WM, Sadik RA, Downs MB, Parker GW.; 1995 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173029
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Relationship of Structure and Biological Activity of Monosaccharide Lipid A Analogues to Induction of Nitric Oxide Production by Murine Macrophage RAW264.7 Cells. by Funatogawa K, Matsuura M, Nakano M, Kiso M, Hasegawa A.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108732
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Relative role of heme nitrosylation and [beta]-cysteine 93 nitrosation in the transport and metabolism of nitric oxide by hemoglobin in the human circulation. by Gladwin MT, Ognibene FP, Pannell LK, Nichols JS, Pease-Fye ME, Shelhamer JH, Schechter AN.; 2000 Aug 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27634
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Release of Hepatocyte Growth Factor from Mechanically Stretched Skeletal Muscle Satellite Cells and Role of pH and Nitric Oxide. by Tatsumi R, Hattori A, Ikeuchi Y, Anderson JE, Allen RE.; 2002 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117951
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Requirement for nitric oxide activation of p21ras /extracellular regulated kinase in neuronal ischemic preconditioning. by Gonzalez-Zulueta M, Feldman AB, Klesse LJ, Kalb RG, Dillman JF, Parada LF, Dawson TM, Dawson VL.; 2000 Jan 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26681
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Resistance to Murine Hepatitis Virus Strain 3 Is Dependent on Production of Nitric Oxide. by Pope M, Marsden PA, Cole E, Sloan S, Fung LS, Ning Q, Ding JW, Leibowitz JL, Phillips MJ, Levy GA.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109929
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Response to Reactive Nitrogen Intermediates in Mycobacterium tuberculosis: Induction of the 16-Kilodalton [alpha]-Crystallin Homolog by Exposure to Nitric Oxide Donors. by Garbe TR, Hibler NS, Deretic V.; 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96338
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Resting and circadian release of nitric oxide is controlled by leptin in male rats. by Mastronardi CA, Yu WH, McCann SM.; 2002 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122838
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Revisiting the kinetics of nitric oxide (NO) binding to soluble guanylate cyclase: The simple NO-binding model is incorrect. by Ballou DP, Zhao Y, Brandish PE, Marletta MA.; 2002 Sep 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129404
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Role of metallothionein in nitric oxide signaling as revealed by a green fluorescent fusion protein. by Pearce LL, Gandley RE, Han W, Wasserloos K, Stitt M, Kanai AJ, McLaughlin MK, Pitt BR, Levitan ES.; 2000 Jan 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26688
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Role of Nitric Oxide in Eicosanoid Synthesis and Uterine Motility in EstrogenTreated Rat Uteri. by Franchi AM, Chaud M, Rettori V, Suburo A, McCann SM, Gimeno M.; 1994 Jan 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42984
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Role of Nitric Oxide in Host Defense in Murine Salmonellosis as a Function of Its Antibacterial and Antiapoptotic Activities. by Alam MS, Akaike T, Okamoto S, Kubota T, Yoshitake J, Sawa T, Miyamoto Y, Tamura F, Maeda H.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127959
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Role of Nitric Oxide in Lipopolysaccharide-Induced Hepatic Injury in dGalactosamine-Sensitized Mice as an Experimental Endotoxic Shock Model. by Morikawa A, Kato Y, Sugiyama T, Koide N, Chakravortty D, Yoshida T, Yokochi T.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96424
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Role of Nitric Oxide in the Enhancement of Pentylenetetrazole-Induced Seizures Caused by Shigella dysenteriae. by Balter-Seri J, Yuhas Y, Weizman A, Nofech-Mozes Y, Kaminsky E, Ashkenazi S.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97043
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Role of Nitric Oxide Synthase in the Light-Induced Development of Sporangiophores in Phycomyces blakesleeanus. by Maier J, Hecker R, Rockel P, Ninnemann H.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116489
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Role of p42 /p44 mitogen-activated-protein kinase and p21waf1/cip1 in the regulation of vascular smooth muscle cell proliferation by nitric oxide. by Bauer PM, Buga GM, Ignarro LJ.; 2001 Oct 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60134
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Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation. by Ignarro LJ, Buga GM, Wei LH, Bauer PM, Wu G, del Soldato P.; 2001 Mar 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31203
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Role of the NF-[kappa]B Signaling Pathway and [kappa]B cis-Regulatory Elements on the IRF-1 and iNOS Promoter Regions in Mycobacterial Lipoarabinomannan Induction of Nitric Oxide. by Morris KR, Lutz RD, Choi HS, Kamitani T, Chmura K, Chan ED.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=148845
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Salmonella typhimurium Infection in Mice Induces Nitric Oxide-Mediated Immunosuppression through a Natural Killer Cell-Dependent Pathway. by Schwacha MG, Meissler JJ Jr, Eisenstein TK.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108742
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Signal interactions between nitric oxide and reactive oxygen intermediates in the plant hypersensitive disease resistance response. by Delledonne M, Zeier J, Marocco A, Lamb C.; 2001 Nov 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60892
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Simulation of the Diffusion and Reaction of Endogeneously Produced Nitric Oxide. by Lancaster JR Jr.; 1994 Aug 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44560
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S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: Further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. by Leiper J, Murray-Rust J, McDonald N, Vallance P.; 2002 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129707
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S-Nitrosylation of Proteins with Nitric Oxide: Synthesis and Characterization of Biologically Active Compounds. by Stamler JS, Simon DI, Osborne JA, Mullins ME, Jaraki O, Michel T, Singel DJ, Loscalzo J.; 1992 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48254
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Soluble Factors Released by Toxoplasma gondii-Infected Astrocytes Down-Modulate Nitric Oxide Production by Gamma Interferon-Activated Microglia and Prevent Neuronal Degeneration. by Rozenfeld C, Martinez R, Figueiredo RT, Bozza MT, Lima FR, Pires AL, Silva PM, Bonomo A, Lannes-Vieira J, De Souza W, Moura-Neto V.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152043
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Stage-Dependent Role of Nitric Oxide in Control of Trypanosoma cruzi Infection. by Saeftel M, Fleischer B, Hoerauf A.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98153
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Staphylococcal exotoxins stimulate nitric oxide-dependent murine macrophage tumoricidal activity. by Fast DJ, Shannon BJ, Herriott MJ, Kennedy MJ, Rummage JA, Leu RW.; 1991 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=258123
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Staphylococcal glycocalyx activates macrophage prostaglandin E2 and interleukin 1 production and modulates tumor necrosis factor alpha and nitric oxide production. by Stout RD, Li Y, Miller AR, Lambe DW Jr.; 1994 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303091
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Stimulation of Nitric Oxide Production in Macrophages by Babesia bovis. by Stich RW, Shoda LK, Dreewes M, Adler B, Jungi TW, Brown WC.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108496
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Structural and biochemical studies of p21Ras S-nitrosylation and nitric oxidemediated guanine nucleotide exchange. by Williams JG, Pappu K, Campbell SL.; 2003 May 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164454
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T-Cell Hyporesponsiveness Induced by Activated Macrophages through Nitric Oxide Production in Mice Infected with Mycobacterium tuberculosis. by Nabeshima S, Nomoto M, Matsuzaki G, Kishihara K, Taniguchi H, Yoshida SI, Nomoto K.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116499
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Temporal effects of freezing on plasma nitric oxide concentrations in ponies. by Hubert JD, Seahorn TL, Klei TR, Hosgood G, Moore RM.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=227032
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Tests of the Roles of Two Diffusible Substances in Long-Term Potentiation: Evidence for Nitric Oxide as a Possible Early Retrograde Messenger. by O'Dell TJ, Hawkins RD, Kandel ER, Arancio O.; 1991 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53119
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Tetrahydrobiopterin-dependent preservation of nitric oxide --mediated endothelial function in diabetes by targeted transgenic GTP --cyclohydrolase I overexpression. by Alp NJ, Mussa S, Khoo J, Cai S, Guzik T, Jefferson A, Goh N, Rockett KA, Channon KM.; 2003 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=182196
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The biological lifetime of nitric oxide: Implications for the perivascular dynamics of NO and O2. by Thomas DD, Liu X, Kantrow SP, Lancaster JR Jr.; 2001 Jan 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14594
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The Cysteine-Cysteine Family of Chemokines RANTES, MIP-1[alpha], and MIP1[beta] Induce Trypanocidal Activity in Human Macrophages via Nitric Oxide. by Villalta F, Zhang Y, Bibb KE, Kappes JC, Lima MF.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108576
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The effect of nitric oxide on cell respiration: A key to understanding its role in cell survival or death. by Beltran B, Mathur A, Duchen MR, Erusalimsky JD, Moncada S.; 2000 Dec 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18965
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The heme-copper oxidases of Thermus thermophilus catalyze the reduction of nitric oxide: Evolutionary implications. by Giuffre A, Stubauer G, Sarti P, Brunori M, Zumft WG, Buse G, Soulimane T.; 1999 Dec 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24714
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The interaction of nitric oxide (NO) with the yeast transcription factor Ace1: A model system for NO-protein thiol interactions with implications to metal metabolism. by Shinyashiki M, Chiang KT, Switzer CH, Gralla EB, Valentine JS, Thiele DJ, Fukuto JM.; 2000 Mar 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15956
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The Killing of Leishmania major by Human Macrophages is Mediated by Nitric Oxide Induced after Ligation of the Fc[var epsilon]RII/CD23 Surface Antigen. by Vouldoukis I, Riveros-Moreno V, Dugas B, Ouaaz F, Becherel P, Debre P, Moncada S, Mossalayi MD.; 1995 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41234
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The macrophage-activating tetrapeptide tuftsin induces nitric oxide synthesis and stimulates murine macrophages to kill Leishmania parasites in vitro. by Cillari E, Arcoleo F, Dieli M, D'Agostino R, Gromo G, Leoni F, Milano S.; 1994 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=186561
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The oxyhemoglobin reaction of nitric oxide. by Gow AJ, Luchsinger BP, Pawloski JR, Singel DJ, Stamler JS.; 1999 Aug 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17726
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The quantity of nitric oxide released by macrophages regulates Chlamydia-induced disease. by Huang J, DeGraves FJ, Lenz SD, Gao D, Feng P, Li D, Schlapp T, Kaltenboeck B.; 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122623
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The reduction potential of nitric oxide (NO) and its importance to NO biochemistry. by Bartberger MD, Liu W, Ford E, Miranda KM, Switzer C, Fukuto JM, Farmer PJ, Wink DA, Houk KN.; 2002 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123192
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The Requirement of RpoN (Sigma Factor [final sigma]54) in Denitrification by Pseudomonas stutzeri Is Indirect and Restricted to the Reduction of Nitrite and Nitric Oxide. by Hartig E, Zumft WG.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106823
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The role of nitric oxide in experimental murine sepsis due to pyrogenic exotoxin Aproducing Streptococcus pyogenes. by Sriskandan S, Moyes D, Buttery LK, Wilkinson J, Evans TJ, Polak J, Cohen J.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175214
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The tumor necrosis factor alpha-stimulating region of galactose-inhibitable lectin of Entamoeba histolytica activates gamma interferon-primed macrophages for amebicidal activity mediated by nitric oxide. by Seguin R, Mann BJ, Keller K, Chadee K.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175356
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Therapeutic Effects of Nitric Oxide Inhibition during Experimental Fecal Peritonitis: Role of Interleukin-10 and Monocyte Chemoattractant Protein 1. by Hogaboam CM, Steinhauser ML, Schock H, Lukacs N, Strieter RM, Standiford T, Kunkel SL.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107952
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TNF-[alpha] induced endothelial MAdCAM-1 expression is regulated by exogenous, not endogenous nitric oxide. by Oshima T, Jordan P, Grisham MB, Alexander JS, Jennings M, Sasaki M, Manas K.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=35355
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Tonic Stimulation of Renin Gene Expression by Nitric Oxide is Counteracted by Tonic Inhibition Through Angiotensin II. by Schricker K, Hegyi I, Hamann M, Kaissling B, Kurtz A.; 1995 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41275
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Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. by Lee J, Ryu H, Ferrante RJ, Morris SM Jr, Ratan RR.; 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153643
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Truncated hemoglobin HbN protects Mycobacterium bovis from nitric oxide. by Ouellet H, Ouellet Y, Richard C, Labarre M, Wittenberg B, Wittenberg J, Guertin M.; 2002 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122874
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Tumor necrosis factor alpha augments nitric oxide-dependent macrophage cytotoxicity against Entamoeba histolytica by enhanced expression of the nitric oxide synthase gene. by Lin JY, Seguin R, Keller K, Chadee K.; 1994 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=186349
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Two isofunctional nitric oxide reductases in Alcaligenes eutrophus H16. by Cramm R, Siddiqui RA, Friedrich B.; 1997 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=179608
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Ubiquitination of inducible nitric oxide synthase is required for its degradation. by Kolodziejski PJ, Musial A, Koo JS, Eissa NT.; 2002 Sep 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129442
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Uncoupling protein 2 plays an important role in nitric oxide production of lipopolysaccharide-stimulated macrophages. by Kizaki T, Suzuki K, Hitomi Y, Taniguchi N, Saitoh D, Watanabe K, Onoe K, Day NK, Good RA, Ohno H.; 2002 Jul 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123151
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Up-regulation of inducible nitric oxide synthase expression in cancer-prone p53 knockout mice. by Ambs S, Ogunfusika MO, Merriam WG, Bennett WP, Billiar TR, Harris CC.; 1998 Jul 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21161
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Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension. by Fagan KA, Morrissey B, Fouty BW, Sato K, Harral JW, Morris KG Jr, Hoedt-Miller M, Vidmar S, McMurtry IF, Rodman DM.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59521
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Use of a Green Fluorescent Protein-Based Reporter Fusion for Detection of Nitric Oxide Produced by Denitrifiers. by Yin S, Fuangthong M, Laratta WP, Shapleigh JP.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165187
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Wild-Type Puumala Hantavirus Infection Induces Cytokines, C-Reactive Protein, Creatinine, and Nitric Oxide in Cynomolgus Macaques. by Klingstrom J, Plyusnin A, Vaheri A, Lundkvist A.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135710
The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with nitric oxide, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “nitric oxide” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for nitric oxide (hyperlinks lead to article summaries):
6
PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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A randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation. Author(s): Meade MO, Granton JT, Matte-Martyn A, McRae K, Weaver B, Cripps P, Keshavjee SH; Toronto Lung Transplant Program. Source: American Journal of Respiratory and Critical Care Medicine. 2003 June 1; 167(11): 1483-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12770854
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A review of the L-arginine - nitric oxide - guanylate cyclase pathway as a mediator of lower urinary tract physiology and symptoms. Author(s): Stothers L, Laher I, Christ GT. Source: Can J Urol. 2003 October; 10(5): 1971-80. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14633324
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A study of the efficacy of cervical ripening with nitric oxide donor versus placebo for cervical priming before second-trimester termination of pregnancy. Author(s): Li CF, Chan CW, Ho PC. Source: Contraception. 2003 October; 68(4): 269-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14572890
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Adjacent sequence controls the response polarity of nitric oxide-sensitive Sp factor binding sites. Author(s): Zhang J, Wang S, Wesley RA, Danner RL. Source: The Journal of Biological Chemistry. 2003 August 1; 278(31): 29192-200. Epub 2003 May 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12759366
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Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized, doubleblind, placebo-controlled multicenter study (study no. 144-002). Author(s): Bakker J, Grover R, McLuckie A, Holzapfel L, Andersson J, Lodato R, Watson D, Grossman S, Donaldson J, Takala J; Glaxo Wellcome International Septic Shock Study Group. Source: Critical Care Medicine. 2004 January; 32(1): 1-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14707554
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An AT1-receptor antagonist and an angiotensin-converting enzyme inhibitor protect against hypoxia-induced apoptosis in human aortic endothelial cells through upregulation of endothelial cell nitric oxide synthase activity. Author(s): Matsumoto N, Manabe H, Ochiai J, Fujita N, Takagi T, Uemura M, Naito Y, Yoshida N, Oka S, Yoshikawa T. Source: Shock (Augusta, Ga.). 2003 June; 19(6): 547-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12785010
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An investigation of nitric oxide metabolites during symptomatic myocardial ischaemia in relation to exercise tolerance test. Author(s): Elfatih A, Anderson NR, Mansoor S, Ahmed S, Horton R, Holland M, Gama R. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 December; 9(12): Cr511-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14646972
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Angiogenic actions of angiopoietin-1 require endothelium-derived nitric oxide. Author(s): Babaei S, Teichert-Kuliszewska K, Zhang Q, Jones N, Dumont DJ, Stewart DJ. Source: American Journal of Pathology. 2003 June; 162(6): 1927-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12759249
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Angiotensin II inhibits endothelial cell motility through an AT1-dependent oxidantsensitive decrement of nitric oxide availability. Author(s): Desideri G, Bravi MC, Tucci M, Croce G, Marinucci MC, Santucci A, Alesse E, Ferri C. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 July 1; 23(7): 1218-23. Epub 2003 May 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12763763
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Antiangiogenic properties of selected ruthenium(III) complexes that are nitric oxide scavengers. Author(s): Morbidelli L, Donnini S, Filippi S, Messori L, Piccioli F, Orioli P, Sava G, Ziche M. Source: British Journal of Cancer. 2003 May 6; 88(9): 1484-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12778081
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Antibody-mediated endothelial cell damage via nitric oxide. Author(s): Lin YS, Lin CF, Lei HY, Liu HS, Yeh TM, Chen SH, Liu CC. Source: Current Pharmaceutical Design. 2004; 10(2): 213-21. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14754400
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Anti-inflammatory compounds of plant origin. Part I. Action on arachidonic acid pathway, nitric oxide and nuclear factor kappa B (NF-kappaB). Author(s): Calixto JB, Otuki MF, Santos AR. Source: Planta Medica. 2003 November; 69(11): 973-83. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14735432
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APOE genotype-specific differences in human and mouse macrophage nitric oxide production. Author(s): Colton CA, Needham LK, Brown C, Cook D, Rasheed K, Burke JR, Strittmatter WJ, Schmechel DE, Vitek MP. Source: Journal of Neuroimmunology. 2004 February; 147(1-2): 62-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14741429
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Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Author(s): Sharshar T, Gray F, Lorin de la Grandmaison G, Hopkinson NS, Ross E, Dorandeu A, Orlikowski D, Raphael JC, Gajdos P, Annane D. Source: Lancet. 2003 November 29; 362(9398): 1799-805. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14654318
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Arteriogenesis: role of nitric oxide. Author(s): Prior BM, Lloyd PG, Ren J, Li Z, Yang HT, Laughlin MH, Terjung RL. Source: Endothelium : Journal of Endothelial Cell Research. 2003; 10(4-5): 207-16. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14660080
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Association analysis for neuronal nitric oxide synthase gene polymorphism with major depression and fluoxetine response. Author(s): Yu YW, Chen TJ, Wang YC, Liou YJ, Hong CJ, Tsai SJ. Source: Neuropsychobiology. 2003; 47(3): 137-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12759556
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Association of a 27-bp repeat polymorphism in intron 4 of endothelial constitutive nitric oxide synthase gene with serum uric acid levels in Chinese subjects with type 2 diabetes. Author(s): Lee YJ, Chang DM, Tsai JC. Source: Metabolism: Clinical and Experimental. 2003 November; 52(11): 1448-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624405
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Association of endothelial constitutive nitric oxide synthase gene polymorphism with acute coronary syndrome in Koreans. Author(s): Park KW, You KH, Oh S, Chae IH, Kim HS, Oh BH, Lee MM, Park YB. Source: Heart (British Cardiac Society). 2004 March; 90(3): 282-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14966047
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Association of expired nitric oxide with urinary metal concentrations in boilermakers exposed to residual oil fly ash. Author(s): Kim JY, Hauser R, Wand MP, Herrick RF, Houk RS, Aeschliman DB, Woodin MA, Christiani DC. Source: American Journal of Industrial Medicine. 2003 November; 44(5): 458-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14571509
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Astrovirus-induced synthesis of nitric oxide contributes to virus control during infection. Author(s): Koci MD, Kelley LA, Larsen D, Schultz-Cherry S. Source: Journal of Virology. 2004 February; 78(3): 1564-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722310
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Basal and nitroglycerin-induced exhaled nitric oxide before and after cardiac surgery with cardiopulmonary bypass. Author(s): Kovesi T, Royston D, Yacoub M, Marczin N. Source: British Journal of Anaesthesia. 2003 May; 90(5): 608-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12697588
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Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontantype operation. Author(s): Khambadkone S, Li J, de Leval MR, Cullen S, Deanfield JE, Redington AN. Source: Circulation. 2003 July 1; 107(25): 3204-8. Epub 2003 June 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12821557
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Basal serum nitric oxide levels in patients with type 2 diabetes mellitus and different stages of retinopathy. Author(s): Ozden S, Tatlipinar S, Bicer N, Yaylali V, Yildirim C, Ozbay D, Guner G. Source: Can J Ophthalmol. 2003 August; 38(5): 393-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12956281
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BAY41-2272, a novel nitric oxide independent soluble guanylate cyclase activator, relaxes human and rabbit corpus cavernosum in vitro. Author(s): Kalsi JS, Rees RW, Hobbs AJ, Royle M, Kell PD, Ralph DJ, Moncada S, Cellek S. Source: The Journal of Urology. 2003 February; 169(2): 761-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12544359
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Beauty and the beast. The nitric oxide paradox in systemic sclerosis. Author(s): Matucci Cerinic M, Kahaleh MB. Source: Rheumatology (Oxford, England). 2002 August; 41(8): 843-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12154200
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Behcet's disease and nitric oxide production. Author(s): Kocak M, Erbas D, Karabulut AA, Ozturk G, Eksioglu M. Source: International Journal of Dermatology. 2003 March; 42(3): 244-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12653926
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Bench-to-bedside review: microvascular dysfunction in sepsis--hemodynamics, oxygen transport, and nitric oxide. Author(s): Bateman RM, Sharpe MD, Ellis CG. Source: Critical Care (London, England). 2003 October; 7(5): 359-73. Epub 2003 July 28. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12974969
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Beneficial clinical effects of perhexiline in patients with stable angina pectoris and acute coronary syndromes are associated with potentiation of platelet responsiveness to nitric oxide. Author(s): Willoughby SR, Stewart S, Chirkov YY, Kennedy JA, Holmes AS, Horowitz JD. Source: European Heart Journal. 2002 December; 23(24): 1946-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12473257
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Beta(2)-adrenergic receptor polymorphism and nitric oxide-dependent forearm blood flow responses to isoproterenol in humans. Author(s): Garovic VD, Joyner MJ, Dietz NM, Boerwinkle E, Turner ST. Source: The Journal of Physiology. 2003 January 15; 546(Pt 2): 583-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12527744
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Beyond lipid-lowering: effects of statins on endothelial nitric oxide. Author(s): Laufs U. Source: European Journal of Clinical Pharmacology. 2003 March; 58(11): 719-31. Epub 2003 February 18. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634978
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Biglycan, a nitric oxide-regulated gene, affects adhesion, growth, and survival of mesangial cells. Author(s): Schaefer L, Beck KF, Raslik I, Walpen S, Mihalik D, Micegova M, Macakova K, Schonherr E, Seidler DG, Varga G, Schaefer RM, Kresse H, Pfeilschifter J. Source: The Journal of Biological Chemistry. 2003 July 11; 278(28): 26227-37. Epub 2003 April 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12719420
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Biochemical characterization of the arginine degrading enzymes arginase and arginine deiminase and their effect on nitric oxide production. Author(s): Dillon BJ, Holtsberg FW, Ensor CM, Bomalaski JS, Clark MA. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2002 July; 8(7): Br248-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12118186
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Biochemical targets of nitric oxide-induced toxicity. Author(s): Grudzinski IP. Source: Rocz Panstw Zakl Hig. 2003; 54(1): 1-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12870292
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Black rice (Oryza sativa L. indica) pigmented fraction suppresses both reactive oxygen species and nitric oxide in chemical and biological model systems. Author(s): Hu C, Zawistowski J, Ling W, Kitts DD. Source: Journal of Agricultural and Food Chemistry. 2003 August 27; 51(18): 5271-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12926869
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Blockade of NF-kappaB activation and donation of nitric oxide: new treatment options in inflammatory bowel disease? Author(s): Dijkstra G, Moshage H, Jansen PL. Source: Scandinavian Journal of Gastroenterology. Supplement. 2002; (236): 37-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12408502
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Blood serum and neutrophil L-arginine concentrations and nitric oxide release by neutrophils in chronic uremic patients and healthy persons. Author(s): Rysz J, Guga P, Grycewicz T, Mudyna J, Luciak M. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 July; 9(7): Cr311-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883450
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Both inflammation and remodeling influence nitric oxide output in children with refractory asthma. Author(s): Mahut B, Delclaux C, Tillie-Leblond I, Gosset P, Delacourt C, Zerah-Lancner F, Harf A, de Blic J. Source: The Journal of Allergy and Clinical Immunology. 2004 February; 113(2): 252-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14767438
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Brain in the brawn: the neuronal nitric oxide synthase as a regulator of myogenic tone. Author(s): Fleming I. Source: Circulation Research. 2003 October 3; 93(7): 586-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14525919
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Branched chain fatty acids induce nitric oxide-dependent apoptosis in vascular smooth muscle cells. Author(s): Idel S, Ellinghaus P, Wolfrum C, Nofer JR, Gloerich J, Assmann G, Spener F, Seedorf U. Source: The Journal of Biological Chemistry. 2002 December 20; 277(51): 49319-25. Epub 2002 October 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12368296
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Butanolides from Machilus thunbergii and their inhibitory activity on nitric oxide synthesis in activated macrophages. Author(s): Kim NY, Ryu JH. Source: Phytotherapy Research : Ptr. 2003 April; 17(4): 372-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12722143
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Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Author(s): Kielstein JT, Impraim B, Simmel S, Bode-Boger SM, Tsikas D, Frolich JC, Hoeper MM, Haller H, Fliser D. Source: Circulation. 2004 January 20; 109(2): 172-7. Epub 2003 December 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14662708
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Cardiovascular effects of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) in patients with septic shock: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002). Author(s): Watson D, Grover R, Anzueto A, Lorente J, Smithies M, Bellomo R, Guntupalli K, Grossman S, Donaldson J, Le Gall JR; Glaxo Wellcome International Septic Shock Study Group. Source: Critical Care Medicine. 2004 January; 32(1): 13-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14707555
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Chain-breaking antioxidant and cytoprotective action of nitric oxide on photodynamically stressed tumor cells. Author(s): Niziolek M, Korytowski W, Girotti AW. Source: Photochemistry and Photobiology. 2003 September; 78(3): 262-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14556313
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Changes in circulating levels of calcitonin gene-related peptide and nitric oxide metabolites in septic patients during direct hemoperfusion with polymyxin Bimmobilized fiber. Author(s): Shimizu T, Hanasawa K, Tani T, Endo Y, Kurumi Y, Ikeda T, Fujita N, Morita H, Imaizumi H, Sato T, Katayama H. Source: Blood Purification. 2003; 21(3): 237-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12784050
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Characterization of cationic amino acid transporters and expression of endothelial nitric oxide synthase in human placental microvascular endothelial cells. Author(s): Dye JF, Vause S, Johnston T, Clark P, Firth JA, D'Souza SW, Sibley CP, Glazier JD. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2004 January; 18(1): 125-7. Epub 2003 November 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14597568
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Circulating nitric oxide levels increase after anti-androgen treatment in male-tofemale transsexuals. Author(s): Valenti S, Fazzuoli L, Giusti M. Source: J Endocrinol Invest. 2003 June; 26(6): 522-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12952365
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c-Jun N-terminal kinase and, to a lesser extent, p38 mitogen-activated protein kinase regulate inducible nitric oxide synthase expression in hyaluronan fragmentsstimulated BV-2 microglia. Author(s): Wang MJ, Jeng KC, Kuo JS, Chen HL, Huang HY, Chen WF, Lin SZ. Source: Journal of Neuroimmunology. 2004 January; 146(1-2): 50-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14698847
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Clinical course of cardiomyopathy in HIV-infected patients with or without encephalopathy related to the myocardial expression of tumour necrosis factor-alpha and nitric oxide synthase. Author(s): Levy JA, Autran B, Coutinho R, Phair JP; GISCA. Source: Aids (London, England). 2003 May 23; 17(8): 1119. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12819511
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Combined loss of neuronal and endothelial nitric oxide synthase causes premature mortality and age-related hypertrophic cardiac remodeling in mice. Author(s): Barouch LA, Cappola TP, Harrison RW, Crone JK, Rodriguez ER, Burnett AL, Hare JM. Source: Journal of Molecular and Cellular Cardiology. 2003 June; 35(6): 637-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12788381
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Comparisons of the complementary effect on exhaled nitric oxide of salmeterol vs montelukast in asthmatic children taking regular inhaled budesonide. Author(s): Buchvald F, Bisgaard H. Source: Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology. 2003 September; 91(3): 309-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14533665
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Concomitant production of nitric oxide and superoxide in human macrophages. Author(s): Juliet PA, Hayashi T, Iguchi A, Ignarro LJ. Source: Biochemical and Biophysical Research Communications. 2003 October 17; 310(2): 367-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14521919
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Conjugated linoleic acids lower the release of eicosanoids and nitric oxide from human aortic endothelial cells. Author(s): Eder K, Schleser S, Becker K, Korting R. Source: The Journal of Nutrition. 2003 December; 133(12): 4083-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14652352
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Control of neuronal nitric oxide synthase and brain-derived neurotrophic factor levels by GABA-A receptors in the developing rat cortex. Author(s): Mantelas A, Stamatakis A, Kazanis I, Philippidis H, Stylianopoulou F. Source: Brain Research. Developmental Brain Research. 2003 November 12; 145(2): 18595. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14604759
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Control of respiration by nitric oxide in Keilin-Hartree particles, mitochondria and SH-SY5Y neuroblastoma cells. Author(s): Mastronicola D, Genova ML, Arese M, Barone MC, Giuffre A, Bianchi C, Brunori M, Lenaz G, Sarti P. Source: Cellular and Molecular Life Sciences : Cmls. 2003 August; 60(8): 1752-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14504660
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Correlated expression of inducible nitric oxide synthase and P53, Bax in benign and malignant diseased gallbladder. Author(s): Zhang M, Pan JW, Ren TR, Zhu YF, Han YJ, Kuhnel W. Source: Ann Anat. 2003 December; 185(6): 549-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704000
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Cost-effectiveness of inhaled nitric oxide in the treatment of neonatal respiratory failure in the United States. Author(s): Angus DC, Clermont G, Watson RS, Linde-Zwirble WT, Clark RH, Roberts MS. Source: Pediatrics. 2003 December; 112(6 Pt 1): 1351-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14654609
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Cost-effectiveness of inhaled nitric oxide in the treatment of neonatal respiratory failure in the US. Author(s): Field D, Normand C, Elbourne D. Source: Pediatrics. 2003 December; 112(6 Pt 1): 1422-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14654622
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Cough frequency in children with stable asthma: correlation with lung function, exhaled nitric oxide, and sputum eosinophil count. Author(s): Li AM, Lex C, Zacharasiewicz A, Wong E, Erin E, Hansel T, Wilson NM, Bush A. Source: Thorax. 2003 November; 58(11): 974-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14586052
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C-peptide increases forearm blood flow in patients with type 1 diabetes via a nitric oxide-dependent mechanism. Author(s): Johansson BL, Wahren J, Pernow J. Source: American Journal of Physiology. Endocrinology and Metabolism. 2003 October; 285(4): E864-70. Epub 2003 June 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12799312
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Decreased haem oxygenase-1 and increased inducible nitric oxide synthase in the lung of severe COPD patients. Author(s): Maestrelli P, Paska C, Saetta M, Turato G, Nowicki Y, Monti S, Formichi B, Miniati M, Fabbri LM. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 June; 21(6): 971-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12797490
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Dehydroepiandrosterone modulates endothelial nitric oxide synthesis via direct genomic and nongenomic mechanisms. Author(s): Simoncini T, Mannella P, Fornari L, Varone G, Caruso A, Genazzani AR. Source: Endocrinology. 2003 August; 144(8): 3449-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865324
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Depletion of endogenous nitric oxide enhances cisplatin-induced apoptosis in a p53dependent manner in melanoma cell lines. Author(s): Tang CH, Grimm EA. Source: The Journal of Biological Chemistry. 2004 January 2; 279(1): 288-98. Epub 2003 October 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14576150
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Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. Author(s): Smith AD, Cowan JO, Filsell S, McLachlan C, Monti-Sheehan G, Jackson P, Taylor DR. Source: American Journal of Respiratory and Critical Care Medicine. 2004 February 15; 169(4): 473-8. Epub 2003 November 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14644933
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Differences in the effects of extended-release aspirin and plain-formulated aspirin on prostanoids and nitric oxide in healthy volunteers. Author(s): De La Cruz JP, Gonzalez-Correa JA, Guerrero A, Marquez E, Martos F, Sanchez De La Cuesta F. Source: Fundamental & Clinical Pharmacology. 2003 June; 17(3): 363-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12803576
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Different populations of tyrosine-hydroxylase-immunoreactive neurons defined by differential expression of nitric oxide synthase in the human temporal cortex. Author(s): Benavides-Piccione R, DeFelipe J. Source: Cerebral Cortex (New York, N.Y. : 1991). 2003 March; 13(3): 297-307. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12571119
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Differential biological effects of products of nitric oxide (NO) synthase: it is not enough to say NO. Author(s): Pagliaro P. Source: Life Sciences. 2003 September 12; 73(17): 2137-49. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12927585
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Differential effect of nitric oxide synthase inhibition on sigmoid colon longitudinal and circular muscle responses to nicotine and nerve stimulation in vitro. Author(s): McKirdy HC, Richardson CE, Green JT, Rhodes J, Williams GT, Marshall RW. Source: The British Journal of Surgery. 2004 February; 91(2): 229-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14760673
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Differential expression of inducible nitric oxide synthase and peroxisome proliferator-activated receptor gamma in non-small cell lung carcinoma. Author(s): Lee TW, Chen GG, Xu H, Yip JH, Chak EC, Mok TS, Yim AP. Source: European Journal of Cancer (Oxford, England : 1990). 2003 June; 39(9): 1296-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12763220
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Differential interleukin-8 and nitric oxide production in epithelial cells induced by mucosally invasive and noninvasive Trypanosoma cruzi trypomastigotes. Author(s): Eickhoff CS, Eckmann L, Hoft DF. Source: Infection and Immunity. 2003 September; 71(9): 5394-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12933891
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Differential regulation of xanthine and NAD(P)H oxidase by hypoxia in human umbilical vein endothelial cells. Role of nitric oxide and adenosine. Author(s): Sohn HY, Krotz F, Gloe T, Keller M, Theisen K, Klauss V, Pohl U. Source: Cardiovascular Research. 2003 June 1; 58(3): 638-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798437
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Differing roles of mitochondrial nitric oxide synthase in cardiomyocytes and urothelial cells. Author(s): Kanai A, Epperly M, Pearce L, Birder L, Zeidel M, Meyers S, Greenberger J, de Groat W, Apodaca G, Peterson J. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2004 January; 286(1): H13-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684357
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Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Author(s): Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger MC, Wang BY, Tsao PS, Kimoto M, Vallance P, Patterson AJ, Cooke JP. Source: Circulation. 2003 December 16; 108(24): 3042-7. Epub 2003 November 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638548
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Does endothelial nitric oxide synthase gene variation play a role in the occurrence of hypertension in pregnancy? Author(s): Grandone E, Colaizzo D, Martinelli P, Pavone G, Errico M, Vecchione G, Margaglione M. Source: Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hypertension in Pregnancy. 2003; 22(2): 149-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12908999
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Does interplay between nitric oxide and mitochondria affect hypoxia-inducible transcription factor-1 activity? Author(s): Murphy MP. Source: The Biochemical Journal. 2003 December 1; 376(Pt 2): E5-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627433
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Down-regulation of nitric oxide production by droloxifene and toremifene in human breast cancer cells. Author(s): Martin JH, Symonds A, Chohan S. Source: Oncol Rep. 2003 July-August; 10(4): 979-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12792756
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Down-regulation of nitric oxide synthase-2 and cyclooxygenase-2 pathways by p53 in squamous cell carcinoma. Author(s): Gallo O, Schiavone N, Papucci L, Sardi I, Magnelli L, Franchi A, Masini E, Capaccioli S. Source: American Journal of Pathology. 2003 August; 163(2): 723-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12875991
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DPPH radical scavenging and nitric oxide inhibitory activities of the constituents from the wood of Taxus yunnanensis. Author(s): Banskota AH, Tezuka Y, Nguyen NT, Awale S, Nobukawa T, Kadota S. Source: Planta Medica. 2003 June; 69(6): 500-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865966
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Drugs that activate specific nitric oxide sensitive guanylyl cyclase isoforms independent of nitric oxide release. Author(s): Behrends S. Source: Current Medicinal Chemistry. 2003 February; 10(4): 291-301. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12570702
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Dysregulation of endogenous carbon monoxide and nitric oxide production in patients with advanced ischemic or nonischemic cardiomyopathy. Author(s): Seshadri N, Dweik RA, Laskowski D, Pothier C, Rodriguez L, Young JB, Migrino RQ. Source: The American Journal of Cardiology. 2003 October 1; 92(7): 820-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14516883
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Effect of glycaemic control on the vascular nitric oxide system in patients with type 1 diabetes. Author(s): Rodriguez-Manas L, Lopez-Doriga P, Petidier R, Neira M, Solis J, Pavon I, Peiro C, Sanchez-Ferrer CF. Source: Journal of Hypertension. 2003 June; 21(6): 1137-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12777950
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Effect of nitric oxide-donating agents on human monocyte cyclooxygenase-2. Author(s): Corazzi T, Leone M, Roberti R, Del Soldato P, Gresele P. Source: Biochemical and Biophysical Research Communications. 2003 November 28; 311(4): 897-903. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14623265
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Effects of brief ischemia and reperfusion on the myocardium and the role of nitric oxide. Author(s): Baker CS, Kumar S, Rimoldi OE. Source: Heart Failure Reviews. 2003 April; 8(2): 127-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766492
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Effects of expiratory pressure on nitric oxide in exhaled breath. Is exhaled nitric oxide really unaffected by pressure? Author(s): Kondo R, Haniuda M, Yamanda T, Sato E, Fujimoto K, Kubo K, Amano J. Source: Respiratory Physiology & Neurobiology. 2003 December 16; 139(1): 33-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14637308
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Effects of hypoxia and nitric oxide on ferritin content of alveolar cells. Author(s): Smith JJ, O'Brien-Ladner AR, Kaiser CR, Wesselius LJ. Source: The Journal of Laboratory and Clinical Medicine. 2003 May; 141(5): 309-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12761474
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Effects of mifepristone on expression of endothelial nitric oxide synthase in human endometrium during the implantation phase. Author(s): Sun X, Qiu X, Gemzell-Danielsson K. Source: Fertility and Sterility. 2003 December; 80(6): 1454-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14667883
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Endothelial dysfunction and alteration of nitric oxide/ cyclic GMP pathway in patients with exercise-induced hypertension. Author(s): Chang HJ, Chung JH, Choi BJ, Choi TY, Choi SY, Yoon MH, Hwang GS, Shin JH, Tahk SJ, Choi BI. Source: Yonsei Medical Journal. 2003 December 30; 44(6): 1014-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14703610
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Endurance training enhances vasodilation induced by nitric oxide in human skin. Author(s): Boegli Y, Gremion G, Golay S, Kubli S, Liaudet L, Leyvraz PF, Waeber B, Feihl F. Source: The Journal of Investigative Dermatology. 2003 November; 121(5): 1197-204. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14708626
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Exhaled nitric oxide and asthma: complex interactions between atopy, airway responsiveness, and symptoms in a community population of children. Author(s): Franklin PJ, Turner SW, Le Souef PN, Stick SM. Source: Thorax. 2003 December; 58(12): 1048-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645971
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Exhaled nitric oxide and cardiac surgery with extracorporeal circulation. Author(s): Marczin N. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 November; 126(5): 1673-4; Author Reply 1674-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14666068
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Exhaled nitric oxide in chronically ventilated preterm infants. Author(s): Williams O, Bhat RY, Cheeseman P, Rafferty GF, Hannam S, Greenough A. Source: Archives of Disease in Childhood. Fetal and Neonatal Edition. 2004 January; 89(1): F88-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14711866
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Exhaled nitric oxide in pathophysiologic states: the substance behind the gas. Author(s): Beilman G. Source: Chest. 2004 January; 125(1): 11-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14718413
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Exhaled nitric oxide in the assessment of asthma. Author(s): Zeidler MR, Kleerup EC, Tashkin DP. Source: Current Opinion in Pulmonary Medicine. 2004 January; 10(1): 31-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14749603
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Exhaled nitric oxide is highly increased in a case of Hodgkin's disease. Author(s): Holmkvist T, Erlanson M, Merilainen P, Hogman M. Source: Acta Oncologica (Stockholm, Sweden). 2003; 42(7): 788-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14690167
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Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma. Author(s): Malmberg LP, Pelkonen AS, Haahtela T, Turpeinen M. Source: Thorax. 2003 June; 58(6): 494-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12775859
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Explaining decreased nitric oxide production in psoriatic lesions: arginase 1 overexpression versus calcitonin gene-related peptide. Author(s): Namazi MR. Source: American Journal of Pathology. 2003 December; 163(6): 2642; Author Reply 2642-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14633638
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Expression of a muscle-specific, nitric oxide synthase transgene prevents muscle membrane injury and reduces muscle inflammation during modified muscle use in mice. Author(s): Nguyen HX, Tidball JG. Source: The Journal of Physiology. 2003 July 15; 550(Pt 2): 347-56. Epub 2003 May 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766242
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Expression of inducible nitric oxide synthase in cutaneous adnexal tumours of the head and neck. Author(s): Umar T, Bowden J, Cameron S, Willy PJ, Anand R, Baker AW, Ilankoran V, Brennan PA. Source: International Journal of Oral and Maxillofacial Surgery. 2003 October; 32(5): 5348. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14759114
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Expression of nitric oxide synthase immunoreactivity in the human female intramural striated urethral sphincter. Author(s): Ho KM, Borja MC, Persson K, Brading AF, Andersson KE. Source: The Journal of Urology. 2003 June; 169(6): 2407-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12771807
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Expression of NOS1 and soluble guanylyl cyclase by human kidney epithelial cells: morphological evidence for an autocrine/paracrine action of nitric oxide. Author(s): Jarry A, Renaudin K, Denis MG, Robard M, Buffin-Meyer B, Karam G, Buzelin F, Paris H, Laboisse CL, Vallette G. Source: Kidney International. 2003 July; 64(1): 170-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12787407
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F blast production correlates strongly with upregulation of inducible nitric oxide synthase in myelodysplastic syndromes. Author(s): Choi JW, Kim Y, Fujino M, Ito M. Source: Annals of Hematology. 2002 September; 81(9): 548-50. Epub 2002 September 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12373361
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Fasting plasma nitric oxide products in coeliac disease. Author(s): Murray IA, Bullimore DW, Long RG. Source: European Journal of Gastroenterology & Hepatology. 2003 October; 15(10): 10915. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14501617
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Flavohemoglobin Hmp protects Salmonella enterica serovar typhimurium from nitric oxide-related killing by human macrophages. Author(s): Stevanin TM, Poole RK, Demoncheaux EA, Read RC. Source: Infection and Immunity. 2002 August; 70(8): 4399-405. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12117950
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Follicular fluid adrenomedullin concentrations in spontaneous and stimulated cycles: relationship to ovarian function and endothelin-1 and nitric oxide. Author(s): Marinoni E, Di Iorio R, Villaccio B, Letizia C, Aragona C, Schimberni M, Cosmi EV. Source: Regulatory Peptides. 2002 July 15; 107(1-3): 125-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12137974
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Formation of nitrosothiols from gaseous nitric oxide at pH 7.4. Author(s): Palmerini CA, Saccardi C, Arienti G, Palombari R. Source: Journal of Biochemical and Molecular Toxicology. 2002; 16(3): 135-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12112713
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Formation of reactive nitrogen species at biologic heme centers: a potential mechanism of nitric oxide-dependent toxicity. Author(s): Casella L, Monzani E, Roncone R, Nicolis S, Sala A, De Riso A. Source: Environmental Health Perspectives. 2002 October; 110 Suppl 5: 709-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12426117
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Free nitric oxide diffusion in the bronchial microcirculation. Author(s): Condorelli P, George SC. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2002 December; 283(6): H2660-70. Epub 2002 August 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12388292
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Free radical and nitric oxide toxicity in Parkinson's disease. Author(s): Przedborski S, Jackson-Lewis V, Vila M, Wu du C, Teismann P, Tieu K, Choi DK, Cohen O. Source: Adv Neurol. 2003; 91: 83-94. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12442666
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From nitric oxide to endothelial cytosolic Ca2+: a negative feedback control. Author(s): Yao X, Huang Y. Source: Trends in Pharmacological Sciences. 2003 June; 24(6): 263-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12823948
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Function and regulation of mitochondrially produced nitric oxide in cardiomyocytes. Author(s): Kanai A, Peterson J. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2004 January; 286(1): H11-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684356
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Functional characterization of Glu298Asp mutant human endothelial nitric oxide synthase purified from a yeast expression system. Author(s): Golser R, Gorren AC, Mayer B, Schmidt K. Source: Nitric Oxide : Biology and Chemistry / Official Journal of the Nitric Oxide Society. 2003 February; 8(1): 7-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12586536
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Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure. Author(s): Dixon LJ, Morgan DR, Hughes SM, McGrath LT, El-Sherbeeny NA, Plumb RD, Devine A, Leahey W, Johnston GD, McVeigh GE. Source: Circulation. 2003 April 8; 107(13): 1725-8. Epub 2003 March 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12665482
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Functional expression of endothelial nitric oxide synthase fused to green fluorescent protein in transgenic mice. Author(s): van Haperen R, Cheng C, Mees BM, van Deel E, de Waard M, van Damme LC, van Gent T, van Aken T, Krams R, Duncker DJ, de Crom R. Source: American Journal of Pathology. 2003 October; 163(4): 1677-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14507674
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Functional interaction of endothelial nitric oxide synthase with a voltage-dependent anion channel. Author(s): Sun J, Liao JK. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 October 1; 99(20): 13108-13. Epub 2002 September 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12228731
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Functional interplay between angiotensin II and nitric oxide: cyclic GMP as a key mediator. Author(s): Yan C, Kim D, Aizawa T, Berk BC. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 January 1; 23(1): 26-36. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12524221
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Functional roles of nasal nitric oxide in nasal patency and mucociliary function. Author(s): Imada M, Nonaka S, Kobayashi Y, Iwamoto J. Source: Acta Oto-Laryngologica. 2002 July; 122(5): 513-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12206261
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G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Author(s): Federici M, Pandolfi A, De Filippis EA, Pellegrini G, Menghini R, Lauro D, Cardellini M, Romano M, Sesti G, Lauro R, Consoli A. Source: Circulation. 2004 January 27; 109(3): 399-405. Epub 2004 Jan 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14707024
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Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans. Author(s): Hawkey CJ, Jones JI, Atherton CT, Skelly MM, Bebb JR, Fagerholm U, Jonzon B, Karlsson P, Bjarnason IT. Source: Gut. 2003 November; 52(11): 1537-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14570719
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Gene expression of nitric oxide synthase by human umbilical vein endothelial cells: the effect of fetal plasma from pregnancy with umbilical placental vascular disease. Author(s): Wang X, Wang J, Trudinger B. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2003 January; 110(1): 53-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12504936
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Gene polymorphisms of endothelial nitric oxide synthase enzyme associated with pulmonary hypertension in patients with COPD. Author(s): Yildiz P, Oflaz H, Cine N, Erginel-Unaltuna N, Erzengin F, Yilmaz V. Source: Respiratory Medicine. 2003 December; 97(12): 1282-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14682408
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Gene therapy with inducible nitric oxide synthase protects against myocardial infarction via a cyclooxygenase-2-dependent mechanism. Author(s): Li Q, Guo Y, Xuan YT, Lowenstein CJ, Stevenson SC, Prabhu SD, Wu WJ, Zhu Y, Bolli R. Source: Circulation Research. 2003 April 18; 92(7): 741-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12702642
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Genes, nitric oxide and malaria in African children. Author(s): Clark IA, Rockett KA, Burgner D. Source: Trends in Parasitology. 2003 August; 19(8): 335-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12901931
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Genetic and environmental contributions to severe preeclampsia: lack of association with the endothelial nitric oxide synthase Glu298Asp variant in a developing country. Author(s): Yoshimura T, Chowdhury FA, Yoshimura M, Okamura H. Source: Gynecologic and Obstetric Investigation. 2003; 56(1): 10-3. Epub 2003 July 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12867761
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Genetic evidence that nitric oxide modulates homocysteine: the NOS3 894TT genotype is a risk factor for hyperhomocystenemia. Author(s): Brown KS, Kluijtmans LA, Young IS, Woodside J, Yarnell JW, McMaster D, Murray L, Evans AE, Boreham CA, McNulty H, Strain JJ, Mitchell LE, Whitehead AS. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 June 1; 23(6): 1014-20. Epub 2003 April 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12689917
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Genetic variants of endothelial nitric oxide synthase in patients with primary biliary cirrhosis: association with disease severity. Author(s): Selmi C, Zuin M, Biondi ML, Invernizzi P, Battezzati PM, Bernini M, Meda F, Gershwin ME, Podda M. Source: Journal of Gastroenterology and Hepatology. 2003 October; 18(10): 1150-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12974901
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Genotype-specific influence on nitric oxide synthase gene expression, protein concentrations, and enzyme activity in cultured human endothelial cells. Author(s): Song J, Yoon Y, Park KU, Park J, Hong YJ, Hong SH, Kim JQ. Source: Clinical Chemistry. 2003 June; 49(6 Pt 1): 847-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12765978
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Ginseng, sex behavior, and nitric oxide. Author(s): Murphy LL, Lee TJ. Source: Annals of the New York Academy of Sciences. 2002 May; 962: 372-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12076988
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Gleditsia sinensis fruit extract induced growth inhibition involves basic fibroblast growth factor and nitric oxide. Author(s): Chui CH, Tang JC, Lau FY, Teo IT, Yau MY, Wong RS, Cheng GY, Ho SK, Leung TW, Hui KS, Wong MM, Fatima S, Cheng CH, Cheung F, Tan WQ, Chow LM, Guo D, Chan AS. Source: International Journal of Molecular Medicine. 2004 January; 13(1): 169-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14654990
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Global loss of Na,K-ATPase and its nitric oxide-mediated regulation in a transgenic mouse model of amyotrophic lateral sclerosis. Author(s): Ellis DZ, Rabe J, Sweadner KJ. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2003 January 1; 23(1): 43-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12514200
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Glutamate and nitric oxide pathway in chronic daily headache: evidence from cerebrospinal fluid. Author(s): Gallai V, Alberti A, Gallai B, Coppola F, Floridi A, Sarchielli P. Source: Cephalalgia : an International Journal of Headache. 2003 April; 23(3): 166-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12662182
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Glypican-1 is a vehicle for polyamine uptake in mammalian cells: a pivital role for nitrosothiol-derived nitric oxide. Author(s): Belting M, Mani K, Jonsson M, Cheng F, Sandgren S, Jonsson S, Ding K, Delcros JG, Fransson LA. Source: The Journal of Biological Chemistry. 2003 November 21; 278(47): 47181-9. Epub 2003 September 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12972423
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Growth hormone induces eNOS expression and nitric oxide release in a cultured human endothelial cell line. Author(s): Thum T, Tsikas D, Frolich JC, Borlak J. Source: Febs Letters. 2003 December 18; 555(3): 567-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675775
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Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and beta-catenin/T-cell factor signaling, nuclear factor-kappaB, and NO synthase 2 inhibition: implications for chemoprevention. Author(s): Williams JL, Nath N, Chen J, Hundley TR, Gao J, Kopelovich L, Kashfi K, Rigas B. Source: Cancer Research. 2003 November 15; 63(22): 7613-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14633677
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Guanylyl cyclase is an ATP sensor coupling nitric oxide signaling to cell metabolism. Author(s): Ruiz-Stewart I, Tiyyagura SR, Lin JE, Kazerounian S, Pitari GM, Schulz S, Martin E, Murad F, Waldman SA. Source: Proceedings of the National Academy of Sciences of the United States of America. 2004 January 6; 101(1): 37-42. Epub 2003 December 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684830
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Guanylyl cyclases, nitric oxide, natriuretic peptides, and airway smooth muscle function. Author(s): Hamad AM, Clayton A, Islam B, Knox AJ. Source: American Journal of Physiology. Lung Cellular and Molecular Physiology. 2003 November; 285(5): L973-83. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14551038
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Guide for the use of nitric oxide (NO) donors as probes of the chemistry of NO and related redox species in biological systems. Author(s): Thomas DD, Miranda KM, Espey MG, Citrin D, Jourd'heuil D, Paolocci N, Hewett SJ, Colton CA, Grisham MB, Feelisch M, Wink DA. Source: Methods Enzymol. 2002; 359: 84-105. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12481562
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HDL stimulation of endothelial nitric oxide synthase: a novel mechanism of HDL action. Author(s): Mineo C, Shaul PW. Source: Trends in Cardiovascular Medicine. 2003 August; 13(6): 226-31. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12922018
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Heat shock protein, inducible nitric oxide synthase and apoptotic markers in the acute phase of human cardiac transplantation. Author(s): Stoica SC, Satchithananda DK, Atkinson C, Charman S, Goddard M, Large SR. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. 2003 December; 24(6): 932-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14643811
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Heme oxygenase-1 induction by endogenous nitric oxide: influence of intracellular glutathione. Author(s): Andre M, Felley-Bosco E. Source: Febs Letters. 2003 July 10; 546(2-3): 223-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12832044
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Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension. Author(s): Leuchte HH, Schwaiblmair M, Baumgartner RA, Neurohr CF, Kolbe T, Behr J. Source: Chest. 2004 February; 125(2): 580-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14769741
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Hemoglobin and nitric oxide. Author(s): Gaston BM, Hare JM. Source: The New England Journal of Medicine. 2003 July 24; 349(4): 402-5; Author Reply 402-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879897
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Hemoglobin and nitric oxide. Author(s): McMahon TJ. Source: The New England Journal of Medicine. 2003 July 24; 349(4): 402-5; Author Reply 402-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879896
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Hemoglobin and nitric oxide. Author(s): Pawloski JR. Source: The New England Journal of Medicine. 2003 July 24; 349(4): 402-5; Author Reply 402-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879895
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Hemoglobin and nitric oxide. Author(s): Singel DJ. Source: The New England Journal of Medicine. 2003 July 24; 349(4): 402-5; Author Reply 402-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879894
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Hemoglobin and nitric oxide. Author(s): Stamler JS. Source: The New England Journal of Medicine. 2003 July 24; 349(4): 402-5; Author Reply 402-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12878751
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Hemolytic anemia-associated pulmonary hypertension of sickle cell disease and the nitric oxide/arginine pathway. Author(s): Jison ML, Gladwin MT. Source: American Journal of Respiratory and Critical Care Medicine. 2003 July 1; 168(1): 3-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826592
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Hepatitis C virus core protein transactivates the inducible nitric oxide synthase promoter via NF-kappaB activation. Author(s): de Lucas S, Bartolome J, Amaro MJ, Carreno V. Source: Antiviral Research. 2003 October; 60(2): 117-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638407
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Hepatocyte growth factor activates endothelial nitric oxide synthase by Ca(2+)- and phosphoinositide 3-kinase/Akt-dependent phosphorylation in aortic endothelial cells. Author(s): Makondo K, Kimura K, Kitamura N, Kitamura T, Yamaji D, Jung BD, Saito M. Source: The Biochemical Journal. 2003 August 15; 374(Pt 1): 63-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12757411
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HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production. Author(s): Simeone AM, Broemeling LD, Rosenblum J, Tari AM. Source: Oncogene. 2003 October 2; 22(43): 6739-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14555987
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High expression of nitric oxide synthases is a favorable prognostic sign in non-small cell lung carcinoma. Author(s): Puhakka A, Kinnula V, Napankangas U, Saily M, Koistinen P, Paakko P, Soini Y. Source: Apmis : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica. 2003 December; 111(12): 1137-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678024
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High nitric oxide production in autistic disorder: a possible role for interferongamma. Author(s): Sweeten TL, Posey DJ, Shankar S, McDougle CJ. Source: Biological Psychiatry. 2004 February 15; 55(4): 434-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14960298
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High plasma level of asymmetric dimethylarginine in patients with acutely exacerbated congestive heart failure: role in reduction of plasma nitric oxide level. Author(s): Saitoh M, Osanai T, Kamada T, Matsunaga T, Ishizaka H, Hanada H, Okumura K. Source: Heart and Vessels. 2003 September; 18(4): 177-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14520484
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Histochemical observation of nitric oxide synthase in trigeminal ganglion of rats with experimental pulpitis. Author(s): Cao Y, Deng Y. Source: J Tongji Med Univ. 1999; 19(1): 77-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12840884
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Hydroxyurea and arginine therapy: impact on nitric oxide production in sickle cell disease. Author(s): Morris CR, Vichinsky EP, van Warmerdam J, Machado L, Kepka-Lenhart D, Morris SM Jr, Kuypers FA. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 August; 25(8): 629-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12902916
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Hypothalamic digoxin, cerebral chemical dominance, and nitric oxide synthesis. Author(s): Kurup RK, Kurup PA. Source: Archives of Andrology. 2003 July-August; 49(4): 281-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12851030
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Hypoxia-induced modification of poly (ADP-ribose) polymerase and dna polymerase beta activity in cerebral cortical nuclei of newborn piglets: role of nitric oxide. Author(s): Mishra OP, Akhter W, Ashraf QM, Delivoria-Papadopoulos M. Source: Neuroscience. 2003; 119(4): 1023-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12831861
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Impact of high-intensity exercise on nitric oxide exchange in healthy adults. Author(s): Shin HW, Rose-Gottron CM, Cooper DM, Hill M, George SC. Source: Medicine and Science in Sports and Exercise. 2003 June; 35(6): 995-1003. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12783048
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In patients with adult respiratory distress syndrome, initial responders to inhaled nitric oxide did not show better outcome than nonresponders. Author(s): Hinohara H, Kadoi Y, Isa Y, Kunimoto F, Ohki S, Saito S, Goto F. Source: Journal of Anesthesia. 2003; 17(4): 270-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14625716
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In search of the prototype of nitric oxide synthase. Author(s): Zemojtel T, Wade RC, Dandekar T. Source: Febs Letters. 2003 November 6; 554(1-2): 1-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14596904
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Increased exhaled nitric oxide following autologous peripheral hematopoietic stemcell transplantation: a potential marker of idiopathic pneumonia syndrome. Author(s): Qureshi MA, Girgis RE, Dandapantula HK, Abrams J, Soubani AO. Source: Chest. 2004 January; 125(1): 281-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14718452
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Increased inflammatory activity parallels increased basal nitric oxide production and blunted response to nitric oxide in vivo in rheumatoid arthritis. Author(s): Yki-Jarvinen H, Bergholm R, Leirisalo-Repo M. Source: Annals of the Rheumatic Diseases. 2003 July; 62(7): 630-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12810424
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Inducible nitric oxide synthase (NOS II) is constitutive in human neutrophils. Author(s): Cedergren J, Follin P, Forslund T, Lindmark M, Sundqvist T, Skogh T. Source: Apmis : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica. 2003 October; 111(10): 963-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14616549
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Inducible nitric oxide synthase (NOS2) promoter CCTTT repeat polymorphism: relationship to in vivo nitric oxide production/NOS activity in an asymptomatic malaria-endemic population. Author(s): Boutlis CS, Hobbs MR, Marsh RL, Misukonis MA, Tkachuk AN, Lagog M, Booth J, Granger DL, Bockarie MJ, Mgone CS, Levesque MC, Weinberg JB, Anstey NM. Source: The American Journal of Tropical Medicine and Hygiene. 2003 December; 69(6): 569-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14740870
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Inducible nitric oxide synthase and bcl-2 expression in nasopharyngeal cancer: correlation with outcome of patients after radiotherapy. Author(s): Jayasurya A, Dheen ST, Yap WM, Tan NG, Ng YK, Bay BH. Source: International Journal of Radiation Oncology, Biology, Physics. 2003 July 1; 56(3): 837-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12788193
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Inducible nitric oxide synthase expression inhibition by adenovirus E1A. Author(s): Cao W, Bao C, Lowenstein CJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 June 24; 100(13): 7773-8. Epub 2003 Jun 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12808130
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Inducible nitric oxide synthase promoter polymorphism in human brucellosis. Author(s): Orozco G, Sanchez E, Lopez-Nevot MA, Caballero A, Bravo MJ, Morata P, de Dios Colmenero J, Alonso A, Martin J. Source: Microbes and Infection / Institut Pasteur. 2003 November; 5(13): 1165-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14623011
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Inducible nitric oxide synthase--time for reappraisal. Author(s): Lirk P, Hoffmann G, Rieder J. Source: Current Drug Targets. Inflammation and Allergy. 2002 March; 1(1): 89-108. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14561209
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Inhaled nitric oxide after lung transplantation: no more cosmesis? Author(s): Glanville AR. Source: American Journal of Respiratory and Critical Care Medicine. 2003 June 1; 167(11): 1463-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12770851
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Inhaled nitric oxide in premature infants with the respiratory distress syndrome. Author(s): Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Source: The New England Journal of Medicine. 2003 November 27; 349(22): 2099-107. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645637
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Inhibition of cytochrome P450 2C9 improves endothelium-dependent, nitric oxidemediated vasodilatation in patients with coronary artery disease. Author(s): Fichtlscherer S, Dimmeler S, Breuer S, Busse R, Zeiher AM, Fleming I. Source: Circulation. 2004 January 20; 109(2): 178-83. Epub 2003 December 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14662709
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Insulin stimulates glucose transport via nitric oxide/cyclic GMP pathway in human vascular smooth muscle cells. Author(s): Bergandi L, Silvagno F, Russo I, Riganti C, Anfossi G, Aldieri E, Ghigo D, Trovati M, Bosia A. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 December; 23(12): 2215-21. Epub 2003 November 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14615391
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Interaction between nitric oxide and cyclooxygenase pathways in endothelial cells. Author(s): Vassalle C, Domenici C, Lubrano V, L'Abbate A. Source: Journal of Vascular Research. 2003 September-October; 40(5): 491-9. Epub 2003 October 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14583660
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Interactions of homocysteine, nitric oxide, folate and radicals in the progressively damaged endothelium. Author(s): Stanger O, Weger M. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2003 November; 41(11): 1444-54. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14656024
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Interrelationships among asthma, atopy, rhinitis and exhaled nitric oxide in a population-based sample of children. Author(s): Jouaville LF, Annesi-Maesano I, Nguyen LT, Bocage AS, Bedu M, Caillaud D. Source: Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology. 2003 November; 33(11): 1506-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14616861
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Intracellular formation of “undisruptable” dimers of inducible nitric oxide synthase. Author(s): Kolodziejski PJ, Rashid MB, Eissa NT. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 November 25; 100(24): 14263-8. Epub 2003 Nov 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14614131
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Is there a place for inhaled nitric oxide in the therapy of acute pulmonary embolism? Author(s): Tanus-Santos JE, Theodorakis MJ. Source: American Journal of Respiratory Medicine : Drugs, Devices, and Other Interventions. 2002; 1(3): 167-76. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14720054
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JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity. Author(s): Shami PJ, Saavedra JE, Wang LY, Bonifant CL, Diwan BA, Singh SV, Gu Y, Fox SD, Buzard GS, Citro ML, Waterhouse DJ, Davies KM, Ji X, Keefer LK. Source: Molecular Cancer Therapeutics. 2003 April; 2(4): 409-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12700285
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Kininase I-type carboxypeptidases enhance nitric oxide production in endothelial cells by generating bradykinin B1 receptor agonists. Author(s): Sangsree S, Brovkovych V, Minshall RD, Skidgel RA. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2003 June; 284(6): H1959-68. Epub 2003 March 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12623793
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Lack of association of the Glu298Asp polymorphism of endothelial nitric oxide synthase with manifest coronary artery disease, carotid atherosclerosis and forearm vascular reactivity in two Austrian populations. Author(s): Schmoelzer I, Renner W, Paulweber B, Malaimare L, Iglseder B, Schmid P, Schallmoser K, Wascher TC. Source: European Journal of Clinical Investigation. 2003 March; 33(3): 191-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12641536
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Lack of evidence for contribution of Glu298Asp (G894T) polymorphism of endothelial nitric oxide synthase gene to plasma nitric oxide levels. Author(s): Moon J, Yoon S, Kim E, Shin C, Jo SA, Jo I. Source: Thrombosis Research. 2002 August 15; 107(3-4): 129-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12431478
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L-arginine and mitomycin C-induced nitric oxide release and apoptosis in human lymphocytes. Author(s): Erden CD, Ekmekci A, Sahin FI, Ergun MA, Ozturk G, Erbas D. Source: Cell Biology International. 2003; 27(4): 337-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12788049
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L-arginine levels in blood as a marker of nitric oxide-mediated brain damage in acute stroke: a clinical and experimental study. Author(s): Armengou A, Hurtado O, Leira R, Obon M, Pascual C, Moro MA, Lizasoain I, Castillo J, Davalos A. Source: Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2003 August; 23(8): 97884. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12902842
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L-arginine-induced relaxation of the internal anal sphincter is not mediated by nitric oxide. Author(s): Acheson AG, Griffin N, Scholefield JH, Wilson VG. Source: The British Journal of Surgery. 2003 September; 90(9): 1155-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12945087
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L-arginine-nitric oxide kinetics in normal and type 2 diabetic subjects: a stablelabelled 15N arginine approach. Author(s): Avogaro A, Toffolo G, Kiwanuka E, de Kreutzenberg SV, Tessari P, Cobelli C. Source: Diabetes. 2003 March; 52(3): 795-802. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12606522
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L-Carnitine alters nitric oxide synthase activity in fibroblasts depending on the peroxisomal status. Author(s): Koeck T, Kremser K. Source: The International Journal of Biochemistry & Cell Biology. 2003 February; 35(2): 149-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12479865
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Leukocyte-depleted terminal blood cardioplegia provides superior myocardial protective effects in association with myocardium-derived nitric oxide and peroxynitrite production for patients undergoing prolonged aortic crossclamping for more than 120 minutes. Author(s): Hayashi Y, Sawa Y, Fukuyama N, Miyamoto Y, Takahashi T, Nakazawa H, Matsuda H. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 December; 126(6): 1813-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14688692
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Lipoic acid and vitamin C potentiate nitric oxide synthesis in human aortic endothelial cells independently of cellular glutathione status. Author(s): Visioli F, Smith A, Zhang W, Keaney JF Jr, Hagen T, Frei B. Source: Redox Report : Communications in Free Radical Research. 2002; 7(4): 223-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12396668
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Lipopolysaccharide and inflammatory cytokines cause an inducible nitric oxide synthase-dependent bladder smooth muscle fibrotic response. Author(s): Austin PF, Casale AJ, Cain MP, Rink RC, Weintraub SJ. Source: The Journal of Urology. 2003 August; 170(2 Pt 1): 645-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12853848
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Local adenoviral-mediated inducible nitric oxide synthase gene transfer inhibits neointimal formation in the porcine coronary stented model. Author(s): Wang K, Kessler PD, Zhou Z, Penn MS, Forudi F, Zhou X, Tarakji K, Kibbe M, Kovesdi I, Brough DE, Topol EJ, Lincoff AM. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2003 May; 7(5 Pt 1): 597-603. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12718902
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Local expression of C-type natriuretic peptide suppresses inflammation, eliminates shear stress-induced thrombosis, and prevents neointima formation through enhanced nitric oxide production in rabbit injured carotid arteries. Author(s): Qian JY, Haruno A, Asada Y, Nishida T, Saito Y, Matsuda T, Ueno H. Source: Circulation Research. 2002 November 29; 91(11): 1063-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12456493
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Localization of nitric oxide synthase type III in the internal thoracic and radial arteries and the great saphenous vein: a comparative immunohistochemical study. Author(s): Gaudino M, Toesca A, Maggiano N, Pragliola C, Possati G. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 June; 125(6): 1510-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12830073
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Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X. Author(s): Chen JW, Hsu NW, Wu TC, Lin SJ, Chang MS. Source: The American Journal of Cardiology. 2002 November 1; 90(9): 974-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12398965
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Low body mass index is a risk factor for impaired endothelium-dependent vasodilation in humans: role of nitric oxide and oxidative stress. Author(s): Higashi Y, Sasaki S, Nakagawa K, Kimura M, Noma K, Sasaki S, Hara K, Matsuura H, Goto C, Oshima T, Chayama K, Yoshizumi M. Source: Journal of the American College of Cardiology. 2003 July 16; 42(2): 256-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12875761
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Low levels of nitric oxide and carbon monoxide in alpha 1-antitrypsin deficiency. Author(s): Machado RF, Stoller JK, Laskowski D, Zheng S, Lupica JA, Dweik RA, Erzurum SC. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 2002 December; 93(6): 2038-43. Epub 2002 August 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12391056
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Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production. Author(s): Lopansri BK, Anstey NM, Weinberg JB, Stoddard GJ, Hobbs MR, Levesque MC, Mwaikambo ED, Granger DL. Source: Lancet. 2003 February 22; 361(9358): 676-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12606182
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Low-dose nitric oxide therapy for persistent pulmonary hypertension: 1-year followup. Author(s): Clark RH, Huckaby JL, Kueser TJ, Walker MW, Southgate WM, Perez JA, Roy BJ, Keszler M; Clinical Inhaled Nitric Oxide Research Group. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 2003 June; 23(4): 300-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12774137
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Luminal nitric oxide and epithelial expression of inducible and endothelial nitric oxide synthase in collagenous and lymphocytic colitis. Author(s): Olesen M, Middelveld R, Bohr J, Tysk C, Lundberg JO, Eriksson S, Alving K, Jarnerot G. Source: Scandinavian Journal of Gastroenterology. 2003 January; 38(1): 66-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12608467
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Lymphocytic infiltration and expression of inducible nitric oxide synthase in human duodenal and colonic mucosa is a characteristic feature of ankylosing spondylitis. Author(s): Lamarque D, Nhieu JT, Breban M, Bernardeau C, Martin-Garcia N, Szepes Z, Delchier JC, Whittle B, Claudepierre P. Source: The Journal of Rheumatology. 2003 November; 30(11): 2428-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14677189
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Malondialdehyde and nitric oxide levels in the plasma of patients with advanced laryngeal cancer. Author(s): Taysi S, Uslu C, Akcay F, Sutbeyaz MY. Source: Surgery Today. 2003; 33(9): 651-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12928839
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Maternal and fetal nitric oxide production in normal and abnormal pregnancy. Author(s): von Mandach U, Lauth D, Huch R. Source: J Matern Fetal Neonatal Med. 2003 January;13(1):22-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12710852
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Measurement of nitric oxide in temporomandibular joint saline aspirates. Author(s): Aghabeigi B, Cintra N, Meghji S, Reher P, Evans AW, Hopper C. Source: International Journal of Oral and Maxillofacial Surgery. 2003 August; 32(4): 4013. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14505624
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Measurement of offline exhaled nitric oxide in a study of community exposure to air pollution. Author(s): Koenig JQ, Jansen K, Mar TF, Lumley T, Kaufman J, Trenga CA, Sullivan J, Liu LJ, Shapiro GG, Larson TV. Source: Environmental Health Perspectives. 2003 October; 111(13): 1625-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14527842
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Measurements of nitric oxide on the heme iron and beta-93 thiol of human hemoglobin during cycles of oxygenation and deoxygenation. Author(s): Xu X, Cho M, Spencer NY, Patel N, Huang Z, Shields H, King SB, Gladwin MT, Hogg N, Kim-Shapiro DB. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 September 30; 100(20): 11303-8. Epub 2003 Sep 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14500899
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Mechanisms and prevention of intimal thickening of the autogenous vein grafts-possible involvement of nitric oxide--. Author(s): Komori K. Source: Nagoya J Med Sci. 2003 May; 66(1-2): 9-19. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12848417
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Medical devices; clinical chemistry and clinical toxicology devices; classification of the breath nitric oxide test system. Final rule. Author(s): Food and Drug Administration, HHS. Source: Federal Register. 2003 July 7; 68(129): 40125-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12858842
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Mice lacking inducible nitric oxide synthase demonstrate impaired killing of Porphyromonas gingivalis. Author(s): Gyurko R, Boustany G, Huang PL, Kantarci A, Van Dyke TE, Genco CA, Gibson FC 3rd. Source: Infection and Immunity. 2003 September; 71(9): 4917-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12933833
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Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid betapeptide presentation to Th1 cells. Author(s): Monsonego A, Imitola J, Zota V, Oida T, Weiner HL. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 September 1; 171(5): 221624. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12928365
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MKP-1-induced dephosphorylation of extracellular signal-regulated kinase is essential for triggering nitric oxide-induced apoptosis in human breast cancer cell lines: implications in breast cancer. Author(s): Pervin S, Singh R, Freije WA, Chaudhuri G. Source: Cancer Research. 2003 December 15; 63(24): 8853-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14695202
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Modeling the influence of superoxide dismutase on superoxide and nitric oxide interactions, including reversible inhibition of oxygen consumption. Author(s): Buerk DG, Lamkin-Kennard K, Jaron D. Source: Free Radical Biology & Medicine. 2003 June 1; 34(11): 1488-503. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12757859
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Modulation of circulating endothelin-1 and big endothelin by nitric oxide inhalation following left ventricular assist device implantation. Author(s): Wagner FD, Buz S, Knosalla C, Hetzer R, Hocher B. Source: Circulation. 2003 September 9; 108 Suppl 1: Ii278-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12970246
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Modulation of nitric oxide on lymphokine-activated killer cells in patients with bladder cancer. Author(s): Wang Z, Fu S, Chen Y, Qin D. Source: Chinese Medical Sciences Journal = Chung-Kuo I Hsueh K'o Hsueh Tsa Chih / Chinese Academy of Medical Sciences. 2001 December; 16(4): 213. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12903758
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Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium. Author(s): Vincent MA, Montagnani M, Quon MJ. Source: Curr Diab Rep. 2003 August; 3(4): 279-88. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12866989
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Molecular variation in endothelial nitric oxide synthase gene (eNOS) in western Mediterranean populations. Author(s): Via M, Gonzalez-Perez E, Esteban E, Lopez-Alomar A, Vacca L, Vona G, Dugoujon JM, Harich N, Moral P. Source: Coll Antropol. 2003 June; 27(1): 117-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12974139
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Mouse models and the role of nitric oxide in reproduction. Author(s): Gregg AR. Source: Current Pharmaceutical Design. 2003; 9(5): 391-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12570816
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Multiple roles of nitric oxide in the airways. Author(s): Ricciardolo FL. Source: Thorax. 2003 February; 58(2): 175-82. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12554905
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Multiple single-breath measurements of nitric oxide in the intubated patient. Author(s): Tornberg DC, Bjorne H, Lundberg JO, Weitzberg E. Source: American Journal of Respiratory and Critical Care Medicine. 2003 November 15; 168(10): 1210-5. Epub 2003 August 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12928312
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Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Author(s): Lopez A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S, Brockway M, Anzueto A, Holzapfel L, Breen D, Silverman MS, Takala J, Donaldson J, Arneson C, Grove G, Grossman S, Grover R. Source: Critical Care Medicine. 2004 January; 32(1): 21-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14707556
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Myeloperoxidase-positive inflammatory cells participate in bile duct damage in primary biliary cirrhosis through nitric oxide-mediated reactions. Author(s): Wu CT, Eiserich JP, Ansari AA, Coppel RL, Balasubramanian S, Bowlus CL, Gershwin ME, Van De Water J. Source: Hepatology (Baltimore, Md.). 2003 October; 38(4): 1018-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14512889
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Nitric oxide and excitation-contraction coupling. Author(s): Hare JM. Source: Journal of Molecular and Cellular Cardiology. 2003 July; 35(7): 719-29. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12818561
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Nitric oxide and the lower urinary tract: current concepts, future prospects. Author(s): Mamas MA, Reynard JM, Brading AF. Source: Urology. 2003 June; 61(6): 1079-85. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12809865
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Nitric oxide has a role in regulating VLA-4-integrin expression on the human neutrophil cell surface. Author(s): Conran N, Gambero A, Ferreira HH, Antunes E, de Nucci G. Source: Biochemical Pharmacology. 2003 July 1; 66(1): 43-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12818364
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Nitric oxide in diabetes mellitus. Author(s): Tuck ML. Source: Journal of Hypertension. 2003 June; 21(6): 1081-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12777942
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Nitric oxide in experimental joint inflammation. Benefit or detriment? Author(s): Wahl SM, McCartney-Francis N, Chan J, Dionne R, Ta L, Orenstein JM. Source: Cells, Tissues, Organs. 2003; 174(1-2): 26-33. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12784039
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Nitric oxide induces phosphorylation of p53 and impairs nuclear export. Author(s): Schneiderhan N, Budde A, Zhang Y, Brune B. Source: Oncogene. 2003 May 15; 22(19): 2857-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12771937
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Nitric oxide pathway and response to nitroglycerin in cluster headache patients: plasma nitrite and citrulline levels. Author(s): Costa A, Ravaglia S, Sances G, Antonaci F, Pucci E, Nappi G. Source: Cephalalgia : an International Journal of Headache. 2003 July; 23(6): 407-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12807519
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Nitric oxide production and mononuclear cell nitric oxide synthase activity in malaria-tolerant Papuan adults. Author(s): Boutlis CS, Tjitra E, Maniboey H, Misukonis MA, Saunders JR, Suprianto S, Weinberg JB, Anstey NM. Source: Infection and Immunity. 2003 July; 71(7): 3682-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12819048
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Nitric oxide signaling in brain: potentiating the gain with YC-1. Author(s): Bredt DS. Source: Molecular Pharmacology. 2003 June; 63(6): 1206-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12761328
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Nitric oxide synthase expression by pulmonary arteries: a predictive marker of Fontan procedure outcome? Author(s): Levy M, Danel C, Laval AM, Leca F, Vouhe PR, Israel-Biet D. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 May; 125(5): 1083-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12771882
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Nitric oxide synthases and protein oxidation in the quadriceps femoris of patients with chronic obstructive pulmonary disease. Author(s): Barreiro E, Gea J, Corominas JM, Hussain SN. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 December; 29(6): 771-8. Epub 2003 June 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12816735
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NO regulation of Na,K-ATPase: nitric oxide regulation of the Na,K-ATPase in physiological and pathological states. Author(s): Ellis DZ, Sweadner KJ. Source: Annals of the New York Academy of Sciences. 2003 April; 986: 534-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12763880
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Oesophageal intraluminal nitric oxide facilitates the acid-induced oesophago-salivary reflex. Author(s): Casselbrant A, Pettersson A, Fandriks L. Source: Scandinavian Journal of Gastroenterology. 2003 March; 38(3): 235-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12737436
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One-year low-dose erythromycin treatment of persistent chronic sinusitis after sinus surgery: clinical outcome and effects on mucociliary parameters and nasal nitric oxide. Author(s): Cervin A, Kalm O, Sandkull P, Lindberg S. Source: Otolaryngology and Head and Neck Surgery. 2002 May; 126(5): 481-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12075221
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Oral arginine reduces systemic blood pressure in type 2 diabetes: its potential role in nitric oxide generation. Author(s): Huynh NT, Tayek JA. Source: Journal of the American College of Nutrition. 2002 October; 21(5): 422-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12356784
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Orthogonal properties of the redox siblings nitroxyl and nitric oxide in the cardiovascular system: a novel redox paradigm. Author(s): Wink DA, Miranda KM, Katori T, Mancardi D, Thomas DD, Ridnour L, Espey MG, Feelisch M, Colton CA, Fukuto JM, Pagliaro P, Kass DA, Paolocci N. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2003 December; 285(6): H2264-76. Epub 2003 July 10. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12855429
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Osmotic swelling induces p75 neurotrophin receptor (p75NTR) expression via nitric oxide. Author(s): Peterson S, Bogenmann E. Source: The Journal of Biological Chemistry. 2003 September 5; 278(36): 33943-50. Epub 2003 June 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12821676
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Overexpression of amyloid precursor protein is associated with degeneration, decreased viability, and increased damage caused by neurotoxins (prostaglandins A1 and E2, hydrogen peroxide, and nitric oxide) in differentiated neuroblastoma cells. Author(s): Hanson AJ, Prasad JE, Nahreini P, Andreatta C, Kumar B, Yan XD, Prasad KN. Source: Journal of Neuroscience Research. 2003 October 1; 74(1): 148-59. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13130517
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Oxidative stress and endothelial nitric oxide bioactivity. Author(s): Thomas SR, Chen K, Keaney JF Jr. Source: Antioxidants & Redox Signalling. 2003 April; 5(2): 181-94. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716478
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Oxygen administration improves the serum level of nitric oxide metabolites in patients with obstructive sleep apnea syndrome. Author(s): Teramoto S, Kume H, Matsuse T, Ishii T, Miyashita A, Akishita M, Toba K, Ouchi Y. Source: Sleep Medicine. 2003 September; 4(5): 403-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14592281
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Oxygen free radical and nitric oxide production in single or combined human schistosomiasis and fascioliasis. Author(s): Abo-Shousha S, Khalil SS, Rashwan EA. Source: J Egypt Soc Parasitol. 1999; 29(1): 149-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12561894
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Oxygen radicals and nitric oxide levels in chondral or meniscal lesions or both. Author(s): Haklar U, Yuksel M, Velioglu A, Turkmen M, Haklar G, Yalcin AS. Source: Clinical Orthopaedics and Related Research. 2002 October; (403): 135-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12360019
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Paroxetine-induced increase in metabolic end products of nitric oxide. Author(s): Lara N, Archer SL, Baker GB, Le Melledo JM. Source: Journal of Clinical Psychopharmacology. 2003 December; 23(6): 641-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624192
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Pathophysiological significance of neuronal nitric oxide synthase in the gastrointestinal tract. Author(s): Takahashi T. Source: Journal of Gastroenterology. 2003; 38(5): 421-30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12768383
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Phagocytic activity and nitric oxide production of circulating polymorphonuclear leukocytes from patients with peritoneal carcinomatosis. Author(s): Baskic D, Acimovic L, Djukic A, Djurdjevic P, Popovic S, Milicic B, Labovic I, Arsenijevic NN. Source: Acta Oncologica (Stockholm, Sweden). 2003; 42(8): 846-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14968946
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Phosphorylation of threonine 497 in endothelial nitric-oxide synthase coordinates the coupling of L-arginine metabolism to efficient nitric oxide production. Author(s): Lin MI, Fulton D, Babbitt R, Fleming I, Busse R, Pritchard KA Jr, Sessa WC. Source: The Journal of Biological Chemistry. 2003 November 7; 278(45): 44719-26. Epub 2003 September 02. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12952971
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Plasma and hepatic tissue levels of thrombomodulin, tissue factor, NFkappaB and nitric oxide in responders and nonresponders to IFNalpha therapy. Author(s): George M, Baluch M, Van Thiel DH. Source: Journal of Viral Hepatitis. 2003 September; 10(5): 360-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12969188
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Plasma endothelin and nitric oxide levels in patients with acute pancreatitis. Author(s): Zeng XH, Zhu SQ, Zhang XM, Luo WJ, Li SW. Source: Hepatobiliary Pancreat Dis Int. 2002 February; 1(1): 140-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14607644
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Plasma interleukin-12 in malaria-tolerant papua new guineans: inverse correlation with Plasmodium falciparum parasitemia and peripheral blood mononuclear cell nitric oxide synthase activity. Author(s): Boutlis CS, Lagog M, Chaisavaneeyakorn S, Misukonis MA, Bockarie MJ, Mgone CS, Wang Z, Morahan G, Weinberg JB, Udhayakumar V, Anstey NM. Source: Infection and Immunity. 2003 November; 71(11): 6354-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14573655
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Polymorphism in glutamate-cysteine ligase modifier subunit gene is associated with impairment of nitric oxide-mediated coronary vasomotor function. Author(s): Nakamura S, Sugiyama S, Fujioka D, Kawabata K, Ogawa H, Kugiyama K. Source: Circulation. 2003 September 23; 108(12): 1425-7. Epub 2003 Sep 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12975258
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Post-transcriptional regulation of inducible nitric oxide synthase in chronic lymphocytic leukemia B cells in pro- and antiapoptotic culture conditions. Author(s): Tiscornia AC, Cayota A, Landoni AI, Brito C, Oppezzo P, Vuillier F, Robello C, Dighiero G, Gabus R, Pritsch O. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 January; 18(1): 48-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14574328
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Prospective evaluation of hydroperoxide plasma levels and stable nitric oxide end products in patients subjected to angioplasty for coronary artery disease. Author(s): Wykretowicz A, Dziarmaga M, Szczepanik A, Guzik P, Wysocki H. Source: International Journal of Cardiology. 2003 June; 89(2-3): 173-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12767540
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Quantitative measurement of endothelial constitutive nitric oxide synthase. Author(s): Meurer J, Blasko E, Orme A, Kauser K. Source: Methods Enzymol. 2002; 359: 433-44. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12481593
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Quercetin-dependent reduction of salivary nitrite to nitric oxide under acidic conditions and interaction between quercetin and ascorbic acid during the reduction. Author(s): Takahama U, Yamamoto A, Hirota S, Oniki T. Source: Journal of Agricultural and Food Chemistry. 2003 September 24; 51(20): 6014-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13129310
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Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1alpha. Author(s): Hagen T, Taylor CT, Lam F, Moncada S. Source: Science. 2003 December 12; 302(5652): 1975-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671307
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Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Author(s): Hambrecht R, Adams V, Erbs S, Linke A, Krankel N, Shu Y, Baither Y, Gielen S, Thiele H, Gummert JF, Mohr FW, Schuler G. Source: Circulation. 2003 July 1; 107(25): 3152-8. Epub 2003 June 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12810615
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Regulation of c-myc gene by nitric oxide via inactivating NF-kappa B complex in P19 mouse embryonal carcinoma cells. Author(s): Park SW, Wei LN. Source: The Journal of Biological Chemistry. 2003 August 8; 278(32): 29776-82. Epub 2003 June 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12783888
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Regulation of neuronal proliferation and differentiation by nitric oxide. Author(s): Gibbs SM. Source: Molecular Neurobiology. 2003 April; 27(2): 107-20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12777682
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Relationship among pulmonary function, bronchial reactivity, and exhaled nitric oxide in a large group of asthmatic patients. Author(s): Langley SJ, Goldthorpe S, Custovic A, Woodcock A. Source: Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology. 2003 October; 91(4): 398-404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14582820
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Relationship between ambient ozone and exhaled nitric oxide in children. Author(s): Nickmilder M, Carbonnelle S, de Burbure C, Bernard A. Source: Jama : the Journal of the American Medical Association. 2003 November 19; 290(19): 2546-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14625330
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Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children. Author(s): Strunk RC, Szefler SJ, Phillips BR, Zeiger RS, Chinchilli VM, Larsen G, Hodgdon K, Morgan W, Sorkness CA, Lemanske RF Jr; Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood Institute. Source: The Journal of Allergy and Clinical Immunology. 2003 November; 112(5): 88392. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14610474
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Replacement of physiologically autoinhaled nitric oxide in intubated patients. Author(s): Rohrig L, Kuhlen R, Baumert J, Rossaint R. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 April; 21(4): 677-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12762356
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Role of c-Myc in nitric oxide-mediated suppression of cytochrome P450 3A4. Author(s): Watabe M, Isogai Y, Numazawa S, Yoshida T. Source: Life Sciences. 2003 November 21; 74(1): 99-108. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14575816
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Role of nitric oxide in cerebral blood flow abnormalities after traumatic brain injury. Author(s): Hlatky R, Goodman JC, Valadka AB, Robertson CS. Source: Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2003 May; 23(5): 582-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12771573
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Serum nitric oxide (NO) levels in systemic sclerosis patients: correlation between NO levels and clinical features. Author(s): Takagi K, Kawaguchi Y, Hara M, Sugiura T, Harigai M, Kamatani N. Source: Clinical and Experimental Immunology. 2003 December; 134(3): 538-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14632763
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Sickle cell anemia is associated with reduced nitric oxide bioactivity in peripheral conduit and resistance vessels. Author(s): Eberhardt RT, McMahon L, Duffy SJ, Steinberg MH, Perrine SP, Loscalzo J, Coffman JD, Vita JA. Source: American Journal of Hematology. 2003 October; 74(2): 104-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14508796
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Signalling pathways regulating inducible nitric oxide synthase expression in human kidney epithelial cells. Author(s): Poljakovic M, Nygren JM, Persson K. Source: European Journal of Pharmacology. 2003 May 23; 469(1-3): 21-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12782181
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Significance of serum vascular endothelial growth factor, insulin-like growth factor-I levels and nitric oxide activity in breast cancer patients. Author(s): Coskun U, Gunel N, Sancak B, Gunel U, Onuk E, Bayram O, Yilmaz E, Candan S, Ozkan S. Source: Breast (Edinburgh, Scotland). 2003 April; 12(2): 104-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14659339
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Sputum induction leads to a decrease of exhaled nitric oxide unrelated to airflow. Author(s): Beier J, Beeh KM, Kornmann O, Buhl R. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 August; 22(2): 354-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12952273
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Statin-mediated correction of STAT1 signaling and inducible nitric oxide synthase expression in cystic fibrosis epithelial cells. Author(s): Kreiselmeier NE, Kraynack NC, Corey DA, Kelley TJ. Source: American Journal of Physiology. Lung Cellular and Molecular Physiology. 2003 December; 285(6): L1286-95. Epub 2003 August 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12948935
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Steroid-naive adolescents with mild intermittent allergic asthma have airway hyperresponsiveness and elevated exhaled nitric oxide levels. Author(s): Spallarossa D, Battistini E, Silvestri M, Sabatini F, Fregonese L, Brazzola G, Rossi GA. Source: The Journal of Asthma : Official Journal of the Association for the Care of Asthma. 2003 May; 40(3): 301-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12807174
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Stimulation of the nitric oxide-guanosine 3', 5'-cyclic monophosphate pathway by sildenafil: effect on rectal muscle tone, distensibility, and perception in health and in irritable bowel syndrome. Author(s): Fritz E, Hammer J, Schmidt B, Eherer AJ, Hammer HF. Source: The American Journal of Gastroenterology. 2003 October; 98(10): 2253-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14572576
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Supplemental nitric oxide and its effect on myocardial injury and function in patients undergoing cardiac surgery with extracorporeal circulation. Author(s): Gianetti J, Del Sarto P, Bevilacqua S, Vassalle C, De Filippis R, Kacila M, Farneti PA, Clerico A, Glauber M, Biagini A. Source: The Journal of Thoracic and Cardiovascular Surgery. 2004 January; 127(1): 44-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14752411
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Suppression of inducible nitric oxide production by indole and isothiocyanate derivatives from Brassica plants in stimulated macrophages. Author(s): Chen YH, Dai HJ, Chang HP. Source: Planta Medica. 2003 August; 69(8): 696-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14531017
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T cell activation-induced mitochondrial hyperpolarization is mediated by Ca2+- and redox-dependent production of nitric oxide. Author(s): Nagy G, Koncz A, Perl A. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 November 15; 171(10): 5188-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14607919
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Tetrahydrobiopterin and nitric oxide: mechanistic and pharmacological aspects. Author(s): Werner ER, Gorren AC, Heller R, Werner-Felmayer G, Mayer B. Source: Experimental Biology and Medicine (Maywood, N.J.). 2003 December; 228(11): 1291-302. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14681545
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The effect of montelukast on bronchial provocation tests and exhaled nitric oxide levels in asthmatic patients. Author(s): Berkman N, Avital A, Bardach E, Springer C, Breuer R, Godfrey S. Source: Isr Med Assoc J. 2003 November; 5(11): 778-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14650101
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The effect of nitric oxide synthase inhibition on histamine induced headache and arterial dilatation in migraineurs. Author(s): Lassen LH, Christiansen I, Iversen HK, Jansen-Olesen I, Olesen J. Source: Cephalalgia : an International Journal of Headache. 2003 November; 23(9): 87786. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14616929
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The effect of the nitric oxide synthase inhibitor N-nitro-L-arginine-methyl ester on neuropeptide-induced vasodilation and protein extravasation in human skin. Author(s): Klede M, Clough G, Lischetzki G, Schmelz M. Source: Journal of Vascular Research. 2003 March-April; 40(2): 105-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12808346
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The Glu298-->Asp polymorphism of the endothelial nitric oxide synthase gene is associated with endometriosis. Author(s): Zervou S, Karteris E, Goumenou AG, Vatish M, Koumantakis EE, Hillhouse EW. Source: Fertility and Sterility. 2003 December; 80(6): 1524-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14667898
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The liver-selective nitric oxide donor O2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2diolate (V-PYRRO/NO) protects HepG2 cells against cytochrome P450 2E1-dependent toxicity. Author(s): Gong P, Cederbaum AI, Nieto N. Source: Molecular Pharmacology. 2004 January; 65(1): 130-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722244
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The pharmacology of nitric oxide in the peripheral nervous system of blood vessels. Author(s): Toda N, Okamura T. Source: Pharmacological Reviews. 2003 June; 55(2): 271-324. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12773630
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Therapeutic interventions targeting the nitric oxide system: current and potential uses in obstetrics, bone disease and erectile dysfunction. Author(s): Grant MK, El-Fakahany EE. Source: Life Sciences. 2004 February 20; 74(14): 1701-21. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14741730
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Tibetan patients with essential hypertension caused by underlying oxidative metabolism dysfunction and depressed nitric oxide synthesis. Author(s): Li D, Wang X, Fu Z, Yu J, Da W, Peng S, Wang X. Source: Chinese Medical Journal. 2003 February; 116(2): 309-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12775254
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Ubiquitination of inducible nitric oxide synthase is required for its degradation. Author(s): Kolodziejski PJ, Musial A, Koo JS, Eissa NT. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 September 17; 99(19): 12315-20. Epub 2002 Sep 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12221289
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Ultrasound stimulates nitric oxide and prostaglandin E2 production by human osteoblasts. Author(s): Reher P, Harris M, Whiteman M, Hai HK, Meghji S. Source: Bone. 2002 July; 31(1): 236-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12110440
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Undetectable levels of tumor necrosis factor-alpha, nitric oxide and inadequate expression of inducible nitric oxide synthase in congenital hypothyroidism. Author(s): Rodriguez-Arnao MD, Rodriguez-Sanchez A, Rodriguez-Arnao J, DulinIniguez E, Cano JM, Munoz-Fernandez MA. Source: European Cytokine Network. 2003 January-March; 14(1): 65-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12799216
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Ups and downs of nitric oxide in chesty children. Author(s): Godfrey S. Source: American Journal of Respiratory and Critical Care Medicine. 2002 August 15; 166(4): 438-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12186816
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Urinary nitric oxide metabolites and lipid peroxidation by-products in migraine. Author(s): Ciancarelli I, Tozzi-Ciancarelli MG, Di Massimo C, Marini C, Carolei A. Source: Cephalalgia : an International Journal of Headache. 2003 February; 23(1): 39-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12534579
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Urotensin II is a nitric oxide-dependent vasodilator and natriuretic peptide in the rat kidney. Author(s): Zhang AY, Chen YF, Zhang DX, Yi FX, Qi J, Andrade-Gordon P, de Garavilla L, Li PL, Zou AP. Source: American Journal of Physiology. Renal Physiology. 2003 October; 285(4): F792-8. Epub 2003 June 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12783779
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Utilization of exogenous tetrahydrobiopterin in nitric oxide synthesis in human neuroblastoma cell line. Author(s): Choi HJ, Kim SW, Im JH, Lee SG, Kim M, Hwang O. Source: Neuroscience Letters. 2003 December 4; 352(2): 89-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14625030
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Vaginal administration of the nitric oxide donor isosorbide mononitrate for cervical ripening at term: a randomized controlled study. Author(s): Ekerhovd E, Bullarbo M, Andersch B, Norstrom A. Source: American Journal of Obstetrics and Gynecology. 2003 December; 189(6): 1692-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14710100
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Variable renal disease progression in autosomal dominant polycystic kidney disease: a role for nitric oxide? Author(s): Devuyst O. Source: Journal of Nephrology. 2003 May-June; 16(3): 449-52. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12832751
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Variations in the serum levels of soluble CD23, nitric oxide and IgE across the spectrum of American cutaneous leishmaniasis. Author(s): Cabrera M, Rodriguez O, Monsalve I, Tovar R, Hagel I. Source: Acta Tropica. 2003 October; 88(2): 145-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14516926
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Variations of nasal nitric oxide in a subject with allergic rhinitis: a longitudinal study. Author(s): Vural C, Gungor A. Source: American Journal of Otolaryngology. 2002 July-August; 23(4): 191-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12105782
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Vascular endothelial growth factor causes pulmonary vasodilation through activation of the phosphatidylinositol-3-kinase-nitric oxide pathway in the late-gestation ovine fetus. Author(s): Grover TR, Zenge JP, Parker TA, Abman SH. Source: Pediatric Research. 2002 December; 52(6): 907-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12438669
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Vasoactive substances: nitric oxide and endothelial dysfunction in atherosclerosis. Author(s): Russo G, Leopold JA, Loscalzo J. Source: Vascular Pharmacology. 2002 May; 38(5): 259-69. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12487030
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Vasoprotection by nitric oxide: mechanisms and therapeutic potential. Author(s): Gewaltig MT, Kojda G. Source: Cardiovascular Research. 2002 August 1; 55(2): 250-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12123764
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VEGF increases endothelial permeability by separate signaling pathways involving ERK-1/2 and nitric oxide. Author(s): Breslin JW, Pappas PJ, Cerveira JJ, Hobson RW 2nd, Duran WN. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2003 January; 284(1): H92-H100. Epub 2002 September 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12388327
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Visceral obesity is characterized by impaired nitric oxide-independent vasodilation. Author(s): Vigili de Kreutzenberg S, Kiwanuka E, Tiengo A, Avogaro A. Source: European Heart Journal. 2003 July; 24(13): 1210-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12831815
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Wei Lun Visiting Professorial Lecture: Nitric oxide in the regulation of vascular function: an historical overview. Author(s): Ignarro LJ. Source: Journal of Cardiac Surgery. 2002 July-August; 17(4): 301-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12546077
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What is the role of surfactant and inhaled nitric oxide in lung transplantation? Author(s): Struber M. Source: Critical Care (London, England). 2002 June; 6(3): 186-7. Epub 2002 May 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12133173
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Withdrawal of inhaled nitric oxide from nonresponders after short exposure. Author(s): Carriedo H, Rhine W. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 2003 October; 23(7): 556-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14566352
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CHAPTER 2. NUTRITION AND NITRIC OXIDE Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and nitric oxide.
Finding Nutrition Studies on Nitric Oxide 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 “nitric oxide” (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 nitric oxide: •
Cholesterol-dependent regulation of nitric oxide production: potential role in atherosclerosis. Author(s): Department of Human Nutrition and Dietetics, University of Illinois, Chicago 60612, USA. Source: Coppinger, R J Baum, C L Nutr-Revolume 1999 September; 57(9 Pt 1): 279-82 0029-6643
The following information is typical of that found when using the “Full IBIDS Database” to search for “nitric oxide” (or a synonym): •
Acute remote ischemic preconditioning II: the role of nitric oxide. Author(s): Department of Plastic and Hand Surgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwig-Guttmann-Strasse 33, 67071 Ludwigshafen, Germany.
[email protected] Source: Kuntscher, M V Kastell, T Altmann, J Menke, H Gebhard, M M Germann, G Microsurgery. 2002; 22(6): 227-31 0738-1085
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Adenosine enhances functional activation of blood flow in cat optic nerve head during photic stimulation independently from nitric oxide. Author(s): Department of Physiology, Department of Bioengineering, and the Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104-6085, USA.
[email protected] Source: Buerk, D G Riva, C E Microvasc-Res. 2002 September; 64(2): 254-64 0026-2862
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Advanced glycation end products quench nitric oxide in vitro. Author(s): Department of Ophthalmology, University of Leipzig, Liebigstr. 10-14, 04103 Leipzig, Germany.
[email protected] Source: Uhlmann, S Rezzoug, K Friedrichs, U Hoffmann, S Wiedemann, P Graefes-ArchClin-Exp-Ophthalmol. 2002 October; 240(10): 860-6 0721-832X
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ATP and nitric oxide modulate a Ca(2+)-activated non-selective cation current in macrovascular endothelial cells. Author(s): Katholieke Universiteit Leuven, Laboratorium voor Fysiologie, Campus Gasthuisberg, 3000 Leuven, Belgium. Source: Suh, S H Watanabe, H Droogmans, G Nilius, B Pflugers-Arch. 2002 June; 444(3): 438-45 0031-6768
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Baicalin-induced vascular response in rat mesenteric artery: role of endothelial nitric oxide. Author(s): Departments of Physiology and Biochemistry, Chinese University of Hong Kong, Hong Kong, China.
[email protected] Source: Huang, Y Tsang, S Y Yao, X Lau, C W Su, Y L Chen, Z Y Clin-Exp-PharmacolPhysiol. 2002 August; 29(8): 721-4 0305-1870
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Beneficial effect of pentaerythrityl tetranitrate on functional and morphological changes in the rat thoracic aorta evoked by long-term nitric oxide synthase inhibition. Author(s): Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Sienkiewiczova 1, 813 71 Bratislava, Slovak Republic.
[email protected] Source: Torok, J Kristek, F Vascul-Pharmacol. 2002 March; 38(3): 177-82 1537-1891
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Contributions of nitric oxide and prostanoids and their signaling pathways to the renal medullary vasodilator effect of U46619 (9-11-dideoxy-11 alpha,9aepoxymethano-prostaglandin F(2a)) in the rat. Author(s): Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004, USA.
[email protected] Source: Oyekan, A O J-Pharmacol-Exp-Ther. 2003 February; 304(2): 507-12 0022-3565
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Edarabone scavenges nitric oxide. Author(s): Department of Medicinal Information, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
[email protected] Source: Satoh, K Ikeda, Y Shioda, S Tobe, T Yoshikawa, T Redox-Repage 2002; 7(4): 21922 1351-0002
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Effect of mycophenolate mofetil on severity of nephritis and nitric oxide production in lupus-prone MRL/lpr mice. Author(s): Division of Nephrology, University Department of Medicine, Queen Mary Hospital, Hong Kong, Republic of China.
[email protected] Source: Lui, S L Tsang, R Wong, D Chan, K W Chan, T M Fung, P C Lai, K N Lupus. 2002; 11(7): 411-8 0961-2033
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Effects of nitric oxide synthase inhibitors and melatonin on the hyperglycemic response to streptozotocin in rats. Author(s): Department of Physiology and Pharmacology, Federal University of Ceara, P.O. Box 3157, Rua Cel. Nunes de Melo 1127, 60430-270 Fortaleza, CE, Brazil.
[email protected] Source: Rao, V S Santos, F A Silva, R M Teixiera, M G Vascul-Pharmacol. 2002 March; 38(3): 127-30 1537-1891
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Electro-acupuncture stimulation to muscle afferents in anesthetized rats modulates the blood flow to the knee joint through autonomic reflexes and nitric oxide. Author(s): Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan. Source: Loaiza, L A Yamaguchi, S Ito, M Ohshima, N Auton-Neurosci. 2002 May 31; 97(2): 103-9 1566-0702
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Evidence for the existence of a constitutive nitric oxide synthase in vascular smooth muscle. Author(s): Department of Pharmacology, National University of Singapore, Singapore, Hong Kong, China. Source: Cheah, L S Gwee, M Das, R Ballard, H Yang, Y F Daniel, E E Kwan, C Y ClinExp-Pharmacol-Physiol. 2002 August; 29(8): 725-7 0305-1870
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Expression of inducible and endothelial nitric oxide synthases, formation of peroxynitrite and reactive oxygen species in human chronic renal transplant failure. Author(s): Departments of Pathology and Nephrology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
[email protected] Source: Albrecht, E W Stegeman, C A Tiebosch, A T Tegzess, A M van Goor, H Am-JTransplant. 2002 May; 2(5): 448-53 1600-6135
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FGF-2, NGF and IGF-1, but not BDNF, utilize a nitric oxide pathway to signal neurotrophic and neuroprotective effects against alcohol toxicity in cerebellar granule cell cultures. Author(s): Department of Pediatrics, College of Medicine University of Iowa, Iowa City, IA, USA.
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Source: Bonthius, D J Karacay, B Dai, D Pantazis, N J Brain-Res-Dev-Brain-Res. 2003 January 10; 140(1): 15-28 0165-3806 •
Glutamine decreases interleukin-8 and interleukin-6 but not nitric oxide and prostaglandins e(2) production by human gut in-vitro. Author(s): Appareil Digestif Environnement et Nutrition (ADEN EA 3234), Rouen, France. Source: Coeffier, M Marion, R Leplingard, A Lerebours, E Ducrotte, P Dechelotte, P Cytokine. 2002 April 21; 18(2): 92-7 1043-4666
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High salt intake inhibits nitric oxide synthase expression and aggravates hypertension in rats with chronic renal failure. Author(s): Department of Medicine, Keck School of Medicine University of Southern California, Los Angeles, USA.
[email protected] Source: Campese, V M Mozayeni, P Ye, S Gumbard, M J-Nephrol. 2002 Jul-August; 15(4): 407-13 1120-3625
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Human-bacteria nitric oxide cycles in HIV-1 infection. Author(s): Food and Drug Administration, Center for Drug Evaluation and Research, Division of Antiviral Drug Products, Rockville, USA. Source: Zhang, H Boring, D Haverkos, H Med-Hypotheses. 2002 June; 58(6): 439-43 0306-9877
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Hydroxocobalamin, a nitric oxide scavenger, in the prophylaxis of migraine: an open, pilot study. Author(s): Department of Clinical Pharmacy and Toxicology, Academic Hospital Maastricht, Maastricht, The Netherlands.
[email protected] Source: van der Kuy, P H Merkus, F W Lohman, J J ter Berg, J W Hooymans, P M Cephalalgia. 2002 September; 22(7): 513-9 0333-1024
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In vitro investigation of the interaction between nitric oxide and cyclo-oxygenase activity in equine ventral colon smooth muscle. Author(s): Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis 95616, USA. Source: van Hoogmoed, L M Harmon, F A Stanley, S White, J Snyder, J Equine-Vet-J. 2002 July; 34(5): 510-5 0425-1644
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Influence of nitric oxide on the in vitro antiaggregant effect of ticlopidine. Author(s): Department of Pharmacology and Therapetics, School of Medicine, University of Malaga, Campus de Teatinos s/n, Malaga 29071, Spain.
[email protected] Source: De La Cruz, J P Arrebola, M M Guerrero, A Sanchez de la Cuesta, F VasculPharmacol. 2002 March; 38(3): 183-6 1537-1891
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Inhibition of fibrin-induced neurogenic pulmonary edema by previous unilateral left-vagotomy correlates with increased levels of brain nitric oxide synthase in the nucleus tractus solitarii of rats. Author(s): Department of Anesthesiology, Nagoya University School of Medicine, Showa-ku, Nagoya 466-8550, Japan. Source: Feng, G G Nishiwaki, K Kondo, H Shimada, Y Ishikawa, N Auton-Neurosci. 2002 November 29; 102(1-2): 1-7 1566-0702
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Inhibition of nitric oxide restores surfactant gene expression following nickelinduced acute lung injury. Author(s): University of Cincinnati, and Children's Hospital Medical Center, Cincinnati, OH 45267-0056, USA.
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Source: McDowell, S A Gammon, K Zingarelli, B Bachurski, C J Aronow, B J Prows, D R Leikauf, G D Am-J-Respir-Cell-Mol-Biol. 2003 February; 28(2): 188-98 1044-1549 •
Inhibitors of Nitric Oxide Production from Hops (Humulus lupulus L.). Author(s): Central Laboratories for Key Technology, Kirin Brewery Co., Ltd. Source: Zhao, F Nozawa, H Daikonnya, A Kondo, K Kitanaka, S Biol-Pharm-Bull. 2003 January; 26(1): 61-5 0918-6158
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Modulation of nitric oxide concentration and lipid metabolism by 15-deoxy Delta12,14prostaglandin J2 in embryos from control and diabetic rats during early organogenesis. Author(s): Centro de Estudios Farmacologicos y Botanicos (CEFYBO), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Serrano 669, (1414) Buenos Aires, Argentina.
[email protected] Source: Jawerbaum, A Sinner, D White, V Pustovrh, C Capobianco, E Gonzalez, E Reproduction. 2002 November; 124(5): 625-31 1470-1626
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N(G)-nitro-L-arginine methylester, a nitric oxide synthase inhibitor, diminishes apoptosis induced by ischemia-reperfusion in the rat bladder. Author(s): Department of Urology, Tottori University Faculty of Medicine, Yonago, Japan.
[email protected] Source: Saito, M Miyagawa, I Neurourol-Urodyn. 2002; 21(6): 566-71 0733-2467
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NF-kappaB inhibition impairs the radioresponse of hypoxic EMT-6 tumour cells through downregulation of inducible nitric oxide synthase. Author(s): Oncology Center, Cancer Research Unit, Academic Hospital Free University Brussels (A.Z.-V.U.B.), Laarbeeklaan 101, B 1090, Brussels, Belgium.
[email protected] Source: De Ridder, M Van den Berge, D L Verovski, V N Monsaert, C Wauters, N Storme, G A Br-J-Cancer. 2003 January 13; 88(1): 120-4 0007-0920
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Nitric oxide and changes of iron metabolism in exercise. Author(s): Laboratory of Iron Metabolism, Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Kowloon.
[email protected] Source: Qian, Z M Biol-Rev-Camb-Philos-Soc. 2002 November; 77(4): 529-36 0006-3231
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Nitric oxide and hydroxyl radical-induced retinal lipid peroxidation in vitro. Author(s): Laboratory of Experimental Optometry, Department of Optometry and Radiography, The Hong Kong Polytechnic University, Hung Hom, Kowloon, China. Source: Siu, A W To, C H Clin-Exp-Optom. 2002 November; 85(6): 378-82 0816-4622
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Nitric oxide in biological denitrification: Fe/Cu metalloenzyme and metal complex NO(x) redox chemistry. Author(s): Department of Chemistry, The Johns Hopkins University, Charles and 34th Streets, Baltimore, MD 21218, USA. Source: Wasser, I M de Vries, S Moenne Loccoz, P Schroder, I Karlin, K D ChemRevolume 2002 April; 102(4): 1201-34 0009-2665
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Nitric oxide induces neutral ceramidase degradation by the ubiquitin/proteasome complex in renal mesangial cell cultures. Author(s): Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang GoetheUniversitat, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany. Source: Franzen, R Pfeilschifter, J Huwiler, A FEBS-Lett. 2002 December 18; 532(3): 441-4 0014-5793
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Nitric oxide inhibits renal cytochrome P450-dependent epoxygenases in the rat. Author(s): Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004, USA.
[email protected] Source: Oyekan, A Clin-Exp-Pharmacol-Physiol. 2002 November; 29(11): 990-5 0305-1870
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Nitric oxide mediated photo-induced cell death in human malignant cells. Author(s): Department of Medical Sciences, National Cancer Centre, Singapore 169610. Source: Ali, S M Olivo, M Int-J-Oncol. 2003 April; 22(4): 751-6 1019-6439
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Nitric oxide modulates low-Mg2+-induced epileptiform activity in rat hippocampalentorhinal cortex slices. Author(s): Johannes-Muller-Institut fur Physiologie, Universitatsklinikum, Charite Humboldt-Universitat Berlin, Germany.
[email protected] Source: Schuchmann, S Albrecht, D Heinemann, U von Bohlen und Halbach, O Neurobiol-Dis. 2002 October; 11(1): 96-105 0969-9961
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Nitric oxide production by carpet shell clam (Ruditapes decussatus) hemocytes. Author(s): Instituto de Investigaciones Marinas, CSIC, Vigo, Spain. Source: Tafalla, C Gomez Leon, J Novoa, B Figueras, A Dev-Comp-Immunol. 2003 March; 27(3): 197-205 0145-305X
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Prevention of nitric oxide-mediated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineinduced Parkinson's disease in mice by tea phenolic epigallocatechin 3-gallate. Author(s): Department of Pharmacology, Medicinal Toxicology Research Center, Inha University, Inchon, South Korea. Source: Choi, J Y Park, C S Kim, D J Cho, M H Jin, B K Pie, J E Chung, W G Neurotoxicology. 2002 September; 23(3): 367-74 0161-813X
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Prostaglandin E1 analog inhibits the microglia function: suppression of lipopolysaccharide-induced nitric oxide and TNF-alpha release. Source: Chuai, M Ogata, T Morino, T Okumura, H Yamamoto, H Schubert, P J-OrthopRes. 2002 November; 20(6): 1246-52 0736-0266
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Role of endogenous reactive oxygen derived species and cyclooxygenase mediators in 5-hydroxytryptamine-induced contractions in rat aorta: relationship to nitric oxide. Author(s): Division of Pharmacology, Central Drug Research Institute, Lucknow 226 001, India.
[email protected] Source: Srivastava, P Rajanikanth, M Raghavan, S A Dikshit, M Pharmacol-Res. 2002 May; 45(5): 375-82 1043-6618
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Role of nitric oxide in chronic allergen-induced airway cell proliferation and inflammation. Author(s): National Heart and Lung Institute, Imperial College School of Science, Technology and Medicine, London, United Kingdom. Source: Eynott, P R Paavolainen, N Groneberg, D A Noble, A Salmon, M Nath, P Leung, S Y Chung, K F J-Pharmacol-Exp-Ther. 2003 January; 304(1): 22-9 0022-3565
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Severe cerebral blood flow reduction inhibits nitric oxide synthesis. Author(s): Department of Neurosurgery, Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan. Source: Uetsuka, S Fujisawa, H Yasuda, H Shima, H Suzuki, M J-Neurotrauma. 2002 September; 19(9): 1105-16 0897-7151
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The effect of chloroquine on renal function and vasopressin secretion: a nitric oxidedependent effect. Author(s): School of Biological Sciences, University of Manchester, Manchester, United Kingdom.
[email protected] Source: Ahmed, M H Ashton, N Balment, R J J-Pharmacol-Exp-Ther. 2003 January; 304(1): 156-61 0022-3565
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The effects of antioxidants and nitric oxide modulators on hepatic ischemicreperfusion injury in rats. Author(s): Department of Emergency Medicine, Seoul National University College of Medicine, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea. Source: Rhee, J E Jung, S E Shin, S D Suh, G J Noh, D Y Youn, Y K Oh, S K Choe, K J JKorean-Med-Sci. 2002 August; 17(4): 502-6 1011-8934
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The effects of exogenous nitric oxide on the function of neuromuscular synapses. Author(s): Department of Normal Physiology, Kazan' State Medical University, 49 Butlerov Street, 420012 Kazan', Russia. Source: Zefirov, A L Khaliullina, R R Anuchin, A A Yakovlev, A V Neurosci-BehavPhysiol. 2002 Nov-December; 32(6): 583-8 0097-0549
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The role of nitric oxide in ocular surface cells. Author(s): Department of Ophthalmology, College of Medicine, Chung-Ang University, Seoul, Korea.
[email protected] Source: Kim, J C Park, G S Kim, J K Kim, Y M J-Korean-Med-Sci. 2002 June; 17(3): 389-94 1011-8934
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Type 2 nitric oxide synthase and protein nitration in chronic lung infection. Author(s): Department of Anatomy and Physiology, University College Dublin, Dublin, Ireland. Source: Hopkins, N Cadogan, E Giles, S Bannigan, J McLoughlin, P J-Pathol. 2003 January; 199(1): 122-9 0022-3417
Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMDHealth: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
The following is a specific Web list relating to nitric oxide; 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 Vitamin C Source: Healthnotes, Inc.; www.healthnotes.com
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Food and Diet Hypertension Source: Healthnotes, Inc.; www.healthnotes.com
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CHAPTER 3. ALTERNATIVE MEDICINE AND NITRIC OXIDE Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to nitric oxide. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to nitric oxide 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 “nitric oxide” (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 nitric oxide: •
20(S)-Protopanaxatriol, one of ginsenoside metabolites, inhibits inducible nitric oxide synthase and cyclooxygenase-2 expressions through inactivation of nuclear factorkappaB in RAW 264.7 macrophages stimulated with lipopolysaccharide. Author(s): Oh GS, Pae HO, Choi BM, Seo EA, Kim DH, Shin MK, Kim JD, Kim JB, Chung HT. Source: Cancer Letters. 2004 March 8; 205(1): 23-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15036657
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3', 4'-dihydroxyflavonol enhances nitric oxide bioavailability and improves vascular function after ischemia and reperfusion injury in the rat. Author(s): Chan EC, Drummond GR, Woodman OL. Source: Journal of Cardiovascular Pharmacology. 2003 December; 42(6): 727-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14639094
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A constituent of green tea, epigallocatechin-3-gallate, activates endothelial nitric oxide synthase by a phosphatidylinositol-3-OH-kinase-, cAMP-dependent protein kinase-, and Akt-dependent pathway and leads to endothelial-dependent vasorelaxation. Author(s): Lorenz M, Wessler S, Follmann E, Michaelis W, Dusterhoft T, Baumann G, Stangl K, Stangl V. Source: The Journal of Biological Chemistry. 2004 February 13; 279(7): 6190-5. Epub 2003 November 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645258
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Absolute stereostructures of new arborinane-type triterpenoids and inhibitors of nitric oxide production from Rubia yunnanensis. Author(s): Morikawa T, Tao J, Ando S, Matsuda H, Yoshikawa M. Source: Journal of Natural Products. 2003 May; 66(5): 638-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12762798
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Acidic polysaccharide isolated from Phellinus linteus induces nitric oxide-mediated tumoricidal activity of macrophages through protein tyrosine kinase and protein kinase C. Author(s): Kim GY, Oh YH, Park YM. Source: Biochemical and Biophysical Research Communications. 2003 September 19; 309(2): 399-407. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12951063
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Acupuncture decreases nitric oxide synthase expression in periaqueductal gray area of rats with streptozotocin-induced diabetes. Author(s): Jang MH, Shin MC, Koo GS, Lee CY, Kim EH, Kim CJ. Source: Neuroscience Letters. 2003 February 13; 337(3): 155-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12536047
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Acupuncture increases nitric oxide synthase expression in hippocampus of streptozotocin-induced diabetic rats. Author(s): Jang MH, Shin MC, Lim BV, Kim HB, Kim YP, Kim EH, Kim H, Shin MS, Kim SS, Kim CJ. Source: The American Journal of Chinese Medicine. 2003; 31(2): 305-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12856869
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Acupuncture modulates expressions of nitric oxide synthase and c-Fos in hippocampus after transient global ischemia in gerbils. Author(s): Kang JE, Lee HJ, Lim S, Kim EH, Lee TH, Jang MH, Shin MC, Lim BV, Kim YJ, Kim CJ. Source: The American Journal of Chinese Medicine. 2003; 31(4): 581-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14587881
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Adiponectin stimulates production of nitric oxide in vascular endothelial cells. Author(s): Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ. Source: The Journal of Biological Chemistry. 2003 November 7; 278(45): 45021-6. Epub 2003 August 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12944390
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Administration of Folium mori extract decreases nitric oxide synthase expression in the hypothalamus of streptozotocin-induced diabetic rats. Author(s): Jang MH, Kim H, Shin MC, Lim BV, Lee TH, Jung SB, Kim CJ, Kim EH. Source: Japanese Journal of Pharmacology. 2002 October; 90(2): 189-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12419890
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Altered expression of inducible nitric oxide synthase (iNOS) in the cochlea. Author(s): Shi X, Dai C, Nuttall AL. Source: Hearing Research. 2003 March; 177(1-2): 43-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12618316
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Angiotensin II inhibits endothelial cell motility through an AT1-dependent oxidantsensitive decrement of nitric oxide availability. Author(s): Desideri G, Bravi MC, Tucci M, Croce G, Marinucci MC, Santucci A, Alesse E, Ferri C. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 July 1; 23(7): 1218-23. Epub 2003 May 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12763763
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Anti-angiogenic and inhibitory activity on inducible nitric oxide production of the mushroom Ganoderma lucidum. Author(s): Song YS, Kim SH, Sa JH, Jin C, Lim CJ, Park EH. Source: Journal of Ethnopharmacology. 2004 January; 90(1): 17-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14698502
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Anti-inflammatory compounds of plant origin. Part I. Action on arachidonic acid pathway, nitric oxide and nuclear factor kappa B (NF-kappaB). Author(s): Calixto JB, Otuki MF, Santos AR. Source: Planta Medica. 2003 November; 69(11): 973-83. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14735432
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Anti-inflammatory effect of the oligomeric stilbene alpha-Viniferin and its mode of the action through inhibition of cyclooxygenase-2 and inducible nitric oxide synthase. Author(s): Chung EY, Kim BH, Lee MK, Yun YP, Lee SH, Min KR, Kim Y. Source: Planta Medica. 2003 August; 69(8): 710-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14531020
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Associations of renal function with polymorphisms in the delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in Korean lead workers. Author(s): Weaver VM, Schwartz BS, Ahn KD, Stewart WF, Kelsey KT, Todd AC, Wen J, Simon DJ, Lustberg ME, Parsons PJ, Silbergeld EK, Lee BK. Source: Environmental Health Perspectives. 2003 October; 111(13): 1613-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14527840
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Biological Reduction of Nitric Oxide in Aqueous Fe(II)EDTA Solutions. Author(s): Van Der Maas P, Van De Sandt T, Klapwijk B, Lens P. Source: Biotechnology Progress. 2003 July-August; 19(4): 1323-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12892497
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Black rice (Oryza sativa L. indica) pigmented fraction suppresses both reactive oxygen species and nitric oxide in chemical and biological model systems. Author(s): Hu C, Zawistowski J, Ling W, Kitts DD. Source: Journal of Agricultural and Food Chemistry. 2003 August 27; 51(18): 5271-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12926869
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Butanolides from Machilus thunbergii and their inhibitory activity on nitric oxide synthesis in activated macrophages. Author(s): Kim NY, Ryu JH. Source: Phytotherapy Research : Ptr. 2003 April; 17(4): 372-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12722143
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Cholecystokinin secretagogue-induced gastroprotection: role of nitric oxide and blood flow. Author(s): West SD, Helmer KS, Chang LK, Cui Y, Greeley GH, Mercer DW. Source: American Journal of Physiology. Gastrointestinal and Liver Physiology. 2003 March; 284(3): G399-410. Epub 2002 November 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12444009
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Copper modulates activities of genistein, nitric oxide, and curcumin in breast tumor cells. Author(s): Verma SP, Goldin BR. Source: Biochemical and Biophysical Research Communications. 2003 October 10; 310(1): 104-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14511655
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Cyanidin 3-O-beta-D-glucoside suppresses nitric oxide production during a zymosan treatment in rats. Author(s): Tsuda T, Horio F, Osawa T.
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Source: J Nutr Sci Vitaminol (Tokyo). 2002 August; 48(4): 305-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12489822 •
Delphinidin, an active compound of red wine, inhibits endothelial cell apoptosis via nitric oxide pathway and regulation of calcium homeostasis. Author(s): Martin S, Giannone G, Andriantsitohaina R, Martinez MC. Source: British Journal of Pharmacology. 2003 July; 139(6): 1095-102. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871827
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Demethylbellidifolin inhibits adhesion of monocytes to endothelial cells via reduction of tumor necrosis factor alpha and endogenous nitric oxide synthase inhibitor level. Author(s): Jiang DJ, Jiang JL, Tan GS, Huang ZZ, Deng HW, Li YJ. Source: Planta Medica. 2003 December; 69(12): 1150-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14750034
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Dietary L-arginine supplementation enhances endothelial nitric oxide synthesis in streptozotocin-induced diabetic rats. Author(s): Kohli R, Meininger CJ, Haynes TE, Yan W, Self JT, Wu G. Source: The Journal of Nutrition. 2004 March; 134(3): 600-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14988454
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Direct scavenging of nitric oxide and superoxide by green tea. Author(s): Nakagawa T, Yokozawa T. Source: Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association. 2002 December; 40(12): 1745-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12419687
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Docosahexaenoic acid ameliorates murine ischemic acute renal failure and prevents increases in mRNA abundance for both TNF-alpha and inducible nitric oxide synthase. Author(s): Kielar ML, Jeyarajah DR, Zhou XJ, Lu CY. Source: Journal of the American Society of Nephrology : Jasn. 2003 February; 14(2): 38996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12538739
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Docosahexaenoic acid suppresses nitric oxide production and inducible nitric oxide synthase expression in interferon-gamma plus lipopolysaccharide-stimulated murine macrophages by inhibiting the oxidative stress. Author(s): Komatsu W, Ishihara K, Murata M, Saito H, Shinohara K. Source: Free Radical Biology & Medicine. 2003 April 15; 34(8): 1006-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12684085
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Down regulation of survivin in nitric oxide-induced cell growth inhibition and apoptosis of the human lung carcinoma cells. Author(s): Chao JI, Kuo PC, Hsu TS. Source: The Journal of Biological Chemistry. 2004 February 26 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14988404
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Doxorubicin induces an increase of nitric oxide synthesis in rat cardiac cells that is inhibited by iron supplementation. Author(s): Aldieri E, Bergandi L, Riganti C, Costamagna C, Bosia A, Ghigo D. Source: Toxicology and Applied Pharmacology. 2002 December 1; 185(2): 85-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12490132
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DPPH radical scavenging and nitric oxide inhibitory activities of the constituents from the wood of Taxus yunnanensis. Author(s): Banskota AH, Tezuka Y, Nguyen NT, Awale S, Nobukawa T, Kadota S. Source: Planta Medica. 2003 June; 69(6): 500-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865966
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Effect of acupuncture on nitric oxide synthase expression in cerebral cortex of streptozotocin-induced diabetic rats. Author(s): Jang MH, Shin MC, Kim YP, Kim EH, Kim CJ. Source: Acupuncture & Electro-Therapeutics Research. 2003; 28(1-2): 1-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12934955
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Effect of diet and exercise intervention on blood pressure, insulin, oxidative stress, and nitric oxide availability. Author(s): Roberts CK, Vaziri ND, Barnard RJ. Source: Circulation. 2002 November 12; 106(20): 2530-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12427646
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Effect of ginsenoside Rd on nitric oxide system induced by lipopolysaccharide plus TNF-alpha in C6 rat glioma cells. Author(s): Choi SS, Lee JK, Han EJ, Han KJ, Lee HK, Lee J, Suh HW. Source: Arch Pharm Res. 2003 May; 26(5): 375-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12785733
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Effect of lignins and their precursors on nitric oxide, citrulline and asparagine production by mouse macrophage-like Raw 264.7 cells. Author(s): Suzuki F, Okayasu H, Tashiro M, Hashimoto K, Yokote Y, Akahane K, Hongo S, Sakagami H. Source: Anticancer Res. 2002 September-October; 22(5): 2719-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12529987
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Effect of nitric oxide on cytotoxicity of Taxol: enhanced Taxol transcellular permeability. Author(s): Jia L, Schweizer J, Wang Y, Cerna C, Wong H, Revilla M. Source: Biochemical Pharmacology. 2003 December 1; 66(11): 2193-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14609744
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Effect of oral magnesium supplementation on experimental pre-eclampsia induced by prolonged blockade of nitric oxide synthesis in pregnant rats. Author(s): Pandhi P, Saha L, Malhotra S. Source: Indian J Exp Biol. 2002 March; 40(3): 349-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12635709
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Effect of Short-Term Phytoestrogen Treatment in Male Rats on Nitric OxideMediated Responses of Carotid and Cerebral Arteries: Comparison With 17{beta}Estradiol. Author(s): Sobey CG, Weiler JM, Boujouade M, Woodman OL. Source: The Journal of Pharmacology and Experimental Therapeutics. 2004 March 30 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15054117
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Effect of Uwhangchungsimwon on expression of nitric oxide synthase and vascular cell adhesion molecule-1 in human endothelial cells. Author(s): Moon SK, Kim YS, Ko CN, Bae HS, Cho KH, Lee KS. Source: The American Journal of Chinese Medicine. 2003; 31(3): 389-402. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12943170
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Effects of L-arginine-derived nitric oxide synthesis on cardiovascular responses to stimulus-evoked somatosympathetic reflexes in the gracile nucleus. Author(s): Chen S, Ma S. Source: Brain Research. 2002 December 27; 958(2): 330-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12470869
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Effects of Salvia miltiorrhiza extracts on rat hypoxic pulmonary hypertension, heme oxygenase-1 and nitric oxide synthase. Author(s): Chen Y, Ruan Y, Li L, Chu Y, Xu X, Wang Q, Zhou X. Source: Chinese Medical Journal. 2003 May; 116(5): 757-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12875696
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Endocannabinoids as autoregulatory signaling molecules: coupling to nitric oxide and a possible association with the relaxation response. Author(s): Stefano GB, Esch T, Cadet P, Zhu W, Mantione K, Benson H.
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Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 April; 9(4): Ra63-75. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12709683 •
Endothelium mediated vasorelaxant response of garlic in isolated rat aorta: role of nitric oxide. Author(s): Ashraf MZ, Hussain ME, Fahim M. Source: Journal of Ethnopharmacology. 2004 January; 90(1): 5-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14698500
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Enhanced nitric oxide concentrations and expression of nitric oxide synthase in acupuncture points/meridians. Author(s): Ma SX. Source: Journal of Alternative and Complementary Medicine (New York, N.Y.). 2003 April; 9(2): 207-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12804074
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Enhanced nitric oxide release/synthesis in the posterior hypothalamus during nitroglycerin tolerance in rats. Author(s): Ma SX, Ji A, Pandjaitan M, Ojije G. Source: European Journal of Pharmacology. 2003 July 11; 472(3): 179-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871752
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Enhancement of vascular targeting by inhibitors of nitric oxide synthase. Author(s): Davis PD, Tozer GM, Naylor MA, Thomson P, Lewis G, Hill SA. Source: International Journal of Radiation Oncology, Biology, Physics. 2002 December 1; 54(5): 1532-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12459382
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Ethyl acetate soluble fraction of Cnidium officinale MAKINO inhibits neuronal cell death by reduction of excessive nitric oxide production in lipopolysaccharide-treated rat hippocampal slice cultures and microglia cells. Author(s): Kim JM, Son D, Lee P, Lee KJ, Kim H, Kim SY. Source: Journal of Pharmacological Sciences. 2003 May; 92(1): 74-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12832858
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Evaluation of natural products on inhibition of inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in cultured mouse macrophage cells. Author(s): Hong CH, Hur SK, Oh OJ, Kim SS, Nam KA, Lee SK. Source: Journal of Ethnopharmacology. 2002 November; 83(1-2): 153-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12413723
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Excessive production of nitric oxide induces the neuronal cell death in lipopolysaccharide-treated rat hippocampal slice culture. Author(s): Lee P, Son D, Lee J, Kim YS, Kim H, Kim SY. Source: Neuroscience Letters. 2003 September 25; 349(1): 33-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12946580
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Extract of the seed coat of Tamarindus indica inhibits nitric oxide production by murine macrophages in vitro and in vivo. Author(s): Komutarin T, Azadi S, Butterworth L, Keil D, Chitsomboon B, Suttajit M, Meade BJ. Source: Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association. 2004 April; 42(4): 649-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15019190
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Falcarindiol inhibits nitric oxide-mediated neuronal death in lipopolysaccharidetreated organotypic hippocampal cultures. Author(s): Min Kim J, Lee P, Son D, Kim H, Yeou Kim S. Source: Neuroreport. 2003 October 27; 14(15): 1941-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14561925
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Fasting plasma nitric oxide products in coeliac disease. Author(s): Murray IA, Bullimore DW, Long RG. Source: European Journal of Gastroenterology & Hepatology. 2003 October; 15(10): 10915. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14501617
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Genetic Models in Applied Physiology. Differential role of nitric oxide synthase isoforms in fever of different etiologies: studies using Nos gene-deficient mice. Author(s): Kozak W, Kozak A. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 2003 June; 94(6): 2534-44. Epub 2003 January 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12562678
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Ginsenoside Rg3 inhibits phenylephrine-induced vascular contraction through induction of nitric oxide synthase. Author(s): Kim ND, Kim EM, Kang KW, Cho MK, Choi SY, Kim SG. Source: British Journal of Pharmacology. 2003 October; 140(4): 661-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14534150
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High-dose biotin may down-regulate hepatic expression of acute phase reactants by mimicking the physiological role of nitric oxide. Author(s): McCarty MF.
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Source: Medical Hypotheses. 2003 October; 61(4): 417-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13679004 •
Homocysteine stimulates inducible nitric oxide synthase expression in macrophages: antagonizing effect of ginkgolides and bilobalide. Author(s): Woo CW, Cheung F, Chan VW, Siow YL, O K. Source: Molecular and Cellular Biochemistry. 2003 January; 243(1-2): 37-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12619887
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Hypoxia-induced modification of the inositol triphosphate receptor in neuronal nuclei of newborn piglets: role of nitric oxide. Author(s): Mishra OP, Qayyum I, Delivoria-Papadopoulos M. Source: Journal of Neuroscience Research. 2003 October 15; 74(2): 333-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14515363
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Identification of nitric oxide metabolites in various honeys: effects of intravenous honey on plasma and urinary nitric oxide metabolites concentrations. Author(s): Al-Waili NS. Source: Journal of Medicinal Food. 2003 Winter; 6(4): 359-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14977445
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Impaired nitric oxide production, brachial artery reactivity and fish oil in offspring of ischaemic heart disease patients. Author(s): Yosefy C, Khalamizer V, Viskoper JR, Iaina A, Manevich I, London D, Jafari J, Magen E, Wollman Y, Reisin L. Source: British Journal of Biomedical Science. 2003; 60(3): 144-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14560790
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Increased neuronal nitric oxide synthase expression in the gracile nucleus of brainstem following electroacupuncture given between cutaneous hindlimb acupuncture points BL 64 & BL 65 in rats. Author(s): Ma SX, Li XY. Source: Acupuncture & Electro-Therapeutics Research. 2002; 27(3-4): 157-69. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12638736
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Inducible nitric oxide synthase is involved in acid-induced gastric hyperemia in rats and mice. Author(s): Phillipson M, Henriksnas J, Holstad M, Sandler S, Holm L. Source: American Journal of Physiology. Gastrointestinal and Liver Physiology. 2003 July; 285(1): G154-62. Epub 2003 March 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12646421
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Induction of nitric oxide synthase (NOS) by soluble glucocorticoid induced tumor necrosis factor receptor (sGITR) is modulated by IFN-gamma in murine macrophage. Author(s): Shin HH, Lee HW, Choi HS. Source: Experimental & Molecular Medicine. 2003 June 30; 35(3): 175-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12858016
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Induction of nitric oxide synthase expression by Withania somnifera in macrophages. Author(s): Iuvone T, Esposito G, Capasso F, Izzo AA. Source: Life Sciences. 2003 February 21; 72(14): 1617-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12551750
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Induction of vasorelaxation through activation of nitric oxide synthase in endothelial cells by brazilin. Author(s): Hu CM, Kang JJ, Lee CC, Li CH, Liao JW, Cheng YW. Source: European Journal of Pharmacology. 2003 May 2; 468(1): 37-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12729841
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Inhibition of inducible isoforms of cyclooxygenase and nitric oxide synthase by flavonoid hesperidin in mouse macrophage cell line. Author(s): Sakata K, Hirose Y, Qiao Z, Tanaka T, Mori H. Source: Cancer Letters. 2003 September 25; 199(2): 139-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12969786
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Inhibition of lipopolysaccharide-induced nitric oxide production by flavonoids in RAW264.7 macrophages involves heme oxygenase-1. Author(s): Lin HY, Juan SH, Shen SC, Hsu FL, Chen YC. Source: Biochemical Pharmacology. 2003 November 1; 66(9): 1821-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14563492
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Inhibition of matrix metalloproteinase-1 and -2 expression using nitric oxide synthase inhibitors in UV-irradiated human dermal fibroblasts. Author(s): Choe T, Lee B, Park I, Hong S. Source: J Cosmet Sci. 2003 May-June; 54(3): 229-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12858222
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Inhibition of nitric oxide production on LPS-activated macrophages by kazinol B from Broussonetia kazinoki. Author(s): Ryu JH, Ahn H, Jin Lee H. Source: Fitoterapia. 2003 June; 74(4): 350-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12781805
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Inhibition of nitric oxide/cyclic GMP-mediated relaxation by purified flavonoids, baicalin and baicalein, in rat aortic rings. Author(s): Huang Y, Wong CM, Lau CW, Yao X, Tsang SY, Su YL, Chen ZY. Source: Biochemical Pharmacology. 2004 February 15; 67(4): 787-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14757179
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Inhibitors of inducible nitric oxide synthase expression from Artemisia iwayomogi. Author(s): Ahn H, Kim JY, Lee HJ, Kim YK, Ryu JH. Source: Arch Pharm Res. 2003 April; 26(4): 301-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12735688
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Inhibitors of nitric oxide production from the bark of Myrica rubra: structures of new biphenyl type diarylheptanoid glycosides and taraxerane type triterpene. Author(s): Tao J, Morikawa T, Toguchida I, Ando S, Matsuda H, Yoshikawa M. Source: Bioorganic & Medicinal Chemistry. 2002 December; 10(12): 4005-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12413852
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Inhibitory activity of plant extracts on nitric oxide synthesis in LPS-activated macrophages. Author(s): Ryu JH, Ahn H, Kim JY, Kim YK. Source: Phytotherapy Research : Ptr. 2003 May; 17(5): 485-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12748984
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Inhibitory effects of a new iridoid, patridoid II and its isomers, on nitric oxide and TNF-alpha production in cultured murine macrophages. Author(s): Ju HK, Moon TC, Lee E, Baek SH, An RB, Bae K, Son KH, Kim HP, Kang SS, Lee SH, Son JK, Chang HW. Source: Planta Medica. 2003 October; 69(10): 950-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14648401
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Inhibitory effects of the stem bark of Catalpa ovata G. Don. (Bignoniaceae) on the productions of tumor necrosis factor-alpha and nitric oxide by the lipopolisaccharidestimulated RAW 264.7 macrophages. Author(s): Pae HO, Oh GS, Choi BM, Shin S, Chai KY, Oh H, Kim JM, Kim HJ, Jang SI, Chung HT. Source: Journal of Ethnopharmacology. 2003 October; 88(2-3): 287-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12963157
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Inhibitory phenolic amides on lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells from Beta vulgaris var. cicla seeds. Author(s): Kim Y, Han MS, Lee JS, Kim J, Kim YC.
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Source: Phytotherapy Research : Ptr. 2003 September; 17(8): 983-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13680842 •
Intracellular expression of Mycobacterium tuberculosis-specific 10-kDa antigen down-regulates macrophage B7.1 expression and nitric oxide release. Author(s): Singh B, Singh G, Trajkovic V, Sharma P. Source: Clinical and Experimental Immunology. 2003 October; 134(1): 70-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12974757
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In-vitro anti-inflammatory effect of Eucalyptus globulus and Thymus vulgaris: nitric oxide inhibition in J774A.1 murine macrophages. Author(s): Vigo E, Cepeda A, Gualillo O, Perez-Fernandez R. Source: The Journal of Pharmacy and Pharmacology. 2004 February; 56(2): 257-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15005885
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Involvement of nitric oxide and hyperbaric oxygen in the pathogenesis of cyclophosphamide induced hemorrhagic cystitis in rats. Author(s): Korkmaz A, Oter S, Deveci S, Ozgurtas T, Topal T, Sadir S, Bilgic H. Source: The Journal of Urology. 2003 December; 170(6 Pt 1): 2498-502. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14634459
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Involvement of nitric oxide in the gastroprotective effects of an aqueous extract of Pfaffia glomerata (Spreng) Pedersen, Amaranthaceae, in rats. Author(s): Freitas CS, Baggio CH, Da Silva-Santos JE, Rieck L, de Moraes Santos CA, Junior CC, Ming LC, Garcia Cortez DA, Marques MC. Source: Life Sciences. 2004 January 16; 74(9): 1167-79. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687657
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Involvement of Ras in survival responsiveness to nitric oxide toxicity in pheochromocytoma cells. Author(s): Jeong HS, Kim SW, Baek KJ, Lee HS, Kwon NS, Kim YM, Yun HY. Source: Journal of Neuro-Oncology. 2002 November; 60(2): 97-107. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12635656
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Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase. Author(s): Jin ZG, Ueba H, Tanimoto T, Lungu AO, Frame MD, Berk BC. Source: Circulation Research. 2003 August 22; 93(4): 354-63. Epub 2003 July 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12893742
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Lipopolysaccharide enhancement of 12-o-tetradecanoylphorbol 13-acetate-mediated transformation in rat glioma C6, accompanied by induction of inducible nitric oxide
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synthase. Author(s): Chen TJ, Shen SC, Lin HY, Chien LL, Chen YC. Source: Toxicology Letters. 2004 February 28; 147(1): 1-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14700523 •
Lipoxygenase products regulate nitric oxide and inducible nitric oxide synthase production in interleukin-1beta stimulated vascular smooth muscle cells. Author(s): Hashimoto T, Kihara M, Yokoyama K, Fujita T, Kobayashi S, Matsushita K, Tamura K, Hirawa N, Toya Y, Umemura S. Source: Hypertens Res. 2003 February; 26(2): 177-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12627879
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Long-chain polyunsaturated fatty acids interact with nitric oxide, superoxide anion, and transforming growth factor-beta to prevent human essential hypertension. Author(s): Das UN. Source: European Journal of Clinical Nutrition. 2004 February; 58(2): 195-203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14749737
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Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Author(s): d'Uscio LV, Milstien S, Richardson D, Smith L, Katusic ZS. Source: Circulation Research. 2003 January 10; 92(1): 88-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12522125
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Modulation of inducible nitric oxide synthase and related proinflammatory genes by the omega-3 fatty acid docosahexaenoic acid in human colon cancer cells. Author(s): Narayanan BA, Narayanan NK, Simi B, Reddy BS. Source: Cancer Research. 2003 March 1; 63(5): 972-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12615711
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Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium. Author(s): Vincent MA, Montagnani M, Quon MJ. Source: Curr Diab Rep. 2003 August; 3(4): 279-88. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12866989
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Neuronal nitric oxide synthase and N-methyl-D-aspartate neurons in experimental carbon monoxide poisoning. Author(s): Thom SR, Fisher D, Zhang J, Bhopale VM, Cameron B, Buerk DG. Source: Toxicology and Applied Pharmacology. 2004 February 1; 194(3): 280-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14761684
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NF-kappa B plays a protective role in nitric oxide-induced neuronal apoptosis. Author(s): Feng ZW, Tan V, Khoo KS, Leck KJ. Source: Ann Acad Med Singapore. 2003 September; 32(5 Suppl): S30-1. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14968726
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Nitric oxide and cyclooxygenase may participate in the analgesic and antiinflammatory effect of the cucurbitacins fraction from Wilbrandia ebracteata. Author(s): Peters RR, Baier Krepsky P, Siqueira-Junior JM, da Silva Rocha JC, Marques Bezerra M, de Albuquerque Ribeiro R, de Brum-Fernandes AJ, Rocha Farias M, Castro da Rocha FA, Ribeiro-do-Valle RM. Source: Life Sciences. 2003 September 12; 73(17): 2185-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12927589
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Nitric oxide and iron metabolism in exercised rat with L-arginine supplementation. Author(s): Xiao DS, Jiang L, Che LL, Lu L. Source: Molecular and Cellular Biochemistry. 2003 October; 252(1-2): 65-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14577577
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Nitric oxide donors inhibit formation of the Apaf-1/caspase-9 apoptosome and activation of caspases. Author(s): Zech B, Kohl R, von Knethen A, Brune B. Source: The Biochemical Journal. 2003 May 1; 371(Pt 3): 1055-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12605597
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Nitric oxide improves internal iron availability in plants. Author(s): Graziano M, Beligni MV, Lamattina L. Source: Plant Physiology. 2002 December; 130(4): 1852-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12481068
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Nitric oxide in the gracile nucleus mediates depressor response to acupuncture (ST36). Author(s): Chen S, Ma SX. Source: Journal of Neurophysiology. 2003 August; 90(2): 780-5. Epub 2003 April 02. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12672780
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Nitric oxide inhibitory isopimarane-type diterpenes from Orthosiphon stamineus of Indonesia. Author(s): Awale S, Tezuka Y, Banskota AH, Adnyana IK, Kadota S. Source: Journal of Natural Products. 2003 February; 66(2): 255-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12608860
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Nitric oxide mediated photo-induced cell death in human malignant cells. Author(s): Ali SM, Olivo M. Source: International Journal of Oncology. 2003 April; 22(4): 751-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12632064
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Nitric oxide production by alveolar macrophages in response to house dust mite fecal pellets and the mite allergens, Der p 1 and Der p 2. Author(s): Peake HL, Currie AJ, Stewart GA, McWilliam AS. Source: The Journal of Allergy and Clinical Immunology. 2003 September; 112(3): 531-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13679812
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Nitric oxide suppresses apoptosis in human colon cancer cells by scavenging mitochondrial superoxide anions. Author(s): Wenzel U, Kuntz S, De Sousa UJ, Daniel H. Source: International Journal of Cancer. Journal International Du Cancer. 2003 September 20; 106(5): 666-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12866025
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Nitric oxide synthase in Entamoeba histolytica: its effect on rat aortic rings. Author(s): Hernandez-Campos ME, Campos-Rodriguez R, Tsutsumi V, Shibayama M, Garcia-Latorre E, Castillo-Henkel C, Valencia-Hernandez I. Source: Experimental Parasitology. 2003 July-August; 104(3-4): 87-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14552855
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Nitric oxide synthase-mediated phytoalexin accumulation in soybean cotyledons in response to the Diaporthe phaseolorum f. sp. meridionalis elicitor. Author(s): Modolo LV, Cunha FQ, Braga MR, Salgado I. Source: Plant Physiology. 2002 November; 130(3): 1288-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12427995
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Nitric oxide triggers the toxicity due to glutathione depletion in midbrain cultures through 12-lipoxygenase. Author(s): Canals S, Casarejos MJ, de Bernardo S, Rodriguez-Martin E, Mena MA. Source: The Journal of Biological Chemistry. 2003 June 13; 278(24): 21542-9. Epub 2003 April 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679339
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Nitric oxide, human diseases and the herbal products that affect the nitric oxide signalling pathway. Author(s): Achike FI, Kwan CY.
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Source: Clinical and Experimental Pharmacology & Physiology. 2003 September; 30(9): 605-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12940876 •
Nitric oxide-mediated vasorelaxation by Rhizoma Ligustici wallichii in isolated rat thoracic aorta. Author(s): Rhyu MR, Kim EY, Kim B. Source: Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2004 January; 11(1): 51-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14971721
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Nitric oxide-related toxicity in cultured astrocytes: effect of Bacopa monniera. Author(s): Russo A, Borrelli F, Campisi A, Acquaviva R, Raciti G, Vanella A. Source: Life Sciences. 2003 August 8; 73(12): 1517-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865091
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Nitric oxide-releasing aspirin protects gastric mucosa against ethanol damage in rats with functional ablation of sensory nerves. Author(s): Konturek PC, Brzozowski T, Kania J, Konturek SJ, Hahn EG. Source: Inflammation Research : Official Journal of the European Histamine Research Society. [et Al.]. 2003 September; 52(9): 359-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14504662
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Oxygen seizure latency and peroxynitrite formation in mice lacking neuronal or endothelial nitric oxide synthases. Author(s): Demchenko IT, Atochin DN, Boso AE, Astern J, Huang PL, Piantadosi CA. Source: Neuroscience Letters. 2003 June 19; 344(1): 53-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12781920
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Plasma nitric oxide level in familial Mediterranean fever and its modulations by Immuno-Guard. Author(s): Panossian A, Hambartsumyan M, Panosyan L, Abrahamyan H, Mamikonyan G, Gabrielyan E, Amaryan G, Astvatsatryan V, Wikman G. Source: Nitric Oxide : Biology and Chemistry / Official Journal of the Nitric Oxide Society. 2003 September; 9(2): 103-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14623176
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Preservation of amino acids during long term ischemia and subsequent reflow with supplementation of L-arginine, the nitric oxide precursor, in the rat heart. Author(s): Desrois M, Sciaky M, Lan C, Cozzone PJ, Bernard M. Source: Amino Acids. 2003; 24(1-2): 141-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12624746
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Production of nitric oxide and tumor necrosis factor-alpha by Smilacis rhizoma in mouse peritoneal macrophages. Author(s): Chung HS, Shin CH, Lee EJ, Hong SH, Kim HM. Source: Comparative Biochemistry and Physiology. Toxicology & Pharmacology : Cbp. 2003 June; 135(2): 197-203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12860059
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Prognostic role of serum vascular endothelial growth factor, basic fibroblast growth factor and nitric oxide in patients with colorectal carcinoma. Author(s): Akbulut H, Altuntas F, Akbulut KG, Ozturk G, Cindoruk M, Unal E, Icli F. Source: Cytokine. 2002 November 24; 20(4): 184-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12543084
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Protein kinase C and protein tyrosine kinase mediate lipopolysaccharide- and cytokine-induced nitric oxide formation in vascular smooth muscle cells of rats. Author(s): Han YL, Kang J, Li SH. Source: Sheng Li Xue Bao. 2003 June 25; 55(3): 265-272. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12817292
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Proteinase-activated receptor-2-induced colonic inflammation in mice: possible involvement of afferent neurons, nitric oxide, and paracellular permeability. Author(s): Cenac N, Garcia-Villar R, Ferrier L, Larauche M, Vergnolle N, Bunnett NW, Coelho AM, Fioramonti J, Bueno L. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 April 15; 170(8): 4296-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12682265
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Purification of gastroprotective triterpenoids from the stem bark of Amphipterygium adstringens; role of prostaglandins, sulfhydryls, nitric oxide and capsaicin-sensitive neurons. Author(s): Arrieta J, Benitez J, Flores E, Castillo C, Navarrete A. Source: Planta Medica. 2003 October; 69(10): 905-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14648392
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Quercetin-dependent reduction of salivary nitrite to nitric oxide under acidic conditions and interaction between quercetin and ascorbic acid during the reduction. Author(s): Takahama U, Yamamoto A, Hirota S, Oniki T. Source: Journal of Agricultural and Food Chemistry. 2003 September 24; 51(20): 6014-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13129310
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Regeneration of nitric oxide chelate absorption solution by two heterotrophic bacterial strains. Author(s): Jing GH, Li W, Shi Y, Ma BY, Tan TE.
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Source: Journal of Zhejiang University. Science. 2004 April; 5(4): 432-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14994433 •
Repeated treatment with the traditional medicine Unsei-in inhibits substance Pinduced itch-associated responses through downregulation of the expression of nitric oxide synthase 1 in mice. Author(s): Andoh T, Al-Akeel A, Tsujii K, Nojima H, Kuraishi Y. Source: Journal of Pharmacological Sciences. 2004 February; 94(2): 207-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14978361
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Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism. Author(s): Bradamante S, Barenghi L, Piccinini F, Bertelli AA, De Jonge R, Beemster P, De Jong JW. Source: European Journal of Pharmacology. 2003 March 28; 465(1-2): 115-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12650840
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Role of nitric oxide in rotenone-induced nigro-striatal injury. Author(s): He Y, Imam SZ, Dong Z, Jankovic J, Ali SF, Appel SH, Le W. Source: Journal of Neurochemistry. 2003 September; 86(6): 1338-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12950443
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Role of protein kinase C in BSA-AGE-mediated inducible nitric oxide synthase expression in RAW 264.7 macrophages. Author(s): Wu CH, Chang CH, Lin HC, Chen CM, Lin CH, Lee HM. Source: Biochemical Pharmacology. 2003 July 15; 66(2): 203-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826263
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Salviae miltiorrhizae ameliorates cirrhosis and portal hypertension by inhibiting nitric oxide in cirrhotic rats. Author(s): Wang H, Chen XP, Qiu FZ. Source: Hepatobiliary Pancreat Dis Int. 2003 August; 2(3): 391-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14599946
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Saponins from Cussonia bancoensis and their inhibitory effects on nitric oxide production. Author(s): Tapondjou LA, Lontsi D, Sondengam BL, Shaheen F, Choudhary MI, Atta-urRahman, van Heerden FR, Park HJ, Lee KT. Source: Journal of Natural Products. 2003 September; 66(9): 1266-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14510614
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Saucernetin-7 and saucernetin-8 isolated from Saururus chinensis inhibit the LPSinduced production of nitric oxide and prostaglandin E2 in macrophage RAW264.7
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cells. Author(s): Park HJ, Kim RG, Seo BR, Ha J, Ahn BT, Bok SH, Lee YS, Kim HJ, Lee KT. Source: Planta Medica. 2003 October; 69(10): 947-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14648400 •
Short polymers of arginine rapidly translocate into vascular cells: effects on nitric oxide synthesis. Author(s): Uemura S, Rothbard JB, Matsushita H, Tsao PS, Fathman CG, Cooke JP. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2002 December; 66(12): 1155-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12499624
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Soluble factor from murine bladder tumor-2 cell elevates nitric oxide production in macrophages and enhances the taxol-mediated macrophage cytotoxicity on tumor cells. Author(s): Choi SC, Oh HM, Park JS, Han WC, Yoon KH, Kim TH, Yun KJ, Kim EC, Nah YH, Cha YN, Chung HT, Jun CD. Source: Cancer Investigation. 2003; 21(5): 708-19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14628429
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Steroid hormones augment nitric oxide synthase activity and expression in rat uterus. Author(s): Ogando D, Farina M, Ribeiro ML, Perez Martinez S, Cella M, Rettori V, Franchi A. Source: Reproduction, Fertility, and Development. 2003; 15(5): 269-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14588184
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Stimulation of perivascular nitric oxide synthesis by oxygen. Author(s): Thom SR, Fisher D, Zhang J, Bhopale VM, Ohnishi ST, Kotake Y, Ohnishi T, Buerk DG. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2003 April; 284(4): H1230-9. Epub 2002 December 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12505879
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Structural requirements of flavonoids for nitric oxide production inhibitory activity and mechanism of action. Author(s): Matsuda H, Morikawa T, Ando S, Toguchida I, Yoshikawa M. Source: Bioorganic & Medicinal Chemistry. 2003 May 1; 11(9): 1995-2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12670650
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Structures of new cyclic diarylheptanoids and inhibitors of nitric oxide production from Japanese folk medicine Acer nikoense. Author(s): Morikawa T, Tao J, Toguchida I, Matsuda H, Yoshikawa M.
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Source: Journal of Natural Products. 2003 January; 66(1): 86-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12542351 •
Study on mechanism of action of Chinese medicine Chan Su: dose-dependent biphasic production of nitric oxide in trophoblastic BeWo cells. Author(s): Bhuiyan MB, Fant ME, Dasgupta A. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2003 April; 330(1-2): 179-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12636938
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Supplementation and inhibition of nitric oxide synthesis influences bacterial transit time during bacterial translocation in rats. Author(s): Samel S, Keese M, Lanig S, Kleczka M, Gretz N, Hafner M, Sturm J, Post S. Source: Shock (Augusta, Ga.). 2003 April; 19(4): 378-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12688551
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Suppression effect of Cinnamomum cassia bark-derived component on nitric oxide synthase. Author(s): Lee HS, Kim BS, Kim MK. Source: Journal of Agricultural and Food Chemistry. 2002 December 18; 50(26): 7700-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12475291
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Suppression of inducible nitric oxide production by indole and isothiocyanate derivatives from Brassica plants in stimulated macrophages. Author(s): Chen YH, Dai HJ, Chang HP. Source: Planta Medica. 2003 August; 69(8): 696-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14531017
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Synergistic suppression of superoxide and nitric oxide generation from inflammatory cells by combined food factors. Author(s): Murakami A, Takahashi D, Koshimizu K, Ohigashi H. Source: Mutation Research. 2003 February-March; 523-524: 151-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12628513
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Tanshinone IIA from Salvia miltiorrhiza inhibits inducible nitric oxide synthase expression and production of TNF-alpha, IL-1beta and IL-6 in activated RAW 264.7 cells. Author(s): Jang SI, Jeong SI, Kim KJ, Kim HJ, Yu HH, Park R, Kim HM, You YO. Source: Planta Medica. 2003 November; 69(11): 1057-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14735448
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Terminoside A, a new triterpene glycoside from the bark of Terminalia arjuna inhibits nitric oxide production in murine macrophages. Author(s): Ali A, Kaur G, Hamid H, Abdullah T, Ali M, Niwa M, Alam MS. Source: Journal of Asian Natural Products Research. 2003 June; 5(2): 137-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12765198
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Ternatin, an anti-inflammatory flavonoid, inhibits thioglycolate-elicited rat peritoneal neutrophil accumulation and LPS-activated nitric oxide production in murine macrophages. Author(s): Rao VS, Paiva LA, Souza MF, Campos AR, Ribeiro RA, Brito GA, Teixeira MJ, Silveira ER. Source: Planta Medica. 2003 September; 69(9): 851-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14598213
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The diuretic effect of Sairei-to is mediated by nitric oxide production in pentobarbital-anesthetized rats. Author(s): Fujitsuka N, Goto K, Takeda S, Aburada M. Source: Journal of Pharmacological Sciences. 2004 February; 94(2): 185-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14978357
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The in vitro effect of aqueous extract of Nigella sativa seeds on nitric oxide production. Author(s): Mahmood MS, Gilani AH, Khwaja A, Rashid A, Ashfaq MK. Source: Phytotherapy Research : Ptr. 2003 September; 17(8): 921-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13680825
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The influence of two different doses of L-arginine oral supplementation on nitric oxide (NO) concentration and total antioxidant status (TAS) in atherosclerotic patients. Author(s): Jablecka A, Checinski P, Krauss H, Micker M, Ast J. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2004 January; 10(1): Cr29-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704633
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The phytoestrogen equol increases nitric oxide availability by inhibiting superoxide production: an antioxidant mechanism for cell-mediated LDL modification. Author(s): Hwang J, Wang J, Morazzoni P, Hodis HN, Sevanian A. Source: Free Radical Biology & Medicine. 2003 May 15; 34(10): 1271-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12726915
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The role of spinal nitric oxide and glutamate in nociceptive behaviour evoked by high-dose intrathecal morphine in rats. Author(s): Watanabe C, Sakurada T, Okuda K, Sakurada C, Ando R, Sakurada S.
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Source: Pain. 2003 December; 106(3): 269-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14659510 •
Thymoquinone suppresses expression of inducible nitric oxide synthase in rat macrophages. Author(s): El-Mahmoudy A, Matsuyama H, Borgan MA, Shimizu Y, El-Sayed MG, Minamoto N, Takewaki T. Source: International Immunopharmacology. 2002 October; 2(11): 1603-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12433061
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Upregulation of endothelial nitric oxide synthase in rat aorta after ingestion of a fish oil-rich diet. Author(s): Lopez D, Orta X, Casos K, Saiz MP, Puig-Parellada P, Farriol M, Mitjavila MT. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2004 April 1 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15059781
Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMDHealth: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
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The following is a specific Web list relating to nitric oxide; 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 Abdominal Wall Inflammation Source: Integrative Medicine Communications; www.drkoop.com Angina Source: Healthnotes, Inc.; www.healthnotes.com Congestive Heart Failure Source: Healthnotes, Inc.; www.healthnotes.com Erectile Dysfunction Source: Healthnotes, Inc.; www.healthnotes.com Gastritis Source: Healthnotes, Inc.; www.healthnotes.com High Blood Pressure Source: Integrative Medicine Communications; www.drkoop.com Hypertension Source: Integrative Medicine Communications; www.drkoop.com Intermittent Claudication Source: Healthnotes, Inc.; www.healthnotes.com Peritonitis Source: Integrative Medicine Communications; www.drkoop.com Shock Source: Integrative Medicine Communications; www.drkoop.com
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Herbs and Supplements Aloe Alternative names: Aloe vera L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Arginine Source: Healthnotes, Inc.; www.healthnotes.com Arginine Source: Prima Communications, Inc.www.personalhealthzone.com Arginine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com
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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10005,00.html Betula Alternative names: Birch; Betula sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Curcuma Alternative names: Turmeric; Curcuma longa L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Eugenia Clove Alternative names: Cloves; Eugenia sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Ginkgo Alternative names: Ginkgo biloba Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Ocimum Alternative names: Basil, Albahaca; Ocimum basilicum Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Panax Alternative names: Ginseng; Panax ginseng Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Zizyphus Alternative names: Jujube; Ziziphus sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
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 NITRIC OXIDE Overview In this chapter, we will give you a bibliography on recent dissertations relating to nitric oxide. 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 “nitric oxide” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on nitric oxide, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Nitric Oxide 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 nitric oxide. 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 Model of Nitric Oxide Emissions from Jet Aircraft Engines by Craig, Roger A; PhD from York University (Canada), 1974 http://wwwlib.umi.com/dissertations/fullcit/NK21533
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A Shock Tube Study of the Thermal Decomposition of Nitric Oxide by Quac, Le Trung; PhD from University of Toronto (Canada), 1972 http://wwwlib.umi.com/dissertations/fullcit/NK15448
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Absolute Absorption Measurements of Molecular Oxygen, Nitric Oxide and Carbon Monoxide by Hasson, Victor; ADVDEG from York University (Canada), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK06984
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Biomimetic Nitric Oxide (no) Generation at Interface of Polymeric Materials Doped with Lipophilic Copper(ii)-complex by Oh, Bong Kyun; PhD from University of Michigan, 2003, 194 pages http://wwwlib.umi.com/dissertations/fullcit/3106138
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Catalytic Reduction of Nitric Oxide by Lamb, Arnold; PhD from University of Calgary (Canada), 1973 http://wwwlib.umi.com/dissertations/fullcit/NK28533
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Cdna Synthesis and Subcloning of Inducible Nitric Oxide Synthase Fragments for Future Secondary Calmodulin Binding Sites by Edwards, Amy Beth; MS from Stephen F. Austin State University, 2003, 58 pages http://wwwlib.umi.com/dissertations/fullcit/1414913
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Controlled Delivery of Nitric Oxide for Cytotoxicity Studies by Wang, Chen; PhD from Massachusetts Institute of Technology, 2003 http://wwwlib.umi.com/dissertations/fullcit/f245169
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Cutaneous Active Vasodilation in Humans: Contribution of Nitric Oxide and Vasoactive Intestinal Peptide by Wilkins, Brad William; PhD from University of Oregon, 2003, 145 pages http://wwwlib.umi.com/dissertations/fullcit/3095286
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Design of Unnatural Isocarbostyril and 2,4-difluorophenyl Pyrimidine Nucleoside Mimics, and Nitric Oxide Donor Nitrate Esters of Pyrimidine Nucleosides for Evaluation As Anticancer and Antiviral Agents by Naimi, Ebrahim; PhD from University of Alberta (Canada), 2003, 175 pages http://wwwlib.umi.com/dissertations/fullcit/NQ82144
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Development and Characterization of Mixed Oxide Catalysts for the Selective Catalytic Reduction of Nitric Oxide from Stationary Sources Using Ammonia by Pena, Donovan Alexander; PhD from University of Cincinnati, 2003, 260 pages http://wwwlib.umi.com/dissertations/fullcit/3093387
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Endothelial Cell Lipid Peroxidation Impairs Nitric Oxide Bioactivity by Samii, Jason Mehraban; PhD from Boston University, 2003, 223 pages http://wwwlib.umi.com/dissertations/fullcit/3077479
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High Resolution Raman Spectroscopy of Gases: (1) Rotation-vibrational Spectra of C2h2, C2d2, and C 2hd; (2) Rotation-electronic Spectrum of Nitric Oxide by Fast, Hans; ADVDEG from University of Toronto (Canada), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK08513
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Interaction between Adrenergic and Nitric Oxide-releasing Nerves in Cerebral Arteries by Mbaku, Emmanuel Ngu; PhD from Loma Linda University, 2003, 165 pages http://wwwlib.umi.com/dissertations/fullcit/3102318
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Interaction of O6-alkylguanine-dna Alkyltransferase with Nitric Oxide and Dihaloalkanes: Biochemical Mechanisms and Implication in Carcinogenesis by Liu, Liping; PhD from The Pennsylvania State University, 2003, 265 pages http://wwwlib.umi.com/dissertations/fullcit/3097007
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Is Xanthine Oxidase an Alternate Source for the Generation of Nitric Oxide during in Vivo Hypoxia? by Sanson, Angela Josephine; PhD from Union Institute and University, 2003, 70 pages http://wwwlib.umi.com/dissertations/fullcit/3104677
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Laser Generation of Vacuum Ultraviolet Radiation and Fluorescence Studies of Nitric Oxide by Banic, John R; PhD from University of Toronto (Canada), 1982 http://wwwlib.umi.com/dissertations/fullcit/NK58314
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Mathematical Modeling of Nitric Oxide Transport Mechanisms by Lamkin-Kennard, Kathleen Ann; PhD from Drexel University, 2003, 163 pages http://wwwlib.umi.com/dissertations/fullcit/3081060
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Measurements of Nitric Oxide, Nitrogen Dioxide and Nitric Acid in Ambient and Captive Air by Second Harmonic Detection with Tunable Diode Lasers by Iguchi, Toshio; PhD from York University (Canada), 1983 http://wwwlib.umi.com/dissertations/fullcit/NK58748
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Mechanism of the Induction of Nitric Oxide Production by Articular Chondrocytes Activated by Hyaluronan Oligosaccharides by Iacob, Stanca; PhD from Rush University, 2003, 85 pages http://wwwlib.umi.com/dissertations/fullcit/3100081
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Nitric Oxide and Carbon Monoxide: Novel Neurotransmitters in the Enteric Nervous System by Watkins, Crystal Chanel; PhD from The Johns Hopkins University, 2003, 196 pages http://wwwlib.umi.com/dissertations/fullcit/3080791
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Nitric Oxide/cyclic Gmp Signaling in the Central Nervous System of Manduca Sexta Larvae by Zayas Ventura, Ricardo Manuel; PhD from Tufts University, 2003, 166 pages http://wwwlib.umi.com/dissertations/fullcit/3074514
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Nitrogen Oxide Cation Formation in Noble Gas-nitric Oxide Rf Discharges by Keskinen, Kai J; PhD from York University (Canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL33176
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Photofragment Ion Imaging in Photodissociation Dynamics: Studies of Sulfur Dioxide, Nitrous Oxide and Nitric Oxide by Cosofret, Bogdan Radu; PhD from Cornell University, 2003, 162 pages http://wwwlib.umi.com/dissertations/fullcit/3075873
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Predissociation of Nitric Oxide by Radiative Recombination in the Delta System, the F-value for the Delta(0,0) Band by Mandelman, Michael; PhD from York University (Canada), 1974 http://wwwlib.umi.com/dissertations/fullcit/NK20018
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Reactions of Methylfluorosilanes with Singlet Methylene and with Nitric Oxide (4pi) by Soto-Garrido, Gabriela E.; PhD from Simon Fraser University (Canada), 1984 http://wwwlib.umi.com/dissertations/fullcit/NK65962
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Regulation of Endothelial Nitric Oxide Synthase Expression by Laminar Shear Stress by Davis, Michael Elliot; PhD from Emory University, 2003, 112 pages http://wwwlib.umi.com/dissertations/fullcit/3080312
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Regulation of Inducible Nitric Oxide Synthase: Consequences in Experimental Models of Bladder Disease by Johansson, Rebecka Karin; PhD from Lunds Universitet (Sweden), 2003, 132 pages http://wwwlib.umi.com/dissertations/fullcit/f332049
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Regulation of the Lps-induced Cytotoxic Response in Murine Macrophages: Roles of Nitric Oxide and Autocrine Ifn-beta; by Jacobs, Aaron Thomas; PhD from University of California, Los Angeles, 2003, 244 pages http://wwwlib.umi.com/dissertations/fullcit/3081152
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Role of Nitric Oxide and K(atp) Channels in Pharmacological Preconditioning of the Heart by Ockaili, Ramzi Ali; PhD from Virginia Commonwealth University, 2003, 196 pages http://wwwlib.umi.com/dissertations/fullcit/3081856
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Role of Nitric Oxide in the Regulation of Tumor Necrosis Factor-alpha Signalling by Barsacchi, Rico; PhD from Open University (United Kingdom), 2003 http://wwwlib.umi.com/dissertations/fullcit/f70257
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Role of Protein Tyrosine Phosphatase-pest in Nitric Oxide-induced Inhibition of Basal and Insulin-stimulated Cell Motility by Lin, Yi; PhD from The University of Tennessee Center for the Health Sciences, 2003, 115 pages http://wwwlib.umi.com/dissertations/fullcit/3085400
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Role of Regulatory Carboxypeptidases in Nitric Oxide Production in Endothelial Cells by Sangsree, Sakonwun; PhD from University of Illinois at Chicago, Health Sciences Center, 2003, 145 pages http://wwwlib.umi.com/dissertations/fullcit/3083956
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S-nitrosothiothiols, Nitric Oxide, and Heme Proteins by Spencer, Netanya Yehudit; PhD from The Medical College of Wisconsin, 2003, 280 pages http://wwwlib.umi.com/dissertations/fullcit/3090061
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Spectroscopy and Dynamics of Vibrationally Autoionizing Nitric Oxide Rydberg States by Konen, Ian Michael; PhD from Stanford University, 2003, 111 pages http://wwwlib.umi.com/dissertations/fullcit/3085317
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The Effects of Nitric Oxide on the Pyrolysis of Ethane by Esser, Joseph; ADVDEG from University of Ottawa (Canada), 1969 http://wwwlib.umi.com/dissertations/fullcit/NK08399
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The Heme Oxygenase/carbon Monoxide System in the Retina: Biochemistry, Anatomy and Interactions with the Nitric Oxide/cgmp Pathway by Cao, Luxiang; PhD from Boston University, 2003, 153 pages http://wwwlib.umi.com/dissertations/fullcit/3072378
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The Photolysis of Hydrogen Iodine in Presence of Nitric Oxide by Sundaram, Embar Venkatachari; ADVDEG from University of Ottawa (Canada), 1965 http://wwwlib.umi.com/dissertations/fullcit/NK04752
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The Pyrolysis of Acetaldehyde in the Presence of Nitric Oxide by Schuchmann, HeinzPeter; PhD from University of Ottawa (Canada), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK12375
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The Role of Nitric Oxide in Cholesteatoma-induced Bone Resorption by Jung, Jae Yeon; PhD from Washington University, 2003, 118 pages http://wwwlib.umi.com/dissertations/fullcit/3095526
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Transcriptional Regulation of the Human Inducible Nitric Oxide Synthase Gene by Warke, Vishal Gangadhar; PhD from University of Maryland College Park, 2003, 198 pages http://wwwlib.umi.com/dissertations/fullcit/3094554
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 NITRIC OXIDE Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning nitric oxide.
Recent Trials on Nitric Oxide The following is a list of recent trials dedicated to nitric oxide.8 Further information on a trial is available at the Web site indicated. •
Development of a Hospital-Based Home Program for the Use of Inhaled Nitric Oxide in the Chronic Management of Severe Cardiopulmonary Diseases Condition(s): Pulmonary Hypertension; Lung Disease; Sickle Cell Disease; Cardiac transplant; Lung transplant Study Status: This study is currently recruiting patients. Sponsor(s): INO Therapeutics Purpose - Excerpt: The purpose of this program is to evaluate the logistic issues and patient requirements for chronic pulsed INOmax delivery in ambulatory, home-care patients. To understand patient needs, patients with a variety of underlying diseases will be included. Safety of chronic therapy will be monitored by serial measurements of methemoglobin, platelet function assay and reported adverse events. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00041574
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Dietary Nitrate and Nitrite to Increase Nitric Oxide in Patients with Coronary Artery Disease Condition(s): Coronary Arteriosclerosis
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These are listed at www.ClinicalTrials.gov.
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Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will determine whether dietary nitrates and nitrites can produce nitric oxide in the body and dilate blood vessels in patients with coronary artery disease. Nitric oxide is normally made by endothelial cells that line blood vessels. It plays an important role in maintaining the normal function of arteries by keeping them open and preventing damage from substances such as cholesterol in the blood stream. Coronary artery disease is caused by atherosclerosis (hardening of the arteries or build-up of cholesterol and scar tissue within the walls of the arteries). Once arteries become clogged, the ability of the endothelium to produce nitric oxide diminishes considerably and may speed up the disease process, leading to shortness of breath, chest pain, and an increased risk of heart attack or stroke. Patients 21 years of age and older with coronary artery disease may be eligible for this study. Participants will have a medical history and physical examination, electrocardiogram (recording of the electrical activity of the heart), echocardiogram (ultrasound test of the heart), treadmill exercise stress test (see below), and will meet with a dietitian. They will be hospitalized at the NIH Clinical Center on two occasions. For 1 week before each admission, they will follow a diet prescribed by an NIH nutritionist. The diet before one admission will be high in nitrates and nitrites, and the diet before the other admission will be low in nitrates and nitrites. Each admission will last 4 days, during which participants will undergo the following tests: - Forearm blood flow study: Small tubes are placed in the artery and vein at the inside of the elbow of the dominant arm (right- or left-handed) and a small tube is placed in a vein of the other arm. The tubes are used for infusing saline (salt water) and for drawing blood samples. A pressure cuff is placed around the upper part of the dominant arm, and a rubber band device called a strain gauge is also placed around the arm to measure blood flow. When the cuff is inflated, blood flows into the arm, stretching the strain gauge at a rate proportional to the flow. Maximum grip-strength of the dominant arm is measured with a dynamometer. Forearm blood flow is measured and blood samples are drawn at the following times: 20 minutes after the tubes are placed; during a hand-grip exercise; and 4 minutes after the exercise is completed. - Brachial artery reactivity study: This test measures how well the patient's arteries widen. For the procedure, the patient rests on a bed for 30 minutes. An ultrasound measuring instrument is then placed over the artery just above the elbow. The artery size and the flow of blood through it are measured before and after a pressure cuff around the forearm is inflated. Fifteen minutes later, the same measurements are taken before and 3 minutes after a nitroglycerin tablet is placed under the patient's tongue. Treadmill exercise testing: Patients exercise on a treadmill until they experience chest pain, shortness of breath, or tiredness. The patient's heart rhythm is monitored continuously and blood pressure is measured every 3 minutes. A nurse and doctor are in attendance throughout the study. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069654 •
Effects of Inhaled Nitric Oxide in the Treatment of Acute Hypoxemic Respiratory Failure (AHRF) in Pediatrics Condition(s): Respiratory Insufficiency; Anoxemia Study Status: This study is currently recruiting patients.
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Sponsor(s): INO Therapeutics Purpose - Excerpt: The purpose of this study is to determine the effect of nitric oxide for inhalation on the duration of mechanical ventilation in pediatric patients with AHRF. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00041561 •
Inhaled Nitric Oxide and Transfusion Therapy for Patients with Sickle Cell Anemia and Secondary Pulmonary Hypertension Condition(s): Sickle Cell Anemia; Pulmonary Hypertension Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will test whether inhaling nitric oxide gas mixed with room air can improve pulmonary hypertension (high blood pressure in the lungs) in patients with sickle cell anemia. It is estimated that 20 to 30 percent of patients with sickle cell anemia have moderate to severe pulmonary hypertension, a disease complication associated with higher rates of illness and death. Patients with sickle cell disease 18 years of age or older may be eligible to participate in one or more parts of this three-stage study. Candidates will be screened with a medical history, physical examination, electrocardiogram, echocardiogram and blood tests. Those enrolled will undergo the following tests and procedures: Stage 1: Patients will be tested to determine the cause of pulmonary hypertension. They will have an echocardiogram (ultrasound study of the heart); a test for asthma, with measurement of arterial blood oxygen levels; oxygen breathing study with measurement of arterial blood oxygen levels; chest X-ray; computed tomography (CT) scans of the lung with and without contrast material; magnetic resonance imaging (MRI) of the heart; 6-minute walk to measure the distance covered in that time at a comfortable pace; night-hawks oxygen measurement while sleeping; blood tests for HIV, hepatitis virus, lupus and arthritis and pregnancy; pulmonary ventilation/perfusion scan with evaluation of shunt fraction to the brain and kidney; and exercise studies will be performed to determine oxygen and carbon dioxide consumption and production and to measure the anaerobic threshold. Stage 2: Patients who proceed with stage 2 will have a detailed MRI evaluation of the heart and will be admitted to the Clinical Center intensive care unit for the following procedure: A small intravenous (IV) catheter (plastic tube) is placed in the patient arm and a longer tube, called a central line, in a deeper neck or leg vein. A long thin tube is then inserted through the vein into the heart and the lung artery to measure all blood pressures in the heart and lungs directly. Following baseline measurements the following medications will be delivered for two hours each, separated by a 30 minute wash-out period. The patients is then given oxygen to breathe for 2 hours, followed by infusion of prostacyclin, a blood pressure-lowering drug, for 2 hours; and finally inhaled nitric oxide for 2 hours. A small blood sample (3 tablespoons) of blood is drawn during the nitric oxide administration. Stage 3: For patients who complete stage II or III and do not respond to NO gas as determined by a decrease in mean or systolic pulmonary artery pressure of greater than 10% from baseline or a 10% increase in 6 minute walk distance, or are unable to receive it due to technical, regulatory (no free standing home structure for storage of NO gas, etc.) or personal lifestyle issues (some patient do not want to carry two tanks of gas - oxygen and NO - or have difficulty learning how to use the NO
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gas system), we will offer regular exchange transfusions and home oxygen for three months with a goal of maintaining hemoglobin levels of 8-10 and hemoglobin S levels of less than 40%. The monitoring of patients receiving exchange transfusions will be the same as for the patients receiving NO gas: Measurements will include pulmonary artery pressure measured by repeat right heart catheterization, other hemodynamic parameters, exercise tolerance by 6-minute walk, plasma adhesion molecule levels, neutrophil and monocyte mRNA gene profiles, and circulating erythroid progenitor cell a/a hemoglobin message and protein levels. This portion of the study is to be undertaken as an outpatient. Clinical follow-up will involve bi-weekly clinic visits with the principal investigator, associate investigators, or study nurse. At these clinic visits venous blood will be obtained for hemoglobin electrophoresis (including hemoglobin F and A2), CBC, ESR, C-reactive protein and standard chemistries. Research blood, for plasma and erythrocyte reactive nitrogen species and plasma adhesion molecule levels, will be collected with total blood drawn per day not to exceed 30 mL. Protocol nurse or principal investigator will record total weekly symptoms, emergency room visits, hospital admissions, and narcotic use. Echocardiograms and 6-minute walk will be repeated at two-week intervals. 32 mL of blood will be drawn prior to the exchange transfusion and a 4 and 8 weeks for neutrophil and monocyte mRNA expression chip profiling. Patients who develop any complication of their disease (i.e. vaso-occlusive crisis, acute chest syndrome, let ulcers, priapism, avascular necrosis of the femoral hip, asthma, etc.) will be strongly encouraged to directly come to the Clinical Center's 10D ICU for evaluation and direct admission by the 10D ICU physician on-call. If they are very ill they will be instructed to either call and ambulance or go to the nearest emergency room. If they are relatively stable, patients will be instructed to call the 10D ICU and speak with the physician on-call. We will follow patients according to the NO protocol with right heart catheterization at 3 months of therapy and serial echocardiograms. The effects of exchange transfusion will be statistically analyzed separately but in a similar fashion as delineated for NO treatment. All patients will complete Stage I and II of the study prior to entering into Exchange Transfusion therapy. Patients with greater than a 10% increase in six-minute walk distance or a 10% reduction in mean or systolic pulmonary artery pressures, who want to continue Exchange Transfusion therapy will have the option of continuing therapy. In these cases, blood draws and clinical follow-up will be reduced to bi-monthly intervals and when clinically indicated. The Clinical Center will continue to pay for these clinic visits and urgent care at the Clinical Center. The Transfusion Therapy and the Clinical Center care will continue until the study has terminated (anticipated three year study duration). Our physicians and social workers will work with patients to help them obtain appropriate insurance to cover Exchange Transfusion therapy. However, it is possible that circumstances may arise that prevent the patient from continuing this therapy after the study is terminated. Alternative Therapies Patients who have enrolled in the NO or transfusion treatment arm of the study who do not respond to the treatment (defined by a 10% reduction in mean or systolic pulmonary artery pressure measured by right heart catheterization or a 10% increase in 6-minute walk distance) will be eligible to receive the alternative therapy (NO or transfusion) or other FDA approved medications. These medications may include oxygen, prostacyclin (flolan or remodulin), L-arginine, bosentan or sidenafil. We will limit the number of patients who are treated with medication other than NO or exchange transfusion to 10 subjects. Such patients will be managed at the NIH, in collaboration with their primary medical providers, according to accepted current standards of care using only FDA approved medication. The effect of such treatments on estimated pulmonary artery pressures, measured by echocardiogram, and on 6-minute walk distance will be assessed at regular intervals (every 1-3 months while on protocol) and all adverse events reported to the IRB and
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DSMB as defined by the current protocol. Patients maintained on alternative therapies will not have research bloods drawn, all laboratory testing will be obtained only for clinical indications. Such patients may be managed on this protocol until the protocol is terminated, the medication used becomes FDA approved specifically for use in sickle cell disease, the patient wishes to end participation, or the patient wishes to enroll in another study for treatment of pulmonary hypertension. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023296 •
Inhaled Nitric Oxide in Neonates with Elevated A-a DO2 Gradients Not Requiring Mechanical Ventilation Condition(s): Lung Disease; Hypoxemia; Respiratory Acidosis Study Status: This study is currently recruiting patients. Sponsor(s): INO Therapeutics Purpose - Excerpt: The purpose of this pilot study is to evaluate whether administration of nitric oxide (NO)gas by oxygen hood at 20 ppm significantly increases PaO2, as compared to placebo gas (oxygen), within one hour of initiation and with no significant adverse effects. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00041548
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Inhaled Nitric Oxide in Prevention/Treatment of Ischemia-Reperfusion Lung Injury Related to Lung Transplantation Condition(s): Ischemia-Reperfusion Injury Study Status: This study is currently recruiting patients. Sponsor(s): INO Therapeutics Purpose - Excerpt: The purpose of this study is to evaluate the effects of inhaled nitric oxide on both short-term physiology as well as on the development of ischemiarepertusion lung injury (IRLI) in the immediate post transplant period. The specific hypothesis is that inhaled NO post lung transplantation will improve gas exchange/hemodynamic and thus reduce the development of post transplant IRLI. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00060450
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Role of nitric oxide in cirrhosis: relationship with systemic hemodynamics, renal function, vasoactive systems and endotoxemia Condition(s): Cirrhosis; Liver Cirrhosis
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Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: This study is to determine whether a compound, nitric oxide, made within the body, is the factor responsible for the changes in blood pressure and renal (kidney) functions that may occur during the course of cirrhosis. Patients with cirrhosis (liver scarring which causes poor liver function) will be eligible to participate. A group of healthy subjects will also be studied to compare the effects of the treatment to patients with cirrhosis and to confirm safety. A total number of 30 patients with cirrhosis and 10 healthy subjects will be enrolled in the study. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005107 •
Study of Inhaled Nitric Oxide for Preterm Infants Condition(s): Respiratory Distress Syndrome; Infant, premature; Sepsis; Pneumonia; Hypertension, Pulmonary Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Child Health and Human Development (NICHD) Purpose - Excerpt: This multicenter trial tests whether inhaled nitric oxide will reduce death or the need for oxygen at 36 weeks postmenstrual age in preterm infants with severe lung disease. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00016523
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The Effects of Nitric Oxide for Inhalation During Left Ventricular Assists Device (LVAD) Implantation Condition(s): Congestive Heart Failure Study Status: This study is currently recruiting patients. Sponsor(s): INO Therapeutics Purpose - Excerpt: The purpose of this study is to assess the effects of nitric oxide for inhalation during left ventricular assist device (LVAD) implantation following cardiopulmonary bypass (CPB). This is to be assessed by the number of patients in each treatment group meeting failure criteria, as defined by two or more of the following: * Left ventricular flow rate index (LVFRI) <= 1.8 L/min/m2 * Administration of >= 1 ug/kg/min epinephrine or norepinephrine * Mean arterial pressure (MAP) <= 50 mmHg * Central venous pressure (CVP) >= 20 mmHg * Mixed venous oxygen saturation (SvO2) <= 55% Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below
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Web Site: http://clinicaltrials.gov/ct/show/NCT00060840
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 “nitric oxide” (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 NITRIC OXIDE 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 “nitric oxide” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on nitric oxide, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Nitric Oxide By performing a patent search focusing on nitric oxide, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 9Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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example of the type of information that you can expect to obtain from a patent search on nitric oxide: •
Amidino compounds useful as nitric oxide synthase inhibitors Inventor(s): Awasthi; Alok K. (Skokie, IL), Bergmanis; Arija A. (Des Plaines, IL), Durley; Richard C. (Chesterfield, MO), Fok; Kam F. (St. Louis, MO), Ganser; Scott S. (Chicago, IL), Hagen; Timothy J. (Gurne, IL), Hallinan; E. Ann (Evanston, IL), Hansen, Jr.; Donald W. (Skokie, IL), Hickory; Brian S. (Wildwood, MO), Manning; Pamela T. (Labadie, MO), Mao; Michael (Chesterfield, MO), Moormann; Alan E. (Weldon Spring, MO), Pitzele; Barnett S. (Skokie, IL), Promo; Michelle A. (Chesterfield, MO), Schartman; Richard R. (Evanston, IL), Scholten; Jeffrey A. (Chesterfield, MO), Snyder; Jeffrey S. (Manchester, MO), Tjoeng; Foe Siong (Ballwin, MO), Toth; Mihaly V. (St. Louis, MO), Trivedi; Mahima (Glenview, IL), Tsymbalov; Sofya (Skokie, IL), Webber; Ronald Keith (St. Charles, MO) Assignee(s): Pharmacia Corporation (st. Louis, Mo) Patent Number: 6,586,474 Date filed: March 23, 2001 Abstract: The present invention relates to amidino compounds and salts and prodrugs thereof. In another embodiment the present invention also provides a use of the present compounds in therapy, particular as nitric oxide synthase inhibitors. In a further embodiment, the present invention provides methods of making the amidino compounds. Excerpt(s): The present invention relates to amidino compounds and their use in therapy, in particular their use as nitric oxide synthase inhibitors. It has been known since the early 1980's that the vascular relaxation caused by acetylcholine is dependent on the vascular endothelium. The endothelium-derived relaxing factor (EDRF), now known to be nitric oxide (NO) is generated in the vascular endothelium by nitric oxide synthase (NOS). The activity of NO as a vasodilator has been known for well over 100 years. In addition, NO is the active species deriving from amylnitrite, glyceryltrinitrate and other nitrovasodilators. The identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesized from the amino acid Larginine by the enzyme NO synthase. Nitric oxide is an endogenous stimulator of the soluble guanylate cyclase. In addition to endothelium-dependent relaxation, NO is involved in a number of biological actions including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system. Web site: http://www.delphion.com/details?pn=US06586474__
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Composition and method of treating arthritis Inventor(s): Petrus; Edward J. (Austin, TX) Assignee(s): Advanced Medical Instruments (austin, Tx) Patent Number: 6,656,925 Date filed: February 5, 2002 Abstract: This invention relates to the compositions and method of treating and preventing arthritis, repairing of articular joint surfaces and the relief of symptoms associated with arthritis. The composition comprises bio-affecting agents to reduce
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nitric oxide production and increase chondroprotective agents. The preferred composition comprises; nitric oxide synthase inhibitors, nitric oxide scavangers, and amino sugars. Nitric oxide synthase inhibitors and nitric oxide scavengers reduce the level of nitric oxide, the free radical responsible for the degradation of articular cartilage. Amino sugars are the building blocks of articular cartilage and have antiinflammatory actions. Excerpt(s): The present invention concerns compositions and methods of treating and preventing arthritis, repairing of articular joint surfaces and relief of symptoms associated with arthritis. Approximately 1-2% of the population suffers from rheumatoid arthritis (RA), which is characterized as an imbalance in the immune system that causes an overproduction of pro-inflammatory cytokines, e.g., tumor necrosis factor alpha (TNF.alpha.), interleukin 1 (IL-1), and a lack of anti-inflammatory cytokines, e.g. IL-10, IL-11. RA is characterized by synovial inflammation, which progresses to cartilage destruction, bone erosion and subsequent joint deformity. The primary symptoms of RA are joint inflammation, swelling, difficulty moving, and pain. During the inflammatory process, polymorphonuclear cells, macrophages, and lymphocytes are released. Activated T-lymphocytes produce cytotoxins and pro-inflammatory cytokines, while macrophages stimulate the release of prostaglandins and cytotoxins. Vasoactive substances (histamine, kinins, and prostaglandins) are released at the site of inflammation and cause edema, warmth, erythema, and pain associated with inflamed joints. Osteoarthritis usually presents as pain, which worsens with exercise or simply an X-ray that clearly shows thinning cartilage. Common joints affected are the knees, hips and spine, finger, base of thumb and base of the big toe. Osteoarthritis is characterized by degenerative changes in the articular cartilage and subsequent new bone formation at the articular margins. The primary defect in hyaline cartilage, at the articular surface of the joint, is an alteration in the ratio of total glycosaminoglyeans to that of the collagen fiber content in the matrix. Yasuda K. Hokkaido Igaku Zasshi July 1997;72(4):369-76. Paleontologists have found osteoarthritis to exist in almost every vertebrate. By age 60, almost all Americans have osteoarthritis in their necks or spines. Joint cartilage consists of only 5 percent cells, and that joint cartilage lesions do heal. Tindall W N. Business & Health December 1997;47-48. Bones directly underneath the cartilage in joints is called subchondral bone. This bone nourishes the cartilage with oxygen, water, and nutrients conveyed through microscopic channels. This supply route carries "chondroprotective agents" from the bloodstream to the cartilage. Web site: http://www.delphion.com/details?pn=US06656925__ •
Compositions and methods for producing platelets and/or proplatelets from megakaryocytes Inventor(s): Battinelli; Elisabeth M. (Sommerville, MA), Loscalzo; Joseph (Dover, MA) Assignee(s): Trustees of Boston University (boston, Ma) Patent Number: 6,589,759 Date filed: December 5, 2001 Abstract: The present invention describes novel compositions and methods to enhance the in vitro and in vivo production of platelets and/or proplatelets from megakaryocytes. The present invention describes compositions comprising megakaryocytes, nitric oxide donors (i.e. compounds that donate, transfer or release nitric oxide, elevate endogenous levels of endothelium-derived relaxing factor, stimulate endogenous synthesis of nitric oxide or are substrates for nitric oxide
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synthase), and, optionally, at least one thrombopoiesis stimulating factor. The thrombopoiesis stimulating factor is preferably thrombopoietin. The nitric oxide donor is preferable S-nitrosoglutathione. The present invention also describes compositions comprising at least one nitric oxide donor and at least one thrombopoiesis stimulating factor. The present invention also provides methods for treating and/or preventing blood platelet disorders, and for producing platelets and/or proplatelets in vitro and in vivo. The compounds and/or compositions of the present invention can be provided in the form of a pharmaceutical kit. Excerpt(s): The present invention describes in vitro and in vivo production of platelets and/or proplatelets from megakaryocytes. The present invention is also directed to compositions comprising megakaryocytes, nitric oxide donors (i.e. compounds that donate, transfer or release nitric oxide, elevate endogenous levels of endotheliumderived relaxing factor, stimulate endogenous synthesis of nitric oxide or are substrates for nitric oxide synthase), and, optionally, at least one thrombopoiesis stimulating factor. The thrombopoiesis stimulating factor is preferably thrombopoietin. The nitric oxide donor is preferable S-nitrosoglutathione. The present invention also describes compositions comprising at least one nitric oxide donor and at least one thrombopoiesis stimulating factor. The present invention also provides methods for treating and/or preventing blood platelet disorders, and for producing platelets and/or proplatelets in vitro and in vivo. The compounds and/or compositions of the present invention can be provided in the form of a pharmaceutical kit. Platelets are circulating cell derived fragments that are required for the maintenance of hemostasis. These small, anucleate fragments represent the first line of defense against hemorrhage following vascular injury, and are crucial for blood coagulation. Platelets are the terminal differentiation product of megakaryocytes, which in turn originate from pluripotent stem cells. The process of platelet production from megakaryocytes, which is complex and incompletely understood, is called thrombopoiesis. Several cytokines have been reported to stimulate the growth and maturation of megakaryocytes. The interaction between the cytokines and growth factors, their kinetic choreography, and the specific molecular steps that commit the megakaryocytes and their precursors to the process of maturation and platelet production have only begun to be rigorously investigated. Megakaryocytes mature by a process of endomitosis and cytoplasmic maturation. Most research to date has focused on the maturation step of megakaryocyte growth rather than on the terminal process of platelet production. Morphological studies of marrow megakaryocytes suggest that platelets form as a result of cytoplasmic fragmentation. With the completion of endomitosis, megakaryocyte cytoplasm expands and, in the process, develops demarcation membranes and granules. Platelets form as the fully mature megakaryocyte develops cytoplasmic extensions, or pseudopodial protrusions, that extend in proximity to sinusoidal endothelial cells (Tavassoli and Aoki, Blood Cells, 15:3-14, (1989)). Platelets bud from the ends of these protusions and thereafter enter the circulation. The megakaryocyte's ability to produce platelet buds is ultimately exhausted, and it undergoes terminal apoptosis. Web site: http://www.delphion.com/details?pn=US06589759__
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Device and method for decomposing nitrogen oxides Inventor(s): Scott; Steven Paul (Fife, GB), Thomson; James (Dundee, GB) Assignee(s): University of Dundee (dundee, Gb) Patent Number: 6,641,789 Date filed: February 22, 2001 Abstract: A device for decomposing the oxides of nitrogen (No.sub.x) contained in effluent compositions, such as the exhaust gases generated by automotive combustion engines, is described. In one embodiment, the device includes a reaction chamber containing an oxidisable material which when the device is in use will undergo an oxidation/reduction reaction with nitrogen oxides of nitrogen oxidation states greater than 2, especially nitrogen dioxide, to generate nitrogen and an oxide of the oxidisable material. The oxidisable material is regenerated using an electromotive force. In a particularly preferred embodiment, the reaction chamber containing the oxidisable material is associated with a further reaction chamber which is arranged upstream of the reaction chamber containing the oxidisable material. This further reaction chamber contains an oxidation catalyst which is able to oxidize nitric oxide (NO) to nitrogen dioxide (NO.sub.2) or other nitrogen oxides having a nitrogen oxidation state greater than 2. also described are processes for decomposing nitrogen oxides. Excerpt(s): This application claims priority from G.B. Patent Application No. 9812459.7, filed Jun. 11, 1998 and G.B. Patent Application No. 9812460.5, filed Jun. 11, 1998, the disclosures of which are incorporated by reference herein in their entirety. The present invention relates to a device for decomposing the oxides of nitrogen and more particularly to a device for removing the oxides of nitrogen contained in gaseous effluents, such as the exhaust gases generated by automotive combustion engines. The present invention also relates to a process for decomposing these oxides, e.g. using such a device. The use of catalytic devices in vehicle exhaust systems to remove the oxides of nitrogen (NO.sub.x) contained in the exhaust gases is well known. These devices, which are more commonly referred to as catalytic converters, typically comprise a surrounding metal shell or casing which houses a ceramic or metal monolith. The ceramic or metal monolith comprises a plurality of parallel flow channels which contain a catalytic material for catalysing the reduction of the nitrogen oxides to molecular nitrogen. In use, the exhaust gas generated by the engine is conveyed through the flow channels in the monolith so that it contacts the catalytic material. Web site: http://www.delphion.com/details?pn=US06641789__
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Diagnosis of pathogen infections through analysis of nitrite production by antigen stimulated leukocytes Inventor(s): Palmer; Mitchell V. (Nevada, IA), Waters; Wade R. (Stratford, IA) Assignee(s): The United States of America AS Represented by the Secretary of Agriculture (washington, Dc) Patent Number: 6,673,566 Date filed: January 10, 2002 Abstract: Peripheral blood mononuclear cells which have been isolated from an animal that is infected with a microbial pathogen produce nitric oxide in response to stimulation with antigens from that pathogen. Determination of nitric oxide production
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in cultures of peripheral blood mononuclear cells stimulated with a pathogen's antigens may thus provide an indication of infection of the animal. Excerpt(s): The invention relates to a novel method for detecting tuberculosis and other infections in animals. Cell-mediated immune responses are critical in the host defense against intracellular bacterial pathogens (Chan and Kaufmann, 1994, Immune mechanisms of protection, In Tuberculosis: Pathogenesis, protection, and control, B. R. Bloom, (ed.), American Society of Microbiology, Washington, D.C., pp. 389-415; Cheville et al., 1993, "Immune responses and protection against infection and abortion in cattle experimentally vaccinated with mutant strains of Brucella abortus," American Journal of Veterinary Research 54:1,591-1,597; Chiodini, 1996. Immunology: Resistance to paratuberculosis, Veterinary Clinics of North America 12:313-342). A key component of this response is the clonal expansion of lymphocytes and the elaboration of cytokines that activate macrophages for the killing of bacteria located within the phagosomal compartment. Potent mediators of intra-phagosomal killing are reactive nitrogen intermediates (e.g., nitric oxide, NO) produced via the induction of inducible NO synthase (NOS), often as a sequalae to IFN-.gamma., TNF-.alpha., or LPS stimulation (MacMicking et al., 1997, "Nitric oxide and macrophage function", Annual Reviews of Immunology, 15:323-350; Kaufmann, 1999, "Cell-mediated immunity: Dealing a direct blow to pathogens", Current Biology, 9:R97-99). We have now discovered that peripheral blood mononuclear cells which have been isolated from an animal that is infected with a microbial pathogen produce nitric oxide in response to stimulation with antigens from that pathogen. Determination of nitric oxide production in cultures of peripheral blood mononuclear cells stimulated with a microbial pathogen's antigens may thus provide a specific indication of infection of the animal by that pathogen. Web site: http://www.delphion.com/details?pn=US06673566__ •
Differential delivery of nitric oxide Inventor(s): Herrmann; Robert A. (Boston, MA), Knapp; David (Wellesley, MA) Assignee(s): Scimed Life Systems, Inc. (maple Grove, Mn) Patent Number: 6,706,274 Date filed: January 18, 2001 Abstract: This invention relates to devices and methods for the local, differential delivery of nitric oxide within the body. The devices include devices having at least two differing nitric oxide donor compounds, such as nitric oxide donor compounds having differing half-lives and nitric oxide donor compounds having different release mechanisms. The devices also include devices having at least two chemically distinct compositions to which nitric oxide donor compounds are adsorbed or attached or within which the donor compounds are disposed. The devices are typically used to increase local nitric oxide concentration in the body upon placement of the medical article at a delivery position on or within a patient. The methods of the present invention include a method of treating an atherosclerotic lesion which comprises: exposing the lesion to a first higher concentration of nitric oxide effective to reduce the number of cells within the lesion; and subsequently exposing the lesion to a second lower concentration of nitric oxide effective to inhibit restenosis. The methods of the present invention also include methods for preferentially providing differing nitric oxide donor compounds within different tissues to effect therapy.
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Excerpt(s): This invention relates to the local, differential delivery of nitric oxide within the body. At present, numerous therapeutic techniques are based on systemic delivery of therapeutic agents. Systemic delivery, however, is not well suited to the treatment of disease entities with a single site of interest. For example, systemic delivery necessitates exposing sites other than the site of interest to medication where the medication may have an adverse reaction. As a result, the agent concentration at the site of interest is often limited by the detrimental effects of the agent at distant sites. Moreover, sufficiently large quantities of agent within the entire volume of the body are required to obtain the desired effect at the desired site. Finally, the agent is exposed to degradation and elimination by an organ system(s) remote from the site of interest. In response to this recognition, numerous techniques and medical articles for the localized delivery of therapeutic agents to the body have been proposed. Nitric oxide is a gaseous molecule produced constitutively in the body through the enzymatic degradation of L-arginine. Under conditions of oxidative stress, an induced nitric oxide is also produced. Nitric Oxide is a highly reactive free radical, properly represented by NO.diamond., however, for purposes of this patent application it will also be represented by "nitric oxide" and "NO". Nitric oxide has been shown at lower doses to relax smooth muscle cells (including vascular smooth muscle cells), inhibit vascular smooth muscle cell proliferation, protect endothelial cells from apoptosis, provide anti-thrombogenic and antioxidant effects, and promote wound healing. At higher dosages, it ultimately becomes cytotoxic. Web site: http://www.delphion.com/details?pn=US06706274__ •
Endothelial NOS transgenic animals and methods of use Inventor(s): Fishman; Mark C. (Newton Center, MA), Huang; Paul L. (Boston, MA), Moskowitz; Michael A. (Belmont, MA) Assignee(s): The General Hospital Corporation (boston, Ma) Patent Number: 6,630,347 Date filed: October 20, 2000 Abstract: This invention relates to transgenic non-human animals comprising a disrupted endothelial nitric oxide synthase gene. These animals exhibit abnormal wound-healing properties and hypertension. This invention also relates to methods of using the transgenic animals to screen for compounds having a potential therapeutic utility for vascular endothelial disorders, such as hypertension, cerebral ischemia or stroke, atherosclerosis and wound-healing activities. Moreover, this invention also relates to methods of treating a patient suffering from hypertension and wound-healing abnormalities with the compounds identified using the transgenic animals, and methods of making the transgenic animals. A method of treating a wound using nitroglycerin is also provided. Excerpt(s): Part of the work performed during the development of this invention was supported by U.S. Government funds. The U.S. Government may have certain rights in this invention. This invention relates to transgenic non-human animals comprising a disrupted endothelial nitric oxide synthase gene. This invention also relates to methods of using these transgenic animals to screen compounds for activity against vascular endothelial disorders such as hypertension, stroke, and atherosclerosis, as well as for wound healing activity; methods of treating a patient suffering from a vascular endothelial disorder; methods of making the transgenic animals; and cell lines comprising a disrupted eNOS gene. In 1980, Furchgott and Zawadzzi first proposed the
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existence of endothelium derived relaxing factor or EDRF, later identified as nitric oxide. Furchgott (1980); Furchgott (1988); Ignarro (1988); Palmer (1987). Nitric oxide is an important messenger molecule produced by endothelial cells, neurons, macrophages, and other tissues. Marietta (1989); Moncada (1991); Nathan (1992); Snyder (1992); and Dawson et al. (1992). Since nitric oxide is a gas with no known storage mechanism, it diffuses freely across membranes and is extremely labile. Nitric oxide has a biological half-life on the order of seconds. Web site: http://www.delphion.com/details?pn=US06630347__ •
Enhancement of vascular function by modulation of endogenous nitric oxide production or activity Inventor(s): Cooke; John P. (Palo Alto, CA), Dzau; Victor J. (Newton, MA), Gibbons; Gary H. (Atlanta, GA) Assignee(s): The Board of Trustees of the Leland Stanford Junior University (palo Alto, Ca) Patent Number: 6,642,208 Date filed: August 15, 2001 Abstract: Vascular function and structure is maintained or improved by long term administration of physiologically acceptable compounds which enhance the level of endogenous nitric oxide or other intermediates in the NO induced relaxation pathway in the host. Alternatively, or in combination, other compounds may be administered which provide for short term enhancement of nitric oxide, either directly or by physiological processes. Excerpt(s): The field of this invention is the modulation of NO activity, which finds application in maintaining and improving vascular function and thereby preventing or improving vascular degenerative diseases. Atherosclerosis and vascular thrombosis are a major cause of morbidity and mortality, leading to coronary artery disease, myocardial infarction, and stroke. Atherosclerosis begins with an alteration in the endothelium, which lines the blood vessels. The endothelial alteration results in adherence of monocytes, which penetrate the endothelial lining and take up residence in the subintimal space between the endothelium and the vascular smooth muscle of the blood vessels. The monocytes absorb increasing amounts of cholesterol (largely in the form of oxidized or modified low-density lipoprotein) to form foam cells. Oxidized low-density lipoprotein (LDL) cholesterol alters the endothelium, and the underlying foam cells distort and eventually may even rupture through the endothelium. Platelets adhere to the area of endothelial disruption and release a number of growth factors, including platelet derived growth factor (PDGF). PDGF, which is also released by foam cells and altered endothelial cells, stimulates migration and proliferation of vascular smooth muscle cells into the lesion. These smooth muscle cells release extracellular, matrix (collagen and elastin) and the lesion continues to expand. Macrophages in the lesion elaborate proteases, and the resulting cell damage creates a necrotic core filled with cellular debris and lipid. The lesion is then referred to as a "complex lesion." Rupture of this lesion can lead to thrombosis and occlusion of the blood vessel. In the case of a coronary artery, rupture of a complex lesion may precipitate a myocardial infarction, whereas in the case of a carotid artery, stroke may ensue. Web site: http://www.delphion.com/details?pn=US06642208__
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Enhancing therapeutic effectiveness of nitric oxide inhalation Inventor(s): Bloch; Kenneth D. (Brookline, MA), Ichinose; Fumito (Brookline, MA), Zapol; Warren M. (Concord, MA) Assignee(s): The General Hospital Corporation (boston, Ma) Patent Number: 6,601,580 Date filed: June 28, 2000 Abstract: Methods for reducing, partially preventing or completely preventing nitric oxide (NO) inhalation-related impairment of HPV in a mammal are disclosed. The methods include administering a therapeutically effective amount of NO by inhalation, and co-administering an effective amount of an anti-reactive oxygen species (anti-ROS) agent, e.g., N-acetylcysteine, or a leukotriene blocker. Methods for reducing, partially preventing or completely preventing loss of pulmonary vasodilatory responsiveness to NO inhalation in a mammal are also disclosed. The methods include administering a therapeutically effective amount of NO by inhalation, and co-administering an effective amount of an anti-ROS agent a therapeutically effective amount of a leukotriene blocker. Excerpt(s): This invention relates to pulmonary physiology and cardiology. Nitric oxide (NO) is a highly reactive free radical compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate (cGMP), leading to vasodilation. When inhaled, NO gas acts as a selective vasodilator of human and animal pulmonary vessels. Consequently, NO inhalation is used to promote vasodilation in well-ventilated regions of the lung. In acute respiratory distress syndrome (ARDS), impaired ventilation of lung tissue reduces oxygenation of arterial blood. Nitric oxide inhalation often improves oxygenation in ARDS patients. It does so by dilating blood vessels in well-ventilated portions of the lung, redistributing blood flow towards the well-ventilated regions and away from poorly-ventilated regions, which receive little NO. However, in 30-40% of ARDS patients, NO inhalation fails to improve arterial oxygenation (Bigatello et al., 1994, Anesthesiology 80:761-770; Dellinger et al., 1998, Crit. Care Med. 26:15-23). It is difficult to predict which patients with ARDS will not respond to NO inhalation or which patients will respond only transiently. However, it is known that up to 60% of patients with ARDS associated with sepsis do not respond to inhaled NO (Krafft et al., 1996, Chest 109:486-493). Web site: http://www.delphion.com/details?pn=US06601580__
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Formation of well-controlled thin SiO, SiN, SiON layer for multilayer high-K dielectric applications Inventor(s): Paton; Eric N. (Morgan Hill, CA), Xiang; Qi (San Jose, CA), Yu; Bin (Cupertino, CA) Assignee(s): Advanced Micro Devices, Inc. (sunnyvale, Ca) Patent Number: 6,682,973 Date filed: May 16, 2002 Abstract: A process for fabricating a semiconductor device having a high-K dielectric layer over a silicon substrate, including steps of growing on the silicon substrate an interfacial layer of a silicon-containing dielectric material; and depositing on the
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interfacial layer a layer comprising at least one high-K dielectric material, in which the interfacial layer is grown by laser excitation of the silicon substrate in the presence of oxygen, nitrous oxide, nitric oxide, ammonia or a mixture of two or more thereof. In one embodiment, the silicon-containing material is silicon dioxide, silicon nitride, silicon oxynitride or a mixture thereof. Excerpt(s): The invention relates generally to the fabrication of semiconductor devices and, more particularly, to the fabrication of an interfacial layer in devices with a high-K dielectric material layer on a silicon substrate. Fabrication of a semiconductor device and an integrated circuit including the same begins with a semiconductor substrate and employs film formation, ion implantation, photolithographic, etching and deposition techniques to form various structural features in or on the semiconductor substrate to attain individual circuit components which are then interconnected to form ultimately an integrated circuit. Escalating requirements for high densification and performance associated with ultra large-scale integration (ULSI) circuits requires smaller design features, increased transistor and circuit speeds, high reliability and increased manufacturing throughput for competitiveness. As the devices and features shrink, and as the drive for higher performing devices escalates, new problems are discovered that require new methods of fabrication or new arrangements or both. There is a demand for large-scale and ultra large-scale integrated circuits employing high performance metaloxide-semiconductor (MOS) devices. MOS devices typically comprise a pair of ion implanted source/drain regions in a semiconductor substrate and a channel region separating the source/drain regions. Above the channel region is typically a thin gate dielectric material, which is usually referred to as a gate oxide since it is conventionally formed of silicon dioxide, and a conductive gate comprising conductive polysilicon or another conductive material. In a typical integrated circuit, a plurality of MOS devices of different conductivity types, such as n-type and p-type, and complementary MOS (CMOS) devices employing both p-type and n-type devices are formed on a common substrate. MOS technology offers advantages of significantly reduced power density and dissipation as well as reliability, circuit performance and cost advantages. Web site: http://www.delphion.com/details?pn=US06682973__ •
Highly cross-linked, extremely hydrophobic nitric oxide-releasing polymers and methods for their manufacture and use Inventor(s): Cafferata; Robert (Santa Rosa, CA), Fitzhugh; Anthony L. (Frederick, MD), Keefer; Larry K. (Bethesda, MD) Assignee(s): Medtronic Ave Inc. (santa Rosa, Ca), United States of America (washington, Dc) Patent Number: 6,703,046 Date filed: October 4, 2001 Abstract: Extremely hydrophobic nitric oxide (NO) releasing polymers are disclosed. The extremely hydrophobic NO-releasing polymers provided are extensively crosslinked polyamine-derivatized divinylbenzene diazeniumdiolates. These polymers can be loaded with extremely high NO levels and designed to release NO in manners than mimic natural biological systems. The NO-releasing extremely hydrophobic polymers provided can maintain a sustained NO release for periods exceeding nine months. Also provided are related medical devices made using these NO-releasing extremely hydrophobic polymers.
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Excerpt(s): The present invention generally provides for methods of preparing nitric oxide releasing highly cross-linked, extremely hydrophobic polymers. The present invention relates to highly cross-linked, extremely hydrophobic polymers capable of providing prolonged release of nitric oxide under physiological conditions. Specifically, the present invention relates to the use of highly cross-linked, extremely hydrophobic polymers as therapeutic agents. More specifically, the present invention is directed at medical devices made from nitric oxide-releasing highly cross-linked, extremely hydrophobic polymers. Nitric oxide (NO) is a simple diatomic molecule that is a powerful signaling compound and cytostatic agent found in nearly every tissue including endothelial cells, neural cells and macrophages. Mammalian cells synthesize NO using a two step enzymatic process that oxidizes L-arginine to N-.omega.-hydroxyL-arginine, which is then converted into L-citrulline and an uncharged NO free radical. Three different nitric oxide synthase enzymes regulate NO production. Neuronal nitric oxide synthase (NOS1, or nNOS) is formed within neuronal tissue and plays an essential role in neurotransmission; endothelial nitric oxide synthase (NOS3 or eNOS), is secreted by endothelial cells and induces vasodilatation; inducible nitric oxide synthase (NOS2 or iNOS) is principally found in macrophages, hepatocytes and chondrocytes and is associated with immune cytotoxicity. Neuronal NOS and eNOS are constitutive enzymes that regulate the rapid, short-term release of small amounts of NO. In these minute amounts NO activates guanylate cyclase which elevates cyclic guanosine monophosphate (cGMP) concentrations which in turn increase intracellular Ca.sup.+2 levels. Increased intracellular Ca.sup.+2 concentrations result in smooth muscle relaxation which accounts for NO's vasodilating effects. Inducible NOS is responsible for the sustained release of larger amounts of NO and is activated by extracellular factors including endotoxins and cytokines. These higher NO levels play a key role in cellular immunity. Web site: http://www.delphion.com/details?pn=US06703046__ •
Immunosuppressive imidazole derivatives and their combination preparations with tacrolimus or cyclosporins Inventor(s): Chida; Noboru (Nishinomiya, JP), Nakayama; Osamu (Kitasouma-gun, JP), Sakai; Fumihiko (Tsukuba, JP), Yamazaki; Harumi (Niihari-gun, JP), Yokota; Yoshihiro (Nishinomiya, JP) Assignee(s): Fujisawa Pharmaceutical Co., Ltd. (osaka, Jp) Patent Number: 6,673,807 Date filed: December 1, 2000 Abstract: Methods for increasing graft survival time comprising administering the combination of a compound that inhibits the production of nitric oxide and a compound that is a tricyclic macrolide, such as tacrolimus. Excerpt(s): This invention relates to a new use of a compound possessing an inhibitory activity on the production of nitric oxide, which is useful in a medical field. Various compounds possessing an inhibitory activity on the production of nitric oxide have already been known, for example, in EP 0 394 989-A2, WO96/16981, WO97/45425, WO98/27108, etc. This invention relates to a new use of a compound possessing an inhibitory activity on the production of nitric oxide, for increasing an effect caused by interleukin 2 inhibitor (hereinafter, referred to IL-2 inhibitor). Web site: http://www.delphion.com/details?pn=US06673807__
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Medical device coated with a polymer containing a nitric oxide releasing organometallic nitrosyl compound useful for the prevention of platelet aggregation Inventor(s): Herzog, Jr.; William R. (Baltimore, MD), Pou; Sovitj (Baltimore, MD), Rosen; Gerald M. (Lutherville, MD), Zhao; Yi-Ju (Baltimore, MD) Assignee(s): Novovascular, Inc. (baltimore, Md) Patent Number: 6,656,217 Date filed: March 1, 1999 Abstract: The aggregation of platelets on the surface of a foreign body exposed to the flowing blood of a living being (such as plastic tubing, a balloon or the end of a catheter surgically inserted in a blood vessel, a stent implanted therein or synthetic grafts, which surface normal promotes such platelet aggregation to form a coating firmly affixed to that surface which would restrict the flow of blood past that surface or to form a blood clot detachable from that surface), is inhibited by a gas permeable coating on the surface of a physiologically acceptable polymer as which contains dissolved or dispersed therein a nitrosyl-containing organometallic compound, such as sodium nitroprusside, which is protected from diffusion from the coating and from direct contact with the blood and which slowly decomposes at the body temperature within the coating and in so doing releases a platelet aggregation-inhibiting amount of nitric oxide which diffuses from the coating during the period when platelet aggregation by the surface of the foreign body would be promoted in the absence of the polymer coating. Excerpt(s): This invention relates generally to novel drug delivery systems containing a nitric oxide-releasing metal compound entrapped therein and methods for using them, more particularly for the inhibition of restenosis after percutaneous transluminal coronary angioplasty and for the inhibition of acute or subacute thrombotic occlusion related to the use or deployment of a synthetic device within the vascular tree or extracorporeally. Sodium nitroprusside (SNP) and similar nitrosyl-containing organometallic compounds, whether ionic salts or chelates, which can release nitric oxide (NO), have been known since the mid-1950's to exhibit short-term hypotensive effects. The mechanism by-which this drug elicited its pharmacological activity was not known until the discovery that endothelial cells secreted a factor, which regulated vascular tone, termed Endothelial-Derived Relaxation Factor (EDRF) (Furchgott and Zawadzki, Nature, 288: 373-376, 1980). In 1987, Palmer and coworkers (Nature, 327: 524526, 1987) determined that the free radical nitric oxide mimicked many of the physiologic properties reported for EDRF. Besides regulating vascular tone, nitric oxide has been found to control a wide variety of physiologic functions, including (a) inhibition of neutrophil adhesion (Kubes, et al., Proc. Natl. Acad. Sci. USA, 88:4651-4655, 1991), (b) enhancement of macrophage-mediated microbial killing (De Groote and Fang, Clin. Infect. Dis. 12 (Suppl 2): S162-S165, 1995) (c) amelioration of impotence (Burnett, et al., Science, 257: 401-403, 1992) and (d) regulation of various CNS functions (Dawson, et al., Ann. Neurol. 32: 297-311, 1992). Of relevance to this invention are those studies demonstrating that nitric oxide inhibits platelet aggregation (Furlong, et al., Brit. J Pharmacol. 90: 687-692, 1987; Radomski, et al., Lancet, ii, 1057-1058, 1987) and prevents restenosis (McNamara, et al., Biochem. Biophys. Res. Commun. 193: 291-296, 1993). Since nitric oxide regulates many physiologic functions, this free radical is an essential ingredient for maintaining normal life processes. However, pharmacological applications of nitric oxide are limited, since systemic use can result in severe toxicity. For instance, administration of gaseous nitric oxide systemically to treat localized abnormalities or diseases is impractical except in a hospital intensive care setting, because control of its dosage in the therapeutic range cannot easily be achieved. Even if
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it were possible to carefully titrate the gaseous dose of nitric oxide to minimize systemic toxicity, it would be very difficult to locally administer this drug to sites of interest. Therefore, the development of therapeutic agents, which would mimic the pharmacological action of nitric oxide, has received considerable attention. Several classes of nitric oxide-releasing compounds have been developed, including syndnoeimine (Noack and Feelisch, J. Cardiovasc. Pharmacol. 14S: 51-55, 1989), nitroglycerin (Noack and Feelisch, J. Cardiovasc. Pharmacol. 14S: 51-55, 1989), S-nitroso derivatives (Ignarro, Lippton, Edwards, Baribos, Hyman, Kadowitz and Gretter, J. Pharmacol. Exp. Ther. 218: 729-739, 1981; Kowaluk and Fung, J Pharmacol. Exp. Ther. 255: 1254-1256, 1990; Stamler, Loscalzo, Slivka, Simon, Brown and Drazen, U.S. Pat. No. 5,380,758, 1995) and N-nitroso compounds (Maragos, Morley, Wink, Dunams, Saavedra, Hoffman, Bove, Issac, Hrabie and Keefer, J. Med Chem. 34: 3242-3247, 1991; Keefer, Dunans and Saavedra, U.S. Pat. No. 5,366,997, 1994, Keefer and Hrabie, U.S. Pat. No. 5,405,919, 1995; Keefer, Hrabie and Saavedra, U.S. Pat. No. 5,525,357, 1996). These compounds require either hydrolysis or metabolic activation, through either oxidation or reduction, to generate nitric oxide. Alternatively, several studies have reported on the development of photolyzed "caged-nitric oxide" compounds. For example, the organometallic compound sodium nitroprusside has been found to release nitric oxide upon light activation (Bates, Baker, Guerra and Harrison, Biochem. Pharmacol. 42S: S157-S165, 1991). Contrary to this, nitric oxide generation from light activation of ruthenium nitrosyl trichioride failed to inhibit platelet aggregation, thereby questioning the utility of this approach (Makings and Tsien, J. Biol. Chem. 269: 6282-6285, 1994). Web site: http://www.delphion.com/details?pn=US06656217__ •
Method and composition for inhibition of nitric oxide production in the oral cavity Inventor(s): Alving; Kjell (Uppsala, SE), Lundberg; Jon (Stockholm, SE) Assignee(s): Aerocrine AB (solna, Se) Patent Number: 6,626,844 Date filed: September 1, 2000 Abstract: The disturbing influence or orally produced nitric oxide in the measuring of exhaled nitric oxide can be ameliorated or totally eliminated through the use of a method and composition according to the present invention. The production of NO in the oral cavity is temporarily inhibited by the application of a composition having antibacterial and/or pH increasing effect. Excerpt(s): The present invention concerns the field of diagnostic measurement of nitric oxide in orally exhaled air and in particular how to avoid the influence of nitric oxide produced in the oral cavity in these measurements. Consequently, a composition, method and device for this purpose are disclosed. It has been shown that increased NO levels in the orally exhaled breathing air is an indication of an inflammatory condition in the airways. A system and method for the determination of NO levels in orally exhaled air for diagnosis of inflammatory conditions is described, for example in WO 95/02181; Alving, K. et al. and WO 93/05709; Gustafsson, L. E. Nitric oxide is normally produced enzymatically by constitutive NO synthases in, e.g. nerves and endothelial cells; these enzymes yield the relatively small amounts of NO involved in physiological regulation of nerve transmission and vascular tone. In contrast, the inducible NO synthase found, e.g. in activated white blood cells and airway epithelium produces NO at a high rate. It was recently shown that nitric oxide is also produced through a second route, i.e. through reduction of nitrite. Nitrite is present in body fluids such as saliva and urine, in
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amounts depending on the individual's diet and health. For example, a diet rich in nitrate (such as certain vegetables) will result in high nitrate levels in saliva and urine. The bacteria normally present in the oral cavity will reduce salivary nitrate to nitrite. Web site: http://www.delphion.com/details?pn=US06626844__ •
Method for forming heavy nitrogen-doped ultra thin oxynitride gate dielectrics Inventor(s): Ajmera; Atul C. (Wappingers Falls, NY), D'Emic; Christopher P. (Ossining, NY), Gousev; Evgeni (Mahopac, NY) Assignee(s): International Business Machines Corporation (armonk, Ny) Patent Number: 6,642,156 Date filed: August 1, 2001 Abstract: A method for forming an ultra thin gate dielectric for an integrated circuit device is disclosed. In an exemplary embodiment of the invention, the method includes forming an initial nitride layer upon a substrate by rapidly heating the substrate in the presence of an ammonia (NH.sub.3) gas, and then re-oxidizing the initial nitride layer by rapidly heating the initial nitride layer in the presence of a nitric oxide (NO) gas, thereby forming an oxynitride layer. The oxynitride layer has a nitrogen concentration therein of at about 1.0.times.10.sup.15 atoms/cm.sup.2 to about 6.0.times.10.sup.15 atoms/cm.sup.2, and has a thickness which may be controlled within a sub 10.ANG. range. Excerpt(s): The present invention relates generally to semiconductor processing and, more particularly, to improved techniques for fabricating gate dielectrics. As integrated circuits have become smaller and more densely packed, so have the dielectric layers of devices such as field effect transistors and capacitors. With the arrival of ULSI (Ultra Large Scale Integrated circuit) technology and gate dielectrics of less than 15 angstroms (.ANG.) in thickness, the use of silicon dioxide (SiO.sub.2) as a traditional gate dielectric material becomes problematic. In larger devices (e.g., where the gate oxide thickness is 40.ANG. or more), leakage currents from a polysilicon gate electrode, through the gate oxide and into the device channel, are only on the order of about 1.times.10.sup.-12 A/cm.sup.2. However, as the thickness of an SiO.sub.2 gate dielectric is decreased below 20.ANG., the leakage currents approach values of about 1 A/cm.sup.2. This magnitude of leakage current, caused by direct tunneling of electrons from the polysilicon gate electrode through the gate oxide, results in prohibitive power consumption of the transistor(s) in the off-state, as well as device reliability concerns over an extended period of time. Web site: http://www.delphion.com/details?pn=US06642156__
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Method for treating pulmonary disease states in mammals by altering indigenous in vivo levels of nitric oxide Inventor(s): Martin; Alain (Ringoes, NJ) Assignee(s): Cellular Sciences, Inc. (flemington, Nj) Patent Number: 6,689,810 Date filed: July 25, 2002
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Abstract: The present invention pertains to a method for treating a pulmonary disease state in mammals by altering indigenous in vivo levels of nitric oxide in mammalian cells. The method comprises contacting the mammalian cells with a therapeutically effective amount of a nitric oxide mediator selected from the group consisting of pyruvates, pyruvate precursors,.alpha.-keto acids having four or more carbon atoms, precursors of.alpha.-keto acids having four or more carbon atoms, and the salts thereof. The method may further comprise contacting the mammalian cells with a therapeutic agent and a nitric oxide source selected from the group consisting of nitric oxide, nitric oxide precursors, and nitric oxide stimulators. Excerpt(s): The present invention pertains to a method for treating a pulmonary disease state in mammals by altering indigenous in vivo levels of nitric oxide in mammalian cells. The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference and, for convenience, are referenced in the following text and respectively grouped in the appended bibliography. Nitric oxide (NO), an oxidation product of nitrogen, is produced normally by many cell types, including endothelial cells and macrophages. Nitric oxide has functions ranging from neurotransmission to vasodilatation. Nitric oxide also produces clinically useful bronchodilation (1) and is also used by the body to kill bacteria, fungal infections, viral infections, and tumors. Nitric oxide can kill these cell types because bacterial, viral, and tumor cells have no defenses against nitric oxide. Normal mammalian cells can cope with normal levels of nitric oxide by using enzyme systems to use or deactivate elevated cellular levels of nitric oxide (28-32). Nitric oxide is the main mediator of the tumoricidal action of activated macrophages (29-32). While over 30,000 papers have been written to date on nitric oxide, the role of nitric oxide in tumor biology is not completely understood. Nitric oxide appears to have both tumor promoting and inhibiting effects (31). Recent publications have implicated the reactive oxygen species made from nitric oxide during the inflammatory process as being the tumor promoting agents, not nitric oxide itself (28). Web site: http://www.delphion.com/details?pn=US06689810__ •
Method to improve oxygenation in subjects suffering impaired oxygenation Inventor(s): Heinonen; Erkki (Helsinki, FI), Hogman; Marieann (Alunda, SE), Merilainen; Pekka (Espoo, FI), Nyman; Gorel (Knivsta, SE) Assignee(s): Instrumentarium Corp. (helsinki, Fi) Patent Number: 6,694,969 Date filed: September 22, 2000 Abstract: A method for improving oxygenation in subjects having essentially healthy lungs, as evidenced by the absence of a diagnosis of lung disease or injury, but having reduced alveolar gas exchange area. This reduction may be caused by such acute circumstances as an unnatural body position, or may be, for example, chronic as caused by obesity. The method employs the administration of nitric oxide (NO) into the breathing gases of such subjects. NO provided to alveoli collapsing during expiration is small compared to those remaining open, thereby to provide net reduction in the shunt and thus an oxygenation improvement. This result may be gained either by precise control of the inspired NO concentration or by pulsed administration of the NO.
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Excerpt(s): Human and animal body metabolism uses oxygen and produces carbon dioxide. The required oxygen is received from the atmospheric air during respiration, in the course of which waste carbon dioxide is released. The gas exchange between the body and the environment takes place in the lung alveoli, where pulmonary blood capillaries are separated from the gas space in the lung in communication with the atmospheric air by only a thin membrane permeable for gases. The pulmonary blood flow passing through the alveoli equilibrates in gas partial pressure with the alveolar gas, resulting in blood oxygen uptake and carbon dioxide release. During each breath the alveolar blood gas concentration is changed as a result of the oxygen supplement and carbon dioxide removal. The blood transports the oxygen from the lungs to the sites of consumption and waste carbon dioxide from the sites of metabolism back to the lungs. Blood flow rates through the lungs and perfusion pressure are regulated by the smooth muscle tension of the pulmonary capillaries. This regulation is mediated by endothelium derived nitric oxide. Insufficient local NO production increases smooth muscle tone. This results in pulmonary vasoconstriction and impaired blood flow or, alternatively, elevated pulmonary artery pressure. Pulmonary hypertension is present in various circumstances, such as pneumonia, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis, inflammation of the lung, adult respiratory distress syndrome, acute pulmonary edema, acute mountain sickness, post cardiac surgery, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, prenatal aspiration syndrome, hyaline membrane disease, acute pulmonary embolism, heparinprotamine reactions, sepsis, or hypoxia (including that which may occur during one-lung anesthesia), as well as those cases of chronic pulmonary vasoconstriction which have a reversible component, such may result from chronic pulmonary hypertension, bronchopulmonary dysplasia, chronic pulmonary embolism, idiopathic or primary pulmonary hypertension, or chronic hypoxia due to chronic obstructive lung disease. U.S. Pat. No. 5,485,827 discloses a method using inhaled nitric oxide (NO) useful for preventing or reversing acute pulmonary vasoconstriction, such as that arising from the foregoing injuries. A method for using NO gas also to achieve bronchodilatation and thereby improve the distribution of other agents administered by inhalation is also disclosed. Web site: http://www.delphion.com/details?pn=US06694969__ •
Methods and means of detecting nitric oxide synthase Inventor(s): Sessa; William C. (Madison, CT), Smith; Shannon D. (Guilford, CT), Weiss; Robert M. (North Haven, CT), Wheeler; Marcia A. (Branford, CT) Assignee(s): Yale University (new Haven, Ct) Patent Number: 6,605,447 Date filed: September 14, 1998 Abstract: Methods for identifying and monitoring increased or decreased levels of inducible nitric oxide synthase in biological samples are provided. A collection device for detecting inducible nitric oxide synthase in biological samples is also provided. Detection of inducible nitric oxide synthase is useful in the diagnosis of inflammatory responses such as infections mediated by bacteria, yeast or viruses, transplant rejection, rheumatoid arthritis, interstitial cystitis and cancer. Excerpt(s): The present invention provides methods and means for identifying and monitoring increased or decreased levels of inducible nitric oxide synthase in biological samples. Nitric oxide synthase activity is elevated in the inflammatory response
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resulting from several diseases or conditions, including, but not limited to, bacterial infections including urogenital tract infections and bacterially related sepsis, organ transplant rejection and cancer. Nitric oxide synthase activity is decreased in urine of patients with interstitial cystitis. One of the most common bacterial infections in humans is that of the urinary tract. Patients who need rapid diagnosis of urinary tract infections (UTIs) include premature newborn infants, prepubertal girls and young boys, sexually active women, elderly males and females, pre-operative patients, patients with chronic disease, patients with neurological disorders, patients with genitourinary congenital disorders including urethral valves and reflux, patients with sickle cell disease, patients with renal disease and polycystic kidney disease, patients having undergone renal transplantation and pregnant patients. The diagnosis of UTI in the elderly and in infants, in particular, is difficult because of different signs and symptoms and the inability to communicate, respectively. Failure to diagnose UTIs can lead to urosepsis, emphysematous cystitis and scarring. Accordingly, there is a need for a rapid, cost effective, sensitive test for UTI. While a definitive diagnosis of urinary tract infections can be obtained by microbial culturing, this test is costly and results from the culture can take up to 48 hours to obtain. Newer technologies involving bacterial antibodies offer no clear advantages over culturing techniques. Studies have confirmed a direct relationship between urine nitrite and urinary tract infections. Accordingly, the Griess reagent which detects nitrite is commonly employed in a dipstick to screen urine for microorganisms. Leukocyte esterase dipstick tests are also used routinely for the rapid diagnosis of urinary tract infections (UTIs). However, these tests have been found to have different sensitivities and specificities for patients with different clinical manifestations. For example, Lachs et al. reported that this dipstick test for urinary tract infection was highly sensitive in patients with a high prior probability of infection but insensitive in patients with a low prior probability of infection (Lachs et al., Ann. Intern. Med. 1992, 117:135-40). Accordingly, as taught by Dr. Martin F. Shapiro in the commentary to this study, the dipstick test for urinary tract infection lacks sensitivity precisely in those patients for whom an effective diagnostic test would be most useful; patients with vague symptoms for whom the diagnosis is not clear. It has been estimated that the current dipstick technologies detect only approximately 50% of UTIs. Web site: http://www.delphion.com/details?pn=US06605447__ •
Methods of treating osteoarthritis with inducible nitric oxide synthase inhibitors Inventor(s): Connor; Jane R. (St. Louis, MO), Currie; Mark G. (St. Charles, MO), Manning; Pamela T. (Labadie, MO), Pelletier; Jean Pierre (St. Lambert, CA), Pelletier; Johanne Martel (St. Lambert, CA) Assignee(s): G.d. Searle & Co. (chicago, Il), Pharmacia Corporation () Patent Number: 6,653,350 Date filed: September 7, 1999 Abstract: Methods of treating osteoarthritis by administering an therapeutically effective amount of NOS inhibitor are provided. Excerpt(s): This invention is generally related to nitric oxide synthase inhibitors and more specifically related to treating patients having osteoarthritis with nitric oxide synthase inhibitors. Nitric oxide (NO) is an inorganic reactive gas molecule, important in many physiological and pathological processes where it is synthesized by cells mediating vital biological functions. Nitric oxide serves as a neurotransmitter in the brain, produced in small amounts on an intermittent basis in response to various
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endogenous molecular signals. Endothelial cells lining the blood vessels also produce nitric oxide in small amounts, relaxing smooth muscle and regulating blood pressure. Indeed, the production of nitric oxide has a significant effect on the function of circulating blood cells such as platelets and neutrophils as well as on smooth muscle including blood vessels and other organs. Nitric oxide is also synthesized in the immune systems. Endotoxin and cytokines induce the production of large amounts of nitric oxide in response to infectious and inflammatory stimuli, contributing to both host defense processes such as killing of bacteria and viruses as well as pathology associated with acute and chronic inflammation in a wide variety of diseases. Web site: http://www.delphion.com/details?pn=US06653350__ •
Microdose therapy Inventor(s): Adams; Michael A. (Kingston, CA), Banting; James D. (Kingston, CA), Heaton; Jeremy P. W. (Gananoque, CA) Assignee(s): Queen's University at Kingston (kingston, Ca) Patent Number: 6,610,652 Date filed: March 8, 2002 Abstract: Methods for treating vascular conditions associated with localized imbalance in vascular tone, which are hypothesized to be largely due to elevated endothelin (ET) are provided. The methods involve administration of nitric oxide (NO), agents which are able to provide NO, such as NO donors, agents which activate guanyl cyclase, such as YC-1, or agents which prolong the actions of endogenous NO or cyclic guanosine monophosphate (cGMP; a 2nd messenger molecule), such as phosphodiesterase (PDE) inhibitors. According to the invention, such agents are administered in minimal doses or microdoses by any route known in the art, so as to provide dosages which are about one half to about one twentieth (1/2 to 1/20) of those known to induce vasodilation in "normal" circulations. The low doses of these agents effectively alleviate vascular conditions associated with a reduction in NO production or an attenuation of NO effect, by restoring balance in vascular tone while exerting almost no systemic effect in normal vasculature. Excerpt(s): The field of invention is the treatment of conditions concerned with peripheral vasoconstriction. More particularly, the invention is concerned with methods for establishing normal vascular tone in regions of the circulation which demonstrate pathophysiology. In particular, the invention concerns a method of treating erectile dysfunction by provision of nitric oxide, nitric oxide producing agents, or activators of guanyl cyclase in small doses or microdoses, i.e., doses that do not induce undesirable side effects, such as systemic vasodilation, under normal conditions. It is widely known that administration of nitric oxide (NO), or compounds which deliver NO (i.e., NO donors, NO producing agents) to a subject, can provoke powerful vasodilator responses. Such administration is often accompanied by a number of undesirable side effects which include headache, flushing, and hypotension. The physiological role of NO has been described as that of a powerful chronic vasodilator agent based on there being a marked increase in vascular tone following NO synthase (NOS) blockade (Johnson et al., Am. J. Hypertens. 5:919, 1992; Tolins et al., Hypertens. 17:909, 1991). The role of NO as a chronic vasodilator has only been inferred by indirect means, i.e., by removal of NOS activity. Endogenously, much more multiplicity and overlap in the control of vasodilation can be inferred from the scientific literature. For example, vasodilation can be induced by acetylcholine, bradykinin, adenosine, adenosine triphosphate (ATP),
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histamine, vasoactive intestinal polypeptide (VIP), and leukotrienes, amongst others. The actions of these endogenous modulators have been shown to be dependent, at least in part, on the presence of the endothelium, an effect likely mediated by endothelial derived relaxing factor/NO (EDRF/NO) (Garg, U. C. et al., J. Biol. Chem. 266:9, 1991; Garg, U. C. et al., J. Clin. Invest. 83:1774, 1989; Palmer, R. M. J. et al., Nature 327:524, 1987). Other vasodilator mechanisms exist which are not endothelium dependent, such as.beta.sub.2 -adrenergic receptor activation, atrial natriuretic peptide (ANP) and certain prostaglandins. The actions of NO have been suggested to be mostly cGMP-mediated via guanylate cyclase activation, although other mechanisms have been suggested. For example, Garg et al. (J. Biol. Chem. 266:9, 1991; J. Clin. Invest. 83:1774, 1989) and others (Assender, J. W. et al., J. Cardiovasc. Pharmacol. 17(Suppl.3):S104, 1991; O'Conner, K. J. et al., J. Cardiovasc. Pharmacol. 17(Suppl.3):S100-S103, 1991) demonstrated a difference in the effects of NO-generating vasodilator agents in inhibiting vascular smooth muscle cell growth in culture; however, it is clear that NO can act not only as a vasodilator but also to inhibit vascular growth responses in a number of conditions (Farhy, R. D. et al., Circ. Res. 72:1202, 1993). Web site: http://www.delphion.com/details?pn=US06610652__ •
Mono- and disaccharides for the treatment of nitric oxide related disorders Inventor(s): Elliott; Gary T. (Stevensville, MT), Johnson; David (Hamilton, MT), Sowell; Greg (Bothell, WA), Weber; Patricia (Stevensville, MT) Assignee(s): Corixa Corporation (seattle, Wa) Patent Number: 6,699,846 Date filed: March 14, 2001 Abstract: Methods for treating diseases or conditions modulated or ameliorated by nitric oxide, particularly ischemia and reperfusion injury, are provided, using glycolipids structurally related to monophosphoryl lipid A but with notable reduction in proinflammatory and pyrogenic activity. Excerpt(s): Damage caused to tissues during ischemia/reperfusion can be extensive. Tissues deprived of oxygen suffer both reversible and irreversible damage. Injured tissues can also display disorders in automaticity. For example, myocardial tissues damaged during ischemia/reperfusion can display irreversible damage or myocardial infarction. Reversible damage, or stunning, is apparent with reduced pump efficiency leading to decreased cardiac output and symptomatology of suboptimal organ perfusion. Reperfusion of ischemic myocardial tissue may also cause electrophysiologic changes causing disorders in automaticity, including lethal arrhythmias. The exact mechanisms by which tissues are damaged during ischemia/reperfusion are unknown. It is hypothesized, however, that a complex series of events occur where tissues are damaged during ischemia as well as during subsequent reperfusion. During ischemia, tissues are deprived of oxygen-giving blood leading to anaerobic metabolism and consequently intracellular acidosis. Lack of circulation can cause infarcts or areas of necrotic, dead tissue. Ischemic tissues produce less of the enzymes needed to scavenge free radicals. Upon reperfusion and re-exposure to oxygen, tissues are damaged when free radicals including hydroxyl radicals are produced. Oxidative damage also disrupts the calcium balance in surrounding tissues causing stunning. Damage due to the oxidative burst is further compounded when injured cells release factors which draw inflammatory neutrophils to the ischemic site. The inflammatory cells produce enzymes which produce more toxic free-radicals and infiltrate the interstitial spaces where they
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kill myocytes. Methods to protect against the damage due to ischemia/reperfusion injury focus on reducing anaerobic metabolism as well as the initial oxidative burst and ensuing calcium overload preventing subsequent inflammation-associated damage. For example, agents which either decrease the production of oxygen-derived free radicals (including allopurinol and deferoxamine) or increase the catabolism of these materials such as superoxide dismutase, catalase, glutathione, and copper complexes, appear to limit infarct size and also may enhance recovery of left ventricular function from cardiac stunning. Agents which block sarcolemmal sodium/hydrogen exchange such as amiloride prevent the obligatory influx of calcium into the cell attendant with sodium extrusion and consequently reduce calcium overload. Web site: http://www.delphion.com/details?pn=US06699846__ •
Nitric oxide donors and pharmaceutical compositions containing them Inventor(s): Haj-Yehia; Abdullah (Jerusalem, IL) Assignee(s): Yissum Research Development Company of the Hebrew University of Jerusalem (jerusalem, Il) Patent Number: 6,642,260 Date filed: January 9, 2002 Abstract: The present invention provides a compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound contains one or more protected sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substitutes bearing at least one terminal --ONO.sub.2 group. The present invention further provides pharmaceutical compositions comprising one or more of said compounds as an active ingredient. Excerpt(s): The present invention relates to nitric oxide donors containing at leas one sulfhydryl group or a group capable of being converted in-vivo to a sulfhydryl group, and at least one nitric oxide donor group. The novel compounds are effective substitutes for existing tolerance-inducing organic or inorganic nitric oxide donors. For over a century, the nitric oxide (NO) donor nitroglycerin (GTN) has been the mainstay in the treatment of angina and heart diseases. However, the existing mechanisms proposing the mediation of GTN action by free NO, intracellular or extracellular Snitrosothiol formation and subsequent activation of guanylyl cyclase (GC), as well as those describing GTN tolerance, have become increasingly controversial. The phenomenon of tolerance to GTN, however, is of special clinical importance. In fact, early tolerance to the anti-anginal effects of the drug is the major drawback of nitrate therapy, especially during acute myocardial infarction. This is particularly important since alternative non-tolerance inducing agents have not yet been developed to successfully replace therapy with GTN. Based on accumulating evidence, Applicant hypothesized that GTN may directly interact with SH-group/s located on its target enzyme (GC) resulting in its S-nitrosylation and activation. However, subsequent autooxidation (disulfide formation) of these SH-groups renders the enzyme inert towards further action with GTN, resulting in tolerance development. Web site: http://www.delphion.com/details?pn=US06642260__
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Nitric oxide gas detector Inventor(s): Birks; John W. (Longmont, CO), Bollinger; Mark J. (Golden, CO), Robinson; Jill K. (Laramie, WY) Assignee(s): 2B Technologies, Inc. (golden, Co) Patent Number: 6,635,415 Date filed: April 19, 2000 Abstract: The concentration of nitric oxide in a gas is determined by oxidizing NO to NO.sub.2 and then measuring the concentration of NO.sub.2 in the gas, which is proportional to the concentration of NO. Preferably, gaseous NO.sub.2 molecules diffuse through a plurality of capillary membrane fibers and undergo a chemiluminescent reaction with a reagent flowing within; the light from the reaction is measured to determine NO.sub.2 concentration. In another aspect of a preferred embodiment, gas is passed through a scrubber before the concentration of NO.sub.2 is measured, in order to substantially remove carbon dioxide and ambient NO.sub.2 from the gas without substantially affecting the concentration of nitric oxide therein. Excerpt(s): This invention generally relates to gas analysis, and more particularly to the detection and measurement of nitric oxide in exhaled human breath. At present, gaseous nitric oxide (NO) is most commonly measured by mixing a gas sample with ozone gas at low pressures. When a nitric oxide molecule reacts with an ozone (O.sub.3) molecule, it forms nitrogen dioxide (NO.sub.2) and oxygen (O.sub.2) and emits a photon in the process. This photon possesses a red or near-infrared wavelength. The concentration of nitric oxide in the gas sample is thus determined by measuring the intensity of those photons. However, red and near-infrared wavelengths are not detected efficiently by standard photodetecting devices such as photomultiplier tubes and photodiodes. Consequently, special photodetector devices that are more sensitive to red light must be used. These devices must be cooled to subambient levels to reduce background noise from thermal effects. These special devices and their cooling requirements add cost and complexity over that required to measure visible light. In addition, an ozone-based nitric oxide gas detector requires a vacuum pump and a method for making ozone, which is typically a high-voltage electrical discharge. As a result, ozone-based detectors are generally bulky and complex, and require a significant amount of electricity to operate. The high voltage required to operate an ozone-based detector can pose a safety risk to the user and to those nearby. Government regulations restrict allowable ozone exposure, making it difficult to use ozone-based nitric oxide gas detectors in the workplace. Furthermore, ozone is a toxic gas, and it must be vented or destroyed after use. Because ozone is a pollutant, environmental regulations may prohibit venting the ozone in many areas, forcing the user of an ozone-based detector to destroy the ozone after use. Destruction of the ozone adds an additional step, and additional cost, to the nitric oxide measurement process. Web site: http://www.delphion.com/details?pn=US06635415__
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Nitric oxide-releasing imidate and thioimidate diazeniumdiolates, compositions, uses thereof and method of making same Inventor(s): Arnold; Ernst V. (Hagerstown, MD), Hrabie; Joseph A. (Frederick, MD), Keefer; Larry K. (Bethesda, MD) Assignee(s): The United States of America AS Represented by the Department of Health and (washington, Dc) Patent Number: 6,673,338 Date filed: September 10, 2001 Abstract: The invention provides NO-- or NO.sup.- -releasing imidate, thioimidate, and amide diazeniumdiolates, in which the N.sub.2 O.sub.2.sup.- functional group is bonded to a carbon atom. The invention also provides compositions comprising such diazeniumdiolate compounds, and methods of using such compounds and compositions. The invention further provides a method of preparing NO-- or NO.sup.- releasing imidate, thioimidate, and amide diazeniumdiolates. Excerpt(s): This invention relates to nitric oxide-releasing imidate and thioimidate diazeniumdiolates, to compositions comprising such compounds, to methods of using such compounds and compositions, and to a method for the preparation of nitric oxidereleasing imidate and thioimidate diazeniumdiolates. Nitric oxide (NO) has been implicated as part of a cascade of interacting agents involved in a wide variety of bioregulatory processes, including the physiological control of blood pressure, macrophage-induced cytostasis and cytotoxicity, and neurotransmission (Moncada et al., "Nitric Oxide from L-Arginine: A Bioregulatory System," Excerpta Medica, International Congress Series 897, Elsevier Science Publishers B. V.: Amsterdam (1990); Marietta et al., Biofactors 2: 219-225 (1990); Ignarro, Hypertension (Dallas) 16: 477-483 (1990); Kerwin et al., J. Med. Chem. 38: 4343-4362 (1995); and Anggard, Lancet 343: 11991206 (1994)). Given that NO plays a role in such a wide variety of bioregulatory processes, great effort has been expended to develop compounds capable of releasing NO. Some of these compounds are capable of releasing NO spontaneously, e.g., by hydrolysis in aqueous media, whereas others are capable of releasing NO upon being metabolized (Lefer et al., Drugs Future 19: 665-672 (1994)). have been known for many years. Traube (Liebigs Ann. Chem. 300: 81-123 (1898)) reported the preparation of a number of such compounds and noted that treatment of the compounds with acid produced a "brown gas." Given that the brown gas is nitrogen dioxide which may be produced directly, the release of brown gas by the compounds prepared by Traube is not, in and of itself, evidence of NO release. Compounds of the structural type reported by Traube are known to require harsh treatment with mineral acids to release any gas and such treatment is, of course, incompatible with biological utility. Web site: http://www.delphion.com/details?pn=US06673338__
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Nucleic acids encoding nitric oxide synthase variants Inventor(s): Adak; Subrata (Cleveland, OH), Stuehr; Dennis J. (Broadview Heights, OH) Assignee(s): The Cleveland Clinic Foundation (cleveland, Oh) Patent Number: 6,620,616 Date filed: September 13, 2000
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Abstract: Isolated polynucleotides which encode a variant of a mammalian nitric oxide synthase protein or polypeptide are provided. The variant nitric oxide synthase protein and polypeptides are substitution mutants, wherein the tryptophan that is normally located on the alpha 3 helix, six residues upstream from the cysteine which binds heme in the corresponding non-variant nitric oxide synthase protein or peptide is replaced with one of the other 19 naturally-occurring amino acid residues. The present invention also relates to vectors and recombinant cells comprising a nucleic acid which encodes a variant of a mammalian nitric oxide synthase protein. The present invention also relates to the nitric oxide synthase variant proteins and polypeptides. Excerpt(s): The free radical nitric oxide (NO) is a chemical messenger that is involved in regulating blood pressure, homeostasis, platelet aggregation, immuno-integrity and neurotransmission. NO is produced in many cell types, including endothelial cells, neurons, airway epithelial cells and macrophages. In blood vessels, NO mediates endothelium-dependent vasodilation. NO is also involved in maintaining basal vascular tone and regulating regional blood flow. In the nervous system NO plays a role in neurotransmission, synaptic plasticity, peristalsis, penile erection, neuro-degenerative disease, and excitotoxicity. In the immune system, NO is produced by activated macrophages and neutrophils as a cytotoxic agent against tumor cells and pathogens. Recent studies have shown that in vivo gene transfer of polynucleotides encoding different NOS isoforms may represent a therapeutic strategy for diseases characterized by decreased bioavailability of NO, such as vascular diseases. Specifically, Lloyd-Jones and Bloch have shown that gene therapy employing an nNOS-expressing adenoviral vector increased the sensitivity of a normal rabbit's carotid arteries to acetylcholine and also reversed the deficit in endothelium-dependent vascular relaxation in cholesterolfed rabbits. (Lloyd-Jones and Bloch (1996) Annual Rev. Med. 47:365-75.) Quian et. al. showed that in vivo transfer of the nNOS gene into cholesterol-fed rabbits reduced vascular adhesion molecule expression, lipid deposition, and inflammatory cell infiltration in the carotid arteries of such animals. (Qian, et. al. (1999) Circulation 98, 2979-2982.) Von der Leyen et al have shown that in vivo transfer of an eNOS-expressing plasmid to balloon denuded rat carotids significantly limited the subsequent development of neointimal hyperplasia. The eNOS-expressing plasmids were delivered via a liposome-Sendai virus hemagglutinin protein complex. (Von der Leyen, et. al. (1995) PNAS 92:1137-1141.) Kullo et al showed that adenovirus-mediated transfer of the gene for eNOS to the adventitia of rabbit carotid arteries had a favorable effect on vascular reactivity (Kullo, et. al. (1996) Circulation 96:7, 2254-2261.) Shears et al have shown that in vivo transfer of an adenovirus expressing iNOS reduced vasculopathy in rat aortic allografts. (Shears, et. al. (1997) J. Clin. Invest. 100:8, 2035-2042.) Thus, all three major NOS isoforms appear to be reasonable candidates for in vivo applications to achieve or augment NO production. Accordingly, it is desirable to have polynucleotides which encode NOS. It is especially desirable to have polynucleotides which encode NOS proteins or polypeptides that are fully active at all possible intracellular concentrations of O.sub.2. Web site: http://www.delphion.com/details?pn=US06620616__
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O2-arylated or O2-glycosylated 1-substituted diazen-1-ium-1,2-diolates and O2substituted 1-[(2-carboxylato) pyrrolidin-1-yl] diazen-1-ium-1,2-diolates Inventor(s): Bogdan; Christian (Wasserturmstrasse, DE), Ji; Xinhua (Gaithersburg, MD), Keefer; Larry K. (Bethesda, MD), Rice; William G. (Frederick, MD), Saavedra; Joseph E. (Thurmount, MD), Srinivasan; Aloka (Wilmington, DE) Assignee(s): The United States of America AS Represented by the Department of Health and (washington, Dc) Patent Number: 6,610,660 Date filed: May 3, 1999 Abstract: Diazeniumdiolates, wherein the N.sup.1 position is substituted by an inorganic or organic moiety and the O.sup.2 -oxygen is bound to a substituted or unsubstituted aromatic group, are provided. Also provided are O.sup.2 -glycosylated 1substituted diazen-1-ium-1,2-diolates (O.sup.2 -glycosylated diazeniumdiolates) and O.sup.2 -substituted 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolates (1-[(2carboxylato)pyrrolidin-1-yl]diazeniumdiolates). The O.sup.2 -aryl diazeniumdiolates are stable with respect to the hydrolytic generation of nitric oxide in neutral to acidic solutions and generate nitric oxide in basic or nucleophilic environments or microenvironments. Also provided are compositions, including pharmaceutical compositions, comprising such compounds and methods of using such compounds. Excerpt(s): The present invention relates to O.sup.2 -aryl 1-substituted diazen-1-ium-1,2diolates (O.sup.2 -aryl diazeniumdiolates) O.sup.2 -glycosylated 1-substituted diazeniumdiolates, and O.sup.2 -substituted 1-[(2-carboxylato)pyrrolidin-1yl]diazeniumdiolates, compositions comprising such diazeniumdiolates, methods of using such diazeniumdiolates, and methods of preparing O.sup.2 -aryl diazeniumdiolates. Nitric oxide (NO) has been implicated in a wide variety of bioregulatory processes, and compounds, which contain nitric oxide or are capable of releasing nitric oxide, have been identified as useful in regulating these processes. Many classes of nitric oxide-containing and/or -releasing adducts are known in the art, such as glyceryl trinitrate and nitroprusside (reviewed in U.S. Pat. No. 5,405,919 (Keefer et al.), including limitations of their use in biological applications). The limited utility of such compounds has, in part, given rise to the development of another class of nitric oxidegenerating compounds, diazeniumdiolates, which are especially useful biologically. in which the O.sup.2 -oxygen of the N.sub.2 O.sub.2.sup.- group is bonded to the functional group R.sup.3. When the R.sup.3 group is cleaved from the O.sup.2 -oxygen, NO can be released spontaneously. Web site: http://www.delphion.com/details?pn=US06610660__
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Optical sensors for the detection of nitric oxide Inventor(s): Barker; Susan (Silver Spring, MD), Clark; Heather (Middletown, CT), Kopelman; Raoul (Ann Arbor, MI) Assignee(s): The Regents of the University of Michigan (ann Arbor, Mi) Patent Number: 6,636,652 Date filed: August 2, 1999 Abstract: Optical fiber sensors and fiberless optical sensors for measuring analytes, and in particular nitric oxide, are described utilizing metals, and more particularly, metal
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colloids. Proteins (or fragments thereof) with selective binding are immobilized on metal particles. The proteins may be dye-labeled for increased sensitivity. Additionally, metals functionally linked to reporter dyes are described in addition to the incorporation of reference compounds for ratiometric measurements. Excerpt(s): Fiber-Optic Chemical Sensor" Anal. Chem. 68:1748 (1996). This sensor was constructed by holding a small amount of an internal reagent solution at the tip of a fiber-optic bundle with a piece of gas-permeable membrane. Nitric oxide diffuses across the membrane into this internal solution, where a chemiluminescent reaction between nitric oxide, hydrogen peroxide, and luminol takes place. The drawbacks of this sensor include the following: 1) the response time (approximately 8-17 seconds) is longer than the time needed for nitric oxide in the solution to be converted to nitrite; 2) the detection of nitric oxide is complicated by interferences from dopamine, uric acid, ascorbic acid, and cysteine, 3) the sensor is relatively large in size (greater than 6 mm in diameter) and thus difficult to use for the measurement of cellular nitric oxide levels (and impossible for intracellular measurements); and 4) the sensor has relatively poor sensitivity, i.e., a relatively high limit of detection (approximately 1.3 mM of nitric oxide). Sensors involving sol-gel technology have also been attempted. The process involves hydrolyzing an alkoxide of silicon to produce a sol, which then undergoes polycondensation to form a gel. Biomolecules are immobilized by being entrapped in the sol-gel. In one case, horse-heart cytochrome c was encapsulated in a sol-gel and absorbance-based spectral shifts were used to monitor the binding of nitric oxide. See Blyth et al., "Sol-Gel Encapsulation of Metalloproteins for the Development of Optical Biosensors for Nitrogen Monoxide and Carbon Monoxide" Analyst 120:2725 (1995). Unfortunately, the sensor reaction is reported to have taken two hours to reverse, making dynamic measurements impossible. What is needed is a sensor of relatively small size and good sensitivity that measures nitric oxide with little or no interference from other analytes in a short enough time period to permit dynamic measurements. Web site: http://www.delphion.com/details?pn=US06636652__ •
Pharmaceutical composition for treating fecal incontinence Inventor(s): Kamm; Michael A. (London, GB), Phillips; Robin K. S. (Northwood, GB) Assignee(s): S.l.a. Pharma AG (liestal, Ch) Patent Number: 6,635,678 Date filed: August 24, 1999 Abstract: Fecal incontinence and anal itch can be treated by administration, more particularly by local application to the anus, of an a adrenergic blocker, nitric oxide synthase inhibitor, prostaglandin F.sub.2.alpha., dopamine, morphine,.beta.-blockers, and 5-Hydroxytryptamine. The patients who benefit most from the invention are those who have a normal or low maximum anal resting pressure and a structurally intact internal anal sphincter muscle, and patients who have had major bowel resection and reanastomisis. Excerpt(s): This invention relates to the treatment of relief of fecal incontinence and anal itch (pruritis ani), particularly for patients who have had a major bowel resection and reanastomosis. Anal or fecal incontinence is the inability to voluntarily control the passage of feces or gas through the anus. It may occur either as fecal soiling or as rare episodes of incontinence for gas or watery stools. It is a very distressing condition that can result in self-inflicted social isolation and despair. Conventional treatments for fecal
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incontinence include drug therapy to improve stool consistency, such as morphine, loperamide and codeine phosphate to reduce gut motility, and laxatives to soften stools and relieve constipation. Biofeedback training is another treatment which involves muscle strengthening exercises to improve anal canal resting pressure, and squeeze pressure, and to teach symmetry of anal canal function. The most common form of treatment however, is surgical repair, such as the creation of a neo-sphincter which involves grafting on muscle from other parts of the anus, or a colostomy. (Gastroenterology in Practice, Summer 1995, p18-21; Dig Dis 1990; 8:179-188; and The New England Journal of Medicine, April 1992, p1002-1004). In mild cases of anal leakage, the patient will often try and plug the anus with a ball of cotton wall. Web site: http://www.delphion.com/details?pn=US06635678__ •
Polydithicarbamate-containing non-targeting marcomolecules and the use thereof for therapeutic and diagnostic applications Inventor(s): Lai; Ching-San (Encinitas, CA) Assignee(s): Medinox, Inc. (san Diego, Ca) Patent Number: 6,649,591 Date filed: October 1, 1999 Abstract: In accordance with the present invention, there is provided a new class of drugs for therapeutic treatment of such indications as cerebral stroke and other ischemia/reperfusion injury. Thus, in accordance with the present invention, dithiocarbamates are linked to the surface of a non-immunogenic, non-targeting macromolecule other than an antibody (e.g., albumin protein) either by using crosslinking reagents or by nonspecific binding to produce polydithiocarbamatemacromolecule-containing compositions, which represent a new class of drugs for therapeutic treatment of such indications as cerebral stroke and other ischemia/reperfusion injury. In accordance with another aspect of the present invention, combinational therapeutic methods have been developed for the in vivo inactivation or inhibition of formation (either directly or indirectly) of species which induce the expression of inducible nitric oxide synthase, as well as reducing nitric oxide levels produced as a result of.NO synthase expression. In accordance with yet another aspect of the present invention, magnetic resonance imaging methods have been developed for the measurement of cerebral and cardiac blood flow and infarct volume in ischemic stroke or heart attack situations. Such methods employ iron-containing complexes of a composition comprising a dithiocarbamate and a non-immunogenic, non-targeting macromolecule other than an antibody as contrast agents. Excerpt(s): The present invention relates to novel non-targeting dithiocarbamatecontaining compositions. In one aspect, the present invention relates to non-targeting dithiocarbamate-containing compositions wherein the dithiocarbamate is noncovalently associated with a macromolecule other than an antibody. Preferably, the macromolecule is non-immunogenic. In another aspect, the present invention relates to non-targeting dithiocarbamate-containing compositions wherein the dithiocarbamate is covalently crosslinked with a macromolecule other than an antibody that is preferably non-immunogenic. In yet another aspect, the present invention relates to diagnostic and therapeutic methods employing the novel non-targeting dithiocarbamate-containing compositions described herein. In 1984, Jolly et al., demonstrated the protection of reperfused myocardial tissue with the combinational use of superoxide dismutase and catalase (see, for example, Jolly et al., Cir. Res., 57:277, 1984). This observation implied
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that oxygen-derived free radicals are a cause of the reperfusion injury to the hypoxic myocardium. It is now known, however, that the phenomenon of ischemia/reperfusion injury is not restricted to the myocardium. Instead, ischemia/reperfusion injury is viewed as a general damaging event in any tissue or organ (such as brain, liver or kidney) subjected to a critical period of ischemia followed by perfusion with oxygenated whole blood. Ischemia/reperfusion injury therefore results from the reintroduction of molecular oxygen at the time of organ reperfusion or restoration of the circulation. While the delivery of dissolved molecular oxygen sustains cellular viability, it also provides oxygen as a substrate for numerous enzymatic oxidation reactions that produce reactive oxygen species which cause oxidative damage, a phenomenon referred to as the "oxygen paradox" (see, for example, Hearse et al., in J. Mol. Cell. Cardiol., 10:641, 1978). Oxygen, a gaseous molecule essential for normal cellular metabolism, can, under certain conditions, be deleterious to life. The cell defends itself against oxidative insults through its antioxidant mechanisms including superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione reductase and cellular antioxidants including glutathione, ascorbate and a-tocopherol (see, for example, Chan, in Stroke, 27:1124-29, 1996). However, when reactive oxygen species are generated at a rate that exceeds the capacity of the cell to defend itself against the resulting oxidative stress (such as in ischemia/reperfusion insults), the cell is irreversibly damaged, resulting in necrotic cell death or ischemic cell death. Web site: http://www.delphion.com/details?pn=US06649591__ •
Respiratory nitric oxide meter Inventor(s): Mault; James R. (Evergreen, CO) Assignee(s): Healthetech, Inc. (golden, Co) Patent Number: 6,612,306 Date filed: October 11, 2000 Abstract: A respiratory nitric oxide meter includes a respiratory connector designed to be supported in contact with a subject and to pass respiratory gases as the subject breathes. A flow pathway receives and passes the respiration gases. One end of the pathway is in fluid communication with the respiratory connector, and the other end is in fluid communication with a reservoir of respiratory gases. A nitric oxide concentration sensor generates electrical signals as a function of the instantaneous fraction of nitric oxide as the respiration gases pass through the flow pathway. Excerpt(s): The present invention relates generally to the detection of nitric oxide in a gaseous mixture and, more specifically, to the detection of nitric oxide in a flow pathway. Nitric oxide, NO, is a colorless gas useful in the detection and treatment of a variety of medical conditions such as asthma. Nitric oxide, NO, should not be confused with nitrous oxide, N.sub.2 O, or nitrogen dioxide, NO.sub.2. Nitrogen and oxygen also form other compounds, especially during combustion processes. These typically take the form of NO.sub.x where x represents an integer. These forms are generally referred to as NOX. Detection of nitric oxide, NO, is the primary focus of the present application. Nitric oxide has a variety of beneficial uses and detection of nitric oxide, especially in small concentrations, is necessary for the proper administration of nitric oxide and diagnosis of disease. Nitric oxide is beneficial in both the treatment and diagnosis of asthma and other forms of lung disorders. Asthma is a chronic disease characterized by intermittent, reversible, widespread constriction of the airways of the lungs in response to any of a variety of stimuli that do not affect the normal lung. A variety of drugs are
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commonly used to treat asthma. It is known that inhalation of nitric oxide (NO) is therapeutically beneficial in the prevention and treatment of asthma attacks and other forms of bronchoconstriction, of acute respiratory failure, or of reversible pulmonary vasoconstriction as discussed in U.S. Pat. No. 5,873,359 to Zapol et al, incorporated herein by reference. U.S. Pat. Nos. 5,904,938 and 6,063,407, both to Zapol et al. and incorporated herein by reference, disclose the use of inhaled nitric oxide in the treatment of vascular thrombosis and retinosis. Typically, treatment utilizing nitric oxide includes the introduction of nitric oxide as a portion of the respiratory gases being inhaled by the patient. The nitric oxide concentration is usually in the range of 1 to 180 parts per million (ppm). The difficulty presented in the administration of controlled amounts of nitric oxide is the determination of the concentration being introduced. It has traditionally been very difficult to quickly and accurately determine the concentration of nitric oxide in the gas mixture, especially where the concentration of nitric oxide is very low. Web site: http://www.delphion.com/details?pn=US06612306__ •
Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use Inventor(s): Earl; Richard A. (Westford, MA), Ezawa; Maiko (Acton, MA), Fang; Xinqin (Lexington, MA), Garvey; David S. (Dover, MA), Gaston; Ricky D. (Malden, MA), Khanapure; Subhash P. (Clinton, MA) Assignee(s): Nitromed, Inc. (bedford, Ma) Patent Number: 6,706,724 Date filed: December 21, 2001 Abstract: The invention describes novel substituted aryl compounds that are cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or, optionally, at least one therapeutic agent, such as, steroids, nonsterodal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B.sub.4 (LTB.sub.4) receptor antagonists, leukotriene A.sub.4 (LTA.sub.4) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) inhibitors, H.sub.2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof. The invention also provides novel kits comprising at least one COX-2 selective inhibitor, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention can be optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal toxicity or other toxicities; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.
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Excerpt(s): Nonsteroidal anti-inflammatory compounds (NSAIDs) are widely used for the treatment of pain, inflammation, and acute and chronic inflammatory disorders such as osteoarthritis and rheumatoid arthritis. These compounds inhibit the activity of the enzyme cyclooxygenase (COX), also known as prostaglandin G/H synthase, which is the enzyme that converts arachidonic acid into prostanoids. The NSAIDs also inhibit the production of other prostaglandins, especially prostaglandin G.sub.2, prostaglandin H.sub.2 and prostaglandin E.sub.2, thereby reducing the prostaglandin-induced pain and swelling associated with the inflammation process. The chronic use of NSAIDs has been associated with adverse effects, such as gastrointestinal ulceration and renal toxicity. The undesirable side effects are also due to the inhibition of prostaglandin in the affected organ. Recently two isoforms of cyclooxygenase, encoded by two distinct genes (Kujubu et al, J. Biol. Chem., 266, 12866-12872 (1991)), have been identified--a constitutive form, cyclooxygenase-1 (COX-1), and an inductive form, cyclooxygenase-2 (COX-2). It is thought that the antiinflammatory effects of NSAIDs are mediated by the inhibition of COX-2, whereas the side effects seem to be caused by the inhibition of COX-1. The NSAIDs currently on the market either inhibit both isoforms of COX with little selectivity for either isoform or are COX-1 selective. Recently compounds that are COX-2 selective inhibitors have been developed and marketed. These COX-2 selective inhibitors have the desired therapeutic profile of an antiinflammatory drug without the adverse effects commonly associated with the inhibition of COX-1. However, these compounds can result in dyspepsia and can cause gastropathy (Mohammed et al, N. Engl. J. Med., 340(25) 2005 (1999)). Additionally the COX-2 selective inhibitors can increase the risk of cardiovascular events in a patient (Mukherjee et al., JAMA 286(8) 954-959 (2001)); Hennan et al., Circulation, 104:820-825 (2001)). Web site: http://www.delphion.com/details?pn=US06706724__ •
Therapeutic methods employing disulfide derivatives of dithiocarbamates and compositions useful therefor Inventor(s): Lai; Ching-San (Encinitas, CA), Vassilev; Vassil (San Diego, CA) Assignee(s): Medinox, Inc. (san Diego, Ca) Patent Number: 6,589,991 Date filed: May 5, 2000 Abstract: The present invention provides a novel dithiocarbamamte disulfide dimer useful in various therapeutic treatments, either alone or in combination with other active agents. In one method, the disulfide derivative of a dithiocarbamate is coadministered with an agent that inactivates (or inhibits the production of) species that induce the expression of nitric oxide synthase to reduce the production of such species, while, at the same time reducing nitric oxide levels in the subject. In another embodiment, free iron ion levels are reduced in a subject by administration of a disulfide derivative of a dithiocarbamate(s) to scavenge free iron ions, for example, in subjects undergoing anthracycline chemotherapy. In another embodiment, cyanide levels are reduced in a subject by administration of a disulfide derivative of a dithiocarbamate so as to bind cyanide in the subject. In a further aspect, the present invention relates to compositions and formulations useful in such therapeutic methods. Excerpt(s): The present invention relates to therapeutic methods employing dithiocarbamates to reduce the level of species associated with disease states in mammals. In one aspect, the invention relates to compositions containing disulfide derivatives of dithiocarbamates and to therapeutic methods employing such
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compositions. In 1987, nitric oxide (.NO), a gaseous free-radical, was discovered in humans (see, for example, Ignarro et al., in Proc. Natl. Acad. Sci., USA 84:9265-69 (1987) and Palmer et al., in Nature 327:524-26 (1987)). As an indication of the significance of this discovery for the understanding of human physiology and pathophysiology, Science magazine selected nitric oxide as the molecule of the year in 1992. Nitric oxide is formed from the terminal guanidino nitrogen atom of L-arginine by nitric oxide synthase (NOS; see, for example, Rodeberg et al., in Am. J. Surg. 170:292-303 (1995), and Bredt and Snyder in Ann. Rev. Biochem. 63:175-95 (1994)). Two major forms of nitric oxide synthase, constitutive and inducible enzymes, have been identified. Web site: http://www.delphion.com/details?pn=US06589991__ •
Therapeutic uses for nitric oxide inhibitors Inventor(s): Cline; Hollis (Cold Spring Harbor, NY), Enikolopov; Grigori N. (Cold Spring Harbor, NY), Kuzin; Boris A. (Moscow, RU), Michurina; Tatyana (Moscow, RU), Peunova; Natalia I. (Cold Spring Harbor, NY) Assignee(s): Cold Spring Harbor Laboratory (cold Spring Harbor, Ny) Patent Number: 6,593,372 Date filed: October 25, 2001 Abstract: The present invention is based on the discovery that nitric oxide (NO) is an important growth regulator in an intact developing organism. In particular, the present invention relates to a method of increasing in a mammal a population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation in hematopoietic tissue, wherein the hematopoietic tissue is contacted with multiple doses of at least one inhibitor of NO, such as one or more inhibitors of nitric oxide synthase (NOS), thereby producing hematopoietic tissue having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation. The present invention also relates to a method of increasing a population of cells in S phase in a tissue of a mammal, comprising contacting the tissue with multiple doses of at least one inhibitor (one or more) of NO, such as an inhibitor of NOS. The invention also pertains to a method of regenerating tissue in an adult mammal comprising contacting a selected tissue (e.g., blood, skin, bone and digestive epithelium), or precursor cells of the selected tissue, with multiple doses of at least one inhibitor (one or more) of NO, thereby inhibiting differentiation and inducing proliferation of cells of the tissue. Excerpt(s): Organ development requires a tightly controlled program of cell proliferation followed by growth arrest and differentiation and, often, programmed cell death. The balance between the number of cell divisions and the extent of subsequent programmed cell death determines the final size of an organ (reviewed by Bryant and Simpson, Quart. Rev. of Biol., 59:387-415 (1984); Raft, Nature, 356:397-400 (1992)). Although much of the cellular machinery that determines the timing of onset and cessation of cell division per se is well understood (reviewed by Hunter and Pines, Cell, 79:573-582 (1994); Morgan, Nature, 374:131-134 (1995); Weinberg, Cell, 81:323-330 (1995)), little is known about the signals that cause discrete groups of cells and organs to terminate growth at the appropriate cell number and size. A better understanding of the signals involved provides possible targets for manipulating the cellular machinery resulting in therapeutic benefits for a number of conditions. The present invention is based on the discovery that nitric oxide (NO) is an important growth regulator in an intact developing organism. In particular, the present invention relates to a method of
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increasing in a mammal a population of hematopoietic cells (e.g., hematopoietic stem cells), including precursors to myeloid, lymphoid and erythroid cells, which are capable of undergoing normal hematopoiesis, differentiation and maturation in hematopoietic tissue, wherein the hematopoietic tissue is contacted with multiple doses of at least one inhibitor of NO, such as multiple doses of one or more inhibitors of nitric oxide synthase (NOS), thereby producing hematopoietic tissue having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation. In one embodiment, the present invention relates to a method of increasing in a mammal a population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation in hematopoietic tissue, comprising contacting the hematopoietic tissue with two inhibitors of nitric oxide synthase, thereby producing hematopoietic tissue having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation. The method can be carried out in vivo or ex vivo. In addition, the method can be used to prevent differentiation of erythroid cells and/or myeloid cells in the mammal. The method can further comprise contacting the hematopoietic tissue with at least one agent (e.g., a hematopoietic growth factor) which induces differentiation of a selected hematopoietic stem cell population. The present invention also relates to a method for treating a mammal to increase a population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation in hematopoietic tissue of the mammal. In the method, the hematopoietic tissue of the mammal is contacted with multiple doses of at least one inhibitor of NOS, thereby producing hematopoietic tissue having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation. In one embodiment, the present invention relates to a method for treating a mammal to increase a population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation in hematopoietic tissue of the mammal, comprising contacting the hematopoietic tissue of the mammal with two inhibitors of nitric oxide synthase, thereby producing hematopoietic tissue having an increased population of hematopoietic stem cells which are capable of undergoing normal hematopoiesis, differentiation and maturation. The method can further comprise contacting the hematopoietic tissue with at least one agent which induces differentiation of a selected hematopoietic stem cell population. Web site: http://www.delphion.com/details?pn=US06593372__ •
Upregulation of type III endothelial cell nitric oxide synthase by agents that disrupt actin cytoskeletal organization Inventor(s): Liao; James K. (Weston, MA) Assignee(s): Brigham and Women's Hospital, Inc. (boston, Ma) Patent Number: 6,696,480 Date filed: May 13, 2002 Abstract: A use for agents that disrupt actin cytoskeletal organization is provided. In the instant invention, agents that disrupt actin cytoskeletal organization are found to upregulate endothelial cell Nitric Oxide Synthase activity. As a result, agents that disrupt actin cytoskeletal organization are useful in treating or preventing conditions that result from the abnormally low expression and/or activity of endothelial cell Nitric Oxide Synthase. Such conditions include hypoxia-induced conditions. Subjects thought
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to benefit mostly from such treatments include nonhyperlipidemics nonhypercholesterolemics, but not necessarily exclude hyperlipidemics hypercholesterolemics.
and and
Excerpt(s): This invention relates to the use of agents that disrupt actin cytoskeletal organization as upregulators of Type III endothelial cell Nitric Oxide Synthase. Further, this invention relates to methods that employ agents that disrupt actin cytoskeletal organization to treat conditions that result from the abnormally low expression and/or activity of endothelial cell Nitric Oxide Synthase in a subject. Nitric oxide (NO) has been recognized as an unusual messenger molecule with many physiologic roles, in the cardiovascular, neurologic and immune systems (Griffith, TM et al., J Am Coll Cardiol, 1988, 12:797-806). It mediates blood vessel relaxation, neurotransmission and pathogen suppression. NO is produced from the guanidino nitrogen of L-arginine by NO Synthase (Moncada, S and Higgs, E A, Eur J Clin Invest, 1991, 21(4):361-374). In mammals, at least three isoenzymes of NO Synthase have been identified. Two, expressed in neurons (nNOS) and endothelial cells (Type III-ecNOS), are calciumdependent, whereas the third is calcium-independent and is expressed by macrophages and other cells after induction with cytokines (Type I-iNOS) (Bredt, D S and Snyder, S H, Proc Natl Acad Sci USA, 1990, 87:682-685, Janssens, S P et al., J Biol Chem, 1992, 267:22964, Lyons, C R et al., J Biol Chem, 1992, 267:6370-6374). The various physiological and pathological effects of NO can be explained by its reactivity and different routes of formation and metabolism. Recent studies suggest that a loss of endothelial-derived NO activity may contribute to the atherogenic process (O'Driscoll, G, et al., Circulation, 1997, 95:1126-1131). For example, endothelial-derived NO inhibits several components of the atherogenic process including monocyte adhesion to the endothelial surface (Tsao, P S et al., Circulation, 1994, 89:2176-2182), platelet aggregation (Radomski, M W, et al., Proc Natl Acad Sci USA, 1990, 87:5193-5197), vascular smooth muscle cell proliferation (Garg, U C and Hassid, A, J Clin Invest, 1989, 83:1774-1777), and vasoconstriction (Tanner, F C et al., Circulation, 1991, 83:2012-2020). In addition, NO can prevent oxidative modification of low-density lipoprotein (LDL) which is a major contributor to atherosclerosis, particularly in its oxidized form (Cox, D A and Cohen, M L, Pharm Rev, 1996, 48:3-19). Web site: http://www.delphion.com/details?pn=US06696480__ •
Use of chitinous materials for inhibiting cellular nitric oxide production Inventor(s): Chen; Chiung-Yun (Hsinchu, TW), Chen; Jian-Chyi (Muili County, TW), Chen; Shan-Shan (Hsinchu, TW), Hwang; Shiaw-Min (Hsinchu, TW) Assignee(s): Food Industry Research & Development Institute (hsinchu, Tw) Patent Number: 6,653,294 Date filed: December 8, 2000 Abstract: The invention relates to a method of reducing nitric oxide production by a cell in vitro or in a mammal by a cell by contacting the cell with chitosan or its derivatives in an amount effective to reduce nitric oxide production in the cell. Excerpt(s): Nitric oxide (NO) is associated with an array of diverse biological phenomena, such as inflammation, septic shock, adverse consequences of ischemia and reperfusion injury, hypotension, cell development, and apoptosis. Inflammation of a tissue in vivo is often characterized by the infiltration or presence of activated macrophages, which in turn produce NO as a mediator of vasodilation in the
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inflammation process. Thus, inflammation can be ameliorated by decreasing NO production by cells such as macrophages. Chitosan is an acid-soluble polymer of.beta.(1,4)-D-glucosamine. Chitin is a relatively insoluble, acetylated form of chitosan. Chitin, chitosan, and derivatives thereof are used in a number of industrial applications, including the production of viscosity control agents, adhesives, chromatography carriers, paper-strengthening agents, flocculent agents, food additives, drugs, and cosmetics. The invention is based on the surprising result that chitosan and derivatives thereof can inhibit cellular NO production. This result was unexpected because it had been reported that chitosan stimulated NO production by rat macrophages in vitro (Peluso et al., Biomaterials 15:1215-1220, 1994). However, it appears that previous studies may have used preparations of chitosan that are contaminated with endotoxin or other agents that cause an increase in NO production. Therefore, the invention is directed to endotoxin-free preparations of chitin or chitosan. Web site: http://www.delphion.com/details?pn=US06653294__ •
Use of inhaled NO as anti-inflammatory agent Inventor(s): Bloch; Kenneth D. (Brookline, MA), Zapol; Warren M. (Concord, MA) Assignee(s): The General Hospital Corporation (boston, Ma) Patent Number: 6,656,452 Date filed: November 14, 1997 Abstract: A method for lessening or preventing non-pulmonary ischemia-reperfusion injury or inflammation in a mammal by identifying a mammal which has ischemiareperfusion or is at risk for developing ischemia-reperfusion in a non-pulmonary tissue; and causing the mammal to inhale a therapeutically effective amount of gaseous nitric oxide sufficient to diminish the ability of leukocytes or platelets to become activated in a manner that contributes to an inflammatory process at the site of the ischemiareperfusion or inflammation in the non-pulmonary tissue, thereby lessening or preventing non-pulmonary ischemia-reperfusion injury in the mammal. Excerpt(s): The field of the invention is treatment of ischemia-reperfusion injury and inflammation. Nitric oxide (NO) is a cell membrane-permeable, free radical molecule which accounts for the vasodilator activity of endothelium-derived relaxing factor (reviewed in Schmidt et al., Cell 78:919-925 [1994]). NO interacts with several intracellular molecular targets, one of which is soluble guanylate cyclase (sGC). Binding of NO to the heme group in sGC stimulates the conversion of guanosine triphosphate (GTP) to guanosine-3',5'-cyclic monophosphate (cGMP). cGMP exerts it effects on cells, in part, through its action on cGMP-dependent protein kinase (cGDPK). Additional cGMP targets include cGMP-gated ion channels and cGMP-regulated cyclic nucleotide phosphodiesterases. Phosphodiesterases (PDEs) inactivate cGMP by converting it to GMP. At least four types of PDEs appear to participate in the metabolism of cyclic nucleotides in non-ocular tissues (types 1-3 and 5), only one of which, type 5 (PDE5), is specific for cGMP metabolism. Several agents act as selective inhibitors of PDE5, including dipyridamole and Zaprinast.TM. The biological effects of NO are also mediated by cGMP-independent mechanisms. NO can serve as an antioxidant, opposing the effect of superoxides. The antioxidant properties of NO appear to account for its ability to modulate proinflammatory activation of endothelial cells. NO may also react with superoxide to form peroxynitrite which may be responsible for the cellular toxicity associated with high levels of NO production.
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Web site: http://www.delphion.com/details?pn=US06656452__ •
Use of nitric oxide scavengers to treat side effects caused by therapeutic administration of sources of nitric oxide Inventor(s): Lai; Ching-San (Encinitas, CA) Assignee(s): Medinox, Inc. (san Diego, Ca) Patent Number: 6,596,733 Date filed: July 24, 2001 Abstract: Nitric oxide scavengers, such as dithiocarbamate-containing compounds, are used to reduce side effects caused by therapeutic administration of nitric oxide sources by administering the nitric oxide scavenger(s) to the subject after the therapeutic effect of the nitric oxide source has been achieved. For example, the nitric oxide source can be coadministered with the nitric oxide scavenger, with the latter formulated in a time release vehicle selected to delay release of the scavenger for a period of time sufficient to ensure that the therapeutic goal of the nitric oxide source has been achieved before release of the scavenger. Formulations and kits, including a bubble pack with pairwise arrangement of unit doses of a desired nitric oxide source and nitric oxide scavenger, are also provided. The side effects of sildenafil citrate (Viagra.RTM.), or of simultaneous administration of such a nitric oxide source in combination with another, such as nitroglycerin, are effectively controlled by the methods, formulations and kits of the invention. Excerpt(s): The present invention relates to therapeutic compositions and their use in treatment of disease states. More particularly, the present invention relates to methods and compositions for reducing side effects caused by administration to a subject of nitric oxide sources. As recently as 10 years go, nitric oxide was considered only a noxious gas that appeared in the exhaust of cars and in city smog, caused acid rain, and destroyed the ozone layer. This view changed tremendously in 1987 when nitric oxide was discovered to be produced in humans (Palmer, et al., Nature, 327:524-526, 1987; and Ignarro, L. J. et al., Proc. Natl. Acad. Sci., 84:9265-9269, 1987).The status of nitric oxide was thus expanded from being an environmental threat to being a new pharmaceutical target of major medical importance (Carter, B. et al., Anaesth Intensive Care, 26(1):67-69, 1988; Moncada, S., Methods Find Exp. Clin Pharmicol, 19 Suppl A: 3-5, 1997; Vallace, P. and Moncada, S., J. Royal College Physicians, London 28: 209-219, 1994; and Romero, R., Hum Reprod. 13:248-250, 1998). Nitric oxide is produced in the body by three different isoforms of the nitric oxide synthase (NOS) enzyme (see, for example, Singh, S. and Evans, T. W., Eur. Respir. J., 10:699-707, 1997). Neuronal NOS (nNOS) is found in neurons and plays a role in memory and pain perception. Endothelial NOS (eNOS) is found in vascular endothelial cells and plays an active role in vasodilatation and blood pressure regulation. Inducible NOS (iNOS) is expressed in astrocytes, microglial cells, neutrophils and in many other tissues in response to stimulation by inflammatory cytokines. Web site: http://www.delphion.com/details?pn=US06596733__
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Patent Applications on Nitric Oxide 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 nitric oxide: •
Apparatus and method for the estimation of flow -independent parameters which characterize the relevant features of nitric oxide production and exchange in the human lungs Inventor(s): George, Steven C.; (Irvine, CA) Correspondence: Daniel L Dawes; Myers Dawes & Andras; Suite 1150; 19900 Macarthur Boulevard; Irvine; CA; 92612; US Patent Application Number: 20030208131 Date filed: October 17, 2002 Abstract: The invention provides an estimation of key flow-independent parameters characteristic of NO exchange in the lungs, namely: 1) the steady state alveolar concentration, C.sub.alv,ss; 2) the maximum flux of NO from the airways, J.sub.NO,max; and 3) the diffusing capacity of NO in the airways, D.sub.NO,air. The parameters were estimated from a single exhalation maneuver comprised of a preexpiratory breathhold, followed by an exhalation in which the flow rate progressively decreased. The mean values for J.sub.NO,max, D.sub.NO,air, and C.sub.alv,ss do not depend on breathhold time for breathhold times greater than approximately 10 seconds. A priori estimates of the parameter confidence intervals demonstrates that a breathhold no longer than 20 seconds may be adequate, and that J.sub.NO,max be can estimated with the smallest uncertainty, and D.sub.NO,air the largest. Excerpt(s): The present application is related to and is a continuation in part of U.S. Provisional application serial. No. 60/200,682, filed Apr. 29, 2000, which is incorporated herein by reference. The invention relates to a method and apparatus for determining physiological parameters indicative of lung condition, which parameters are independent of air flow rates based on nitrogen monoxide content in exhalation, which content is dependent on air flow rates. The concentration of nitric oxide (NO) that appears in the exhaled breath depends strongly on several factors including the presence of inflammation. The fact that inflammatory diseases, such as bronchial asthma, elevate exhaled NO has generated great interest in using exhaled NO as a noninvasive index of pulmonary inflammation. Unfortunately, many early reports collected NO levels under different experimental conditions, and the absolute concentrations, as well as the conclusions, were not consistent. Subsequent work demonstrated that the exhaled NO level also depends on many additional factors including the exhalation flow rate, and the position of the soft palate (which affects nasal cavity contribution). These findings generated formal recommendations by both the American Thoracic Society (ATS) and the European Respiratory Society (ERS) on the conditions under which exhaled NO should be collected. Both reports recommend a constant exhalation flow rate during the maneuver (ERS recommends 250 ml/s, the ATS recommends 50 ml/s). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
10
This has been a common practice outside the United States prior to December 2000.
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Biological methods of use of 4-amino-3-mercapto-triazoles Inventor(s): Guillon, Christophe; (Bethlehem, PA), Heck, Diane E.; (Rumson, NJ), Heindel, Ned H.; (Easton, PA), Laskin, Jeffrey D.; (Piscataway, NJ), Rapp, Robert D.; (Reading, PA) Correspondence: Perkins Coie Llp; Post Office Box 1208; Seattle; WA; 98111-1208; US Patent Application Number: 20030225148 Date filed: September 17, 2002 Abstract: This invention claims the utility of two structural variants of functionalized 4amino-3-mercapto-1,2,4-triazoles as inhibitors of nitric oxide synthase (NOS) and as inhibitors of malignant cell growth. This fundamental molecular construct operates as a heterocyclic mimic of the open-chain N-aminoarginines (or N-aminoguanidines) previously established as NOS inhibitors. A convenient bioassay method, using PAM 212 keratinocytes for detection and quantification of relative NOS inhibition potential in a series of candidate drugs, is described as is a bioassay for growth inhibition. Excerpt(s): This application is a continuation of U.S. patent application Ser. No. 09/790,330, filed Feb. 21, 2001, which is the U.S. national phase of International Application No. PCT/US99/19146, filed Aug. 21, 1999, which claims priority to U.S. Provisional Patent Application No. 60/242,160, filed Aug. 21, 1998, the disclosures of which are incorporated by reference herein in their entirety. From a clinical perspective it is very clear that in vivo pharmacological manipulation of nitric oxide (NO) production will be of considerable therapeutic value. The list of nitric oxide synthase mediated diseases grows longer every year but the broad classes of dysfunctions includes many gastrointestinal motility problems, inflammatory states, and neurodegenerative disorders. A partial array of specific medical circumstances which appear to be certainly associated with NOS are: sunburn, rheumatoid arthritis, ulcerative colitis, Crohn's disease, lupus, septic and toxic shock, asthma, hypertension, myocarditis, diabetes, and many autoiummune and respiratory problems (Macdonald1996). Now that it is known that the various isoforms of NOS utilize the arginine to citrulline deamination as the route to NO, many therapeutic drugs have been designed to target that pathway (Kerwin-1994). With a wide variety of N-gamma-substituted arginines identified as inhibitors of NOS bearing such pendant gamma residues as nitro, amino, and even alkyl, and with the observation that some heterocyclic triazole systems appear to mimic the guanidino portion of arginine (Buchmuller-Rouiller-1992), we proposed the use of planar, fused-ring bio-isosteric models of arginine as new candidate classes of NOS inhibitors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Composition and method for treating hypertension Inventor(s): Stokes, Gordon; (St Leonards, AU) Correspondence: Foley & Lardner; P.O. Box 80278; San Diego; CA; 92138-0278; US Patent Application Number: 20030216384 Date filed: September 25, 2002 Abstract: The present invention relates to a composition for the treatment and/or prevention of hypertension, said composition comprising an synergistic antihypertensive combination of a therapeutically effective amount of at least one
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angiotensin II inhibitor, and a therapeutically effective amount of at least one nitric oxide donor; said composition optionally further comprising a pharmaceutically acceptable carrier, diluent and/or adjuvant. Excerpt(s): The present invention relates generally to a composition and method for treating and/or preventing hypertension. More particularly, the present invention relates to a composition and method for treating isolated systolic hypertension (ISH) and/or for treating systolic hypertension of the elderly (SHE). Isolated systolic hypertension (ISH) and associated widening of pulse pressure have been identified as important risk factors for cardiovascular disease in the elderly,.sup.1-4 and may persist despite the use of conventional antihypertensive drugs.sup.5-6 ISH generally refers to cases where diastolic blood pressure without treatment is normal while systolic blood pressure is high. SHE, on the other hand, generally refers to cases where diastolic blood pressure is normalised by treatment while the systolic blood pressure remains high. The research disclosed in the present application indicates that high systolic blood pressure in the elderly (such as, people greater than 65 years of age) is frequently associated with widened systemic and aortic pulse pressure caused by giant pulse-wave reflection. This wave reflection may signal endothelial dysfunction in conduit arteries. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Composition and method to augment and sustain neurotransmitter production Inventor(s): Charuvastra, Elizabeth; (Los Angeles, CA), Shell, William; (Los Angeles, CA) Correspondence: William Shell; Suite 301; 2980 Beverly Glen Circle; Los Angeles; CA; 90077; US Patent Application Number: 20040043054 Date filed: August 27, 2002 Abstract: This invention describes a method and composition to enhance the synthesis and release of the neurotransmitters by the oral administration of neurotransmitter precursors, along with natural plant substances that stimulate uptake of the neurotransmitters precursors, while adding natural plant substances that activate adenylate cyclase in order to avoid attenuation and prevent pharmacologic tolerance. The invention describes compositions for a medical foods that are designed to improve cognitive function, induced sleep, a improve Parasympathetic function, improve autonomic balance, increase nitric oxide production, reduce blood pressure, increase blood flow, and treat virus infections. The compositions include amino acids such as choline, herbs such ginkgo biloba, and other foods such as coca. The invention also describes the use of physiologic tests such as 24 hour ECG monitoring to create the appropriate combinations and assess the useful proportions Excerpt(s): This invention relates generally to medical foods and dietary supplements that augment neurotransmitter production by simultaneous administration of oral neurotransmitter precursors, a precursor uptake stimulator, a neurotransmitter releaser, a disinhibitor of the adenosine neuron brake, and an activator of adenylate cyclase to prevent tachyphylaxis. There has been increasing attention to the role that neurotransmitters and neuromodulators play in various aspects of health and disease. Neurotransmitters are the chemical messengers that allow one neuron to communicate with either a second neuron or an effector organ. The classic neurotransmitters are acetylcholine and norepinephrine that function within the autonomic nervous system.
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The autonomic nervous system, operating through its neurotransmitters, controls important body functions, such as heart rate, respiratory rate, gastrointestinal function, appetite, sleep, sexual performance, blood pressure and mood. The increased scrutiny has lead to an appreciation of the effects that neurotransmitters and neuromodulators have on derangements of cognitive function, sleep disorders, mood, and memory. It is also known that neurotransmitters and neuromodulators play a crucial role in regulating the function of the cardiovascular, reproductive, musculoskeletal, immune, respiratory, and memory systems. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Composition for the prevention and/or treatment in newborn babies of the effects of complications during childbirth Inventor(s): Groenendaal, Floris; (Houten, NL), Peeters, Cacha Marie Petronelle Catherine Dorothee; (Utrecht, NL), Van Bel, Frank; (Amstelveen, NL) Correspondence: Young & Thompson; 745 South 23rd Street 2nd Floor; Arlington; VA; 22202 Patent Application Number: 20040002530 Date filed: July 10, 2003 Abstract: A selective inhibitor of neuronal nitric oxide synthase (nNOS) and of inducible nitric oxide synthase (iNOS), which does not substantially inhibit endothelial nitric oxide synthase (eNOS), can be effectively used for the treatment, in human or other mammalian neonates, of the effects of complications during childbirth. Such effects include perinatal asphyxia and hypoxia-ischemia. A very useful example of such a selective inhibitor is 2-iminobiotin. Excerpt(s): The present invention relates to pharmaceutical compositions that can be used to prevent and/or treat, in newborn babies the effects of complications that may occur during childbirth. In particular, the invention relates to pharmaceutical preparations that can be used to prevent and/or treat, in newborn babies, the effects of perinatal asphyxia (=hypoxia-ischemia). Specifically, the invention relates to pharmaceutical preparations that can be used to prevent and/or treat in newborn babies, brain damage or brain injury that may result from complications during childbirth such as perinatal asphyxia and/or hypoxia-ischemia. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compositions including ammonia oxidizing bacteria to increase production of nitric oxide and nitric oxide precursors and methods of using same Inventor(s): Whitlock, David R.; (Watertown, MA) Correspondence: Wolf Greenfield & Sacks, PC; Federal Reserve Plaza; 600 Atlantic Avenue; Boston; MA; 02210-2211; US Patent Application Number: 20040014188 Date filed: January 14, 2003 Abstract: A method of enhancing health through the generation in close proximity of a surface of a subject, nitric oxide and nitric oxide precursors using bacteria adapted to oxidize ammonia and urea derived from perspiration is described. Local and systemic
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effects are described including reduction in vascular disease, enhancement of sexual function, improved skin health, and reduced transmission of sexually transmitted diseases. Excerpt(s): This application claims priority to U.S. Provisional Application Serial No. 60/224,598 filed Aug. 11, 2000. The present invention relates to a composition including ammonia oxidizing bacteria to increase production of nitric oxide and nitric oxide precursors on the surface of a subject and methods of using same. Beneficial bacteria have been utilized to suppress the growth of pathogenic bacteria. Bacteria and other microorganisms are ubiquitous in the environment. The discovery of pathogenic bacteria and the germ theory of disease has had a tremendous effect on health and disease states. Bacteria are a normal part of the intestinal contents of all living things. These bacteria are not pathogenic under normal conditions, and in fact improve health by rendering the normal intestinal contents less hospitable for disease causing organisms. This is accomplished in a number of ways: nutrients are consumed, leaving less for pathogens; conditions are produced, such as pH, oxygen tension, which are not hospitable for pathogens; compounds are produced that are toxic to pathogens; pathogens are consumed as food by these microorganisms; less physical space remains available for pathogens; and specific binding sites are occupied leaving fewer for pathogens. The presence of these desirable bacteria is seen as useful in preventing disease states. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Compounds and methods for modulating non-transcriptional effects of steroid hormones Inventor(s): Chin, William; (Indianapolis, IN), Liao, James; (Weston, MA) Correspondence: Wolf Greenfield & Sacks, PC; Federal Reserve Plaza; 600 Atlantic Avenue; Boston; MA; 02210-2211; US Patent Application Number: 20030225046 Date filed: January 15, 2003 Abstract: This invention provides new methods and compounds for controlling the intracellular and physiological effects of steroid hormones, including but not limited to estrogen, through modulation of the interaction of such hormone receptors with phosphatidylinositol-3 kinase. Compounds and methods for controlling the activation of endothelial nitric oxide synthase are also disclosed. Excerpt(s): This application is a divisional of prior nonprovisional U.S. patent application Ser. No. 09/680,695, filed on Oct. 6, 2000, now issued as U.S. Pat. No. 6,566,081, which claims benefit under 35 U.S.C. 119(e) of provisional U.S. Patent Application Serial No. 60/163,964, filed on Nov. 8, 1999, No. 60/163,953, filed on Nov. 8, 1999, No. 60/158,525, filed on Oct. 8, 1999, and No. 60/158,173, filed on 6 7 October 1999. This application is a continuation-in-part of prior provisional United States Patent Application Serial No.: 60/158,173, filed Oct. 6, 1999; No. 60/158,525, filed Oct. 8, 1999; No. 60/163,964, filed Nov. 8, 1999; No. 60/163,953, filed Nov. 8, 1999, all pending at the time of filing of this continuation-in-part application. The disclosure of all of these prior provisional applications is hereby incorporated by reference. Priority under 35 USC 120 is claimed to each of these prior applications. Estrogens elicit endothelium-dependent relaxation, apparently through activation of endothelial nitric oxide synthase, but the precise signaling pathway by which estrogens stimulate endothelial nitric oxide
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synthase (eNOS) activity is unknown. Here it is shown that the estrogen receptor (ER).alpha. interacts directly with phosphatidylinositol (PI) 3-kinase and that estrogeninduced eNOS activity is mediated via a novel non-nuclear mechanism involving the activation of the PI3-kinase/Akt pathway. The role of this pathway in modulation of physiologic conditions mediated by the estrogen and other receptors is disclosed and claimed. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Exogenenous nitric oxide gas (gNO) therapy in wound healing Inventor(s): Ardakani, Ali; (North Vancouver, CA), Ghaffari, Abdi; (Edmonton, CA), Miller, Chris; (North Vancouver, CA) Correspondence: Kevin D. Mccarthy; Roach Brown Mccarthy & Gruber, P.C.; 1620 Liberty Building; 420 Main Street; Buffalo; NY; 14202; US Patent Application Number: 20040009238 Date filed: July 8, 2003 Abstract: The present invention provides a method and device for exposing injured mammalian tissues, in a non-abrasive manner, to an effective amount of exogenous gaseous nitric oxide (gNO) in order to promote healing by reducing the size, duration and severity of wounds as well as controlling the infection by reducing number of pathogens at the site and the surrounding area. Excerpt(s): This application claims priority to U.S. provisional Patent applications Nos. 60/431,876 (filed Dec. 9, 2002), 60/394690 (filed Jul. 9, 2002), and 60/409400 (filed Sep. 10, 2002). This invention pertains to a method and device for delivery of gaseous nitric oxide (gNO). The NO is directed to a wound on a mammal to promote the healing of the wound. Nitric oxide (NO) is an intensely studied molecule in medical science. It is a short-lived free radical. It is also highly reactive and locally diffusible because of its small molecular size and unpaired electron. Since its discovery as an endothelium derived relaxing factor in 1987, it has become evident that NO is a widely distributed multi-functional intra- and inter-cellular messenger. NO is formed from a terminal nitrogen atom of arginine through an oxidation process with molecular oxygen. It is understood that certain enzymes, referred to as nitric oxide synthases (NOS), are responsible for that oxidation process. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Flow-independent parameter estimation based on tidal breathing exhalation profiles Inventor(s): Condorelli, Peter; (Irvine, CA), George, Steven C.; (Irvine, CA) Correspondence: Daniel L. Dawes; Myers, Dawes & Andras Llp; 19900 Macarthur Blvd, Suite 1150; Irvine; CA; 92612; US Patent Application Number: 20030229290 Date filed: February 5, 2003 Abstract: Parametric characterization of nitric oxide (NO) gas exchange using a twocompartment model of the lungs is a non-invasive technique to characterize inflammatory lung diseases. The technique applies the two-compartment model to parametric characterization of NO gas exchange from a tidal breathing pattern. The
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model is used to estimate up to six flow-independent parameters, and to study alternate breathing patterns. Excerpt(s): The application is related to U.S. provisional patent application serial No. 60/354,781 filed Feb. 5, 2002 and entitled FLOW-INDEPENDENT PARAMETER ESTIMATION BASED ON TIDAL BREATHING EXHALATION PROFILES, and to U.S. provisional patent application serial No. 60/380,175 filed May 13, 2002 and entitled CHARACTERIZING NITRIC OXIDE EXCHANGE DYNAMICS DURING TIDAL BREATHING, both of which are incorporated herein by reference and to which priority is claimed pursuant to 5 USC 119. The invention relates to a method and apparatus for determining physiological parameters indicative of lung condition, which parameters are independent of air flow rates based on nitrogen monoxide content in exhalation, which content is dependent on air flow rates. It is known that nitric oxide (NO) is produced in the lung and appears in the exhaled breath. The exhaled concentration is elevated in important inflammatory diseases such as asthma. A significant fraction of exhaled NO which is unique among endogenous gases comes from the airways. A single breath technique has been invented by one of the inventors and is the subject of a copending application in a prior application, which technique required inhalation to total lung capacity followed by a breath hold of up to 20 seconds followed by an exhalation with a decreasing flow rate which lasted approximately 15 seconds. Thus approximately 35 seconds was required to complete the maneuver. This duration is not possible for subjects who cannot follow directions (i.e., small children or subjects who are unconscious) or who have compromised lung function. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Flue gas desulfurization process and apparatus for removing nitrogen oxides Inventor(s): Hammer, Michael T.; (Birdsboro, PA), Mengel, Michael L.; (Fredericksburg, PA) Correspondence: Hartman & Hartman, P.C.; 552 East 700 North; Valparaiso; IN; 46383; US Patent Application Number: 20030228246 Date filed: June 5, 2002 Abstract: An apparatus and process for removing acidic gases and NOx from flue gases produced by utility and industrial plants. The process and apparatus convert NOx, and particularly nitric oxide, to nitrogen dioxide, which is then reacted to form a valuable byproduct. The process generally entails contacting a flue gas with a scrubbing medium to absorb acidic gases from flue gas and produce an intermediate flue gas. The intermediate flue gas is then cooled to cause nitric oxide present therein to be oxidized to form nitrogen dioxide, which is then absorbed from the flue gases to produce a nitrogen dioxide-containing solution and a scrubbed flue gas. The nitrogen dioxide in the nitrogen dioxide-containing solution is then reacted with ammonium hydroxide to form ammonium nitrate as a valuable byproduct. Excerpt(s): This invention generally relates to gas-liquid contactors used in the removal of acidic gases, such as from utility and industrial flue gases. More particularly, this invention is directed to a wet flue gas desulfurization (FGD) process and apparatus that remove nitrogen oxides (NOx) from a flue gas following the removal of acidic gases such as sulfur dioxide. Acidic gases, including sulfur dioxide (SO.sub.2), hydrogen chloride (HCl) and hydrogen fluoride (HF), are known to be hazardous to the
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environment, and as a result their emission into the atmosphere is closely regulated by clean air statutes. For the removal of acidic gases from flue gases produced by utility and industrial plants, gas-liquid contactors and absorbers, or scrubbers, are widely employed. Scrubbers generally employ a liquid media that is brought into intimate contact with a flue gas to remove acidic gases by absorption. The process by which acidic gases are removed from flue gases in this manner is generally referred to as wet flue gas desulfurization (wet FGD). The cleansing action produced by scrubbers is generally derived from the passage of a flue gas through a tower cocurrently or countercurrently to a descending liquid medium. Calcium-based slurries, sodium-based solutions and ammonia-based solutions are typical alkaline scrubbing media used in flue gas scrubbing operations. The cleansed gases are allowed to exit the tower, typically passing through a mist eliminator to atmosphere. The liquid medium and its absorbed gases are collected in a tank, typically at the bottom of the tower, where the absorbed gases are reacted to form byproducts that are useful or at least not harmful to the environment. While scrubbers utilizing calcium-based slurries generally perform satisfactorily, their operation results in the production of large quantities of wastes or gypsum, the latter having only nominal commercial value. In contrast, ammonia-based scrubbing processes have been used in the art to produce a more valuable ammonium sulfate fertilizer, as taught by U.S. Pat. Nos. 4,690,807 and 5,362,458, each of which are assigned to the assignee of the present invention. In these processes, the scrubbing solution is accumulated in a tank where the absorbed sulfur dioxide reacts with ammonia (NH.sub.3) to form ammonium sulfite ((NH.sub.4).sub.2SO.sub.3) and ammonium bisulfite (NH.sub.4HSO.sub.3), which are oxidized in the presence of sufficient oxygen to form ammonium sulfate ((NH.sub.4).sub.2SO.sub.4) and ammonium bisulfate (NH.sub.4HSO.sub.4), the latter of which reacts with ammonia to form additional ammonium sulfate. A portion of the ammonium sulfate solution and/or ammonium sulfate crystals that form in the solution can then be drawn off to yield the desired byproduct of this reaction. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Formulations and methods of using nitric oxide mimetics against a malignant cell phenotype Inventor(s): Adams, Michael A.; (Kingston, CA), Graham, Charles H.; (Kingston, CA), Heaton, Jeremy P.W.; (Gananoque, CA), Postovit, Lynne-Marie; (Kingston, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20030215528 Date filed: March 6, 2003 Abstract: The present invention relates to methods and formulations for inhibiting, treating and preventing a malignant cell phenotype, cell, tumor and/or disease. Administration of nitric oxide mimetics, such as low doses, is sufficient to increase, restore or maintain nitric oxide-mediated signaling in cells so that malignant cell phenotypes, cells, tumors and/or diseases are inhibited or prevented. These methods and formulations are particularly useful in treating and preventing cancer in animals. Excerpt(s): This application claims the benefit of U.S. Provisional Application Serial Nos. 60/362,969 filed Mar. 6, 2002, and 60/362,620 filed Mar. 7, 2002, and U.S. patent application Ser. No. 10/042,039, filed Oct. 25, 2001, which are herein incorporated by reference. U.S. patent application Ser. No. 10/042,039 is a continuation-in-part of U.S.
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application Ser. No. 09/842,547, filed Apr. 26, 2001, which claims the benefit of U.S. Provisional Application Nos. 60/277,469, filed Mar. 21, 2001, and 60/199,757, filed Apr. 26, 2000, which are herein incorporated by reference in their entirety. The present invention relates to methods and formulations for inhibiting, treating and preventing a malignant cell phenotype, cell, tumor and/or disease. We have now found that the mechanism by which hypoxia and hyponitroxia have impact upon cellular phenotype is not necessarily mediated solely by the lack of oxygen but rather also from a deficiency in nitric oxide mediated signaling. Accordingly, as demonstrated herein, administration of nitric oxide mimetics, such as low doses, is sufficient to increase, restore or maintain nitric oxide-mediated signaling in cells so that malignant cell phenotypes, cells, tumors and/or diseases are inhibited or prevented. Thus, provided herein are formulations and methods of using these formulations to deliver low doses of nitric oxide mimetics to cells at levels which inhibit a malignant cell phenotype, cell, tumor and/or disease to treat and/or prevent development of a malignant cell phenotype, cell, tumor and/or disease but which reduce or avoid development of unwanted effects of the NO mimetics. These methods and formulations are particularly useful in treating and preventing cancer in animals. Hypoxia or oxygen tension below normal physiologic levels in cells results in physiologic as well as pathologic alterations in the cells, which alterations have been associated with differential gene expression. For example, hypoxia affects endothelial cellular physiology in vivo and in vitro in various ways including modulating the transcriptionally-regul- ated expression of vasoactive substances and matrix proteins involved in modulating vascular tone or remodeling the vasculature and surrounding tissue (Faller, D. V. Clin. Exp. Pharmacol. and Physiol. 1999 26:74-84). Hypoxia in solid tumors has been shown to protect cancer cells from being killed by Xirradiation and leads to resistance to certain cancer drugs. Hypoxia also appears to accelerate malignant progression and increase metastasis (Brown, J. M. Cancer Res. 1999 59:5863-5870). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Inhalation of nitric oxide Inventor(s): Chen, Luni; (Uppsala, SE), Hedenstierna, Goran; (Djursholm, SE) Correspondence: Burns Doane Swecker & Mathis L L P; Post Office Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20040028753 Date filed: September 5, 2003 Abstract: Use of inhalable gaseous nitric oxide (NO) in combination with a cyclooxygenase inhibitor for the manufacture of a medicament for treating pulmonary vasoconstriction or airway constriction in a mammal, including man, in order to counteract a hypo- or non-response to treatment with gaseous nitric oxide or nitric oxide donor only and/or to counteract a rebound response in the case of withdrawal of treatment with gaseous nitric oxide or nitric oxide donor only said combination being use in a therapeutically effective amount to accomplish relaxation of said pulmonary vasoconstriction or airway constriction. A method and a pharmaceutical preparation for the treatment of pulmonary vasoconstriction or airway constriction while using the above-mentioned combination. Excerpt(s): The present invention is within the field of medicaments for treatment of pulmonary vasoconstriction or airway constriction in a mammal, especially man. More specifically, the invention is intended for the treatment of individuals who are poorly
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responding, or not responding at all, to inhalation of nitric oxide, or who are the subject of a rebound response on discontinuation of nitric oxide inhalation. Nitric oxide relaxes pulmonary vessels, in particular when they are constricted by various disorders, as will be exemplified below. Nitric oxide also relaxes airway smooth muscle (Belvisi M G, Stretton C D, Barnes P J. Eur. J. Pharmacol. 1992; 210: 221-222), and inhalation of exogenous nitric oxide attenuates airway constriction in the response to various agents in laboratory animals and humans (Dupuy P M, Shore S A, Drazen J M, Frostell C, Hill W A, Zapol W M. J.Clin.Invest. 1992; 90:421-428; Hogman M, Frostell C, Arnberg H, Hedenstierna G. Eur.Respir.J. 1993; 6:177-160; Hogman M, Frostell C G, Hedenstrom H, Hedenstierna G. Am.Rev.Respir.Dis. 1993; 148:1474-1478). Thus, for instance EP 560 928, U.S. Pat. Nos. 5,485,827, 5,873,359 and WO 92/10228 disclose the use of nitric oxide for treating bronchoconstriction and pulmonary vasoconstriction. It has however been found that the effect of the treatment shows great inter- and intra-individual variability. Furthermore, although NO inhalation (INO) may be an efficient therapy in patients with pulmonary hypertension, around 1/3 of the patients are hypo- or non-responders to INO. In addition thereto, worsening of the pulmonary hypertension and of the oxygenation have been observed during attempts to withdraw INO, which is termed rebound response. Life-threatening hemodynamic instability and deaths by discontinuing inhalation of nitric oxide have also been reported. Stepwise lowering of the NO dose will prolong the NO therapy but may still not eliminate the rebound response. The mechanisms responsible for the hyporesponsiveness and the rebound response are not fully understood. One of the hypothesisis is that the endogenous NO production can be inhibited by NO inhalation as a negative feedback mechanism with down-regulation of the endogenous synthesis. In a study forming the basis for the present invention an animal model was developed which produced a rebound response on discontinuation of NO inhalation by endotoxin infusion for at least 3 hours. Moreover, the findings indicated that the rebound was not only caused by a downregulation of endogenous NO production but also, and possibly more important, by increased activity of the vasoconstrictor Endothelin 1 (ET-1). Another observation was that there was an inverse correlation between the response to INO and the degree of rebound. Thus, the poorer the effect of INO, the stronger was the rebound response. A similar link between hypo- or non-response and rebound has been found by Davidson and coworkers in neonatal respiratory distress cases. (D. Davidson, MD; Pediatries. 104(2): 231-236, 1999). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Inhibitors and methods of use thereof Inventor(s): Gribble, Gordon W.; (Lebanon, NH), Honda, Tadashi; (Hanover, NH), Honda, Yukiko; (Hanover, NH), Sporn, Michael B.; (Tunbridge, VT), Suh, Nanjoo; (White River Junction, VT) Correspondence: Fulbright & Jaworski L.L.P.; 600 Congress AVE.; Suite 2400; Austin; TX; 78701; US Patent Application Number: 20040002463 Date filed: May 12, 2003 Abstract: New triterpenoid derivatives with various substituents at the C-17 position of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) were synthesized. Among them, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitril- e (CNDDO), 1-(2-cyano-3,12dioxooleana-1,9(11)-dien-28-oyl) imidazole, 1-(2-cyano-3,12-dioxooleana-1,9(11)-dien-28-
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oyl)-2-methylimidazole, 1-(2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl)-4methylimidazole show extremely high inhibitory activity (IC.sub.50=0.01-1 pM level) against production of nitric oxide induced by interferon-.gamma. in mouse macrophages. These compounds can be used in the prevention or treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, rheumatoid arthritis, and other inflammatory diseases. All the new triterpenoid derivatives are more potent than previously known CDDO. Excerpt(s): The present application claims the priority of provisional U.S. Serial No. 60/378,009, filed May 13, 2002, the entire contents of which are incorporated herein by reference and without disclaimer. The present invention disclosed herein was made with the support of the U.S. Government under NIH Grant 1R01-CA78814, U.S. Department of Defense Grants DAMD 17-96-1-6163, DAMD 17-98-1-8604, and DAMD 17-99-1-9168. Accordingly, the U.S. Government may have certain rights in this invention. The present invention provides triterpenoid derivatives, as well as processes for the preparation of such derivatives. The invention also provides methods for prevention and/or treatment of cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotropic lateral sclerosis, rheumatoid arthritis, inflammatory bowel disease, and all other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide (NO) or prostaglandins. One of the major needs in cancer prevention is the development of effective and safe new agents for chemoprevention. In particular, there is a need for chemopreventative agents targeted at mechanisms known to be involved in the process of carcinogenesis. In recent years, there has been a resurgence of interest in the study of mechanisms of inflammation that relate to carcinogenesis and in the use of such mechanisms as the basis for development of new chemopreventative agents. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method and apparatus to detect a gas by measuring ozone depletion Inventor(s): Birks, John W.; (Longmont, CO), Bollinger, Mark J.; (Golden, CO) Correspondence: Rick Martin; Patent Law Offices OF Rick Martin, PC; 416 Coffman Street; Longmont; CO; 80501; US Patent Application Number: 20040018630 Date filed: July 26, 2002 Abstract: The present invention relates to an apparatus and method for determining the concentration of nitric oxide (NO) in a gas mixture such as air. The gas sample containing NO is mixed with a gas containing ozone (O.sub.3), and the change in the ozone concentration is measured after a sufficient time is allowed for the reaction between NO and O.sub.3 to take place and destroy a measurable quantity of O.sub.3. In the preferred embodiment, the concentration of ozone is measured using the technique of UV absorption. In this case, the invention has the advantage over other instruments for measuring NO of having absolute calibration based on the known extinction coefficient for ozone at ultraviolet wavelengths. The invention discloses both static and dynamic flow systems, and the NO concentration measurements may be made over a wide pressure range. Excerpt(s): The present invention relates to gas analysis, and more particularly to the detection and measurement of nitric oxide (NO) in gases such as air and human breath by measuring ozone depletion. A suitable application of the invention is the
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measurement of the concentration of NO in the inhaled or exhaled air of a human being or other living organism. Another suitable application is the measurement of NO in ambient air for air pollution monitoring and for scientific studies of atmospheric chemistry. The invention also applies to measurements of nitrogen dioxide (NO.sub.2) in a gas mixture such as air when NO.sub.2 is first reduced to NO via a photolytic or chemical reaction. In ambient air, the invention may be used to measure the sum of NO and NO.sub.2 concentrations, commonly referred to as NO.sub.x The invention also applies to the measurement of reactive oxides of nitrogen such as NO.sub.2, nitrate radical (NO.sub.3), dinitrogen pentoxide (N.sub.2O.sub.5), nitrous acid (HNO.sub.2), nitric acid (HNO.sub.3), peroxynitric acid (HNO.sub.4), peroxyacetyl nitrate (PAN), chlorine nitrate (ClNO.sub.3) and particulate nitrate, collectively referred to as NO.sub.y, either separately or in combination. These nitrogen oxide species may be caused to produce NO in a chemical reaction, as in the reaction at a heated molybdenum oxide surface or in the reaction at a heated gold surface in the presence of a suitable reducing agent such as hydrogen or carbon monoxide (CO). The present invention measures the concentration of NO produced in such reactions. The invention may be applied to the detection and quantification of any substance that may be treated so as to release gaseous NO. For example, it is known in the art of chromatography that many compounds containing nitrogen can be heated or reacted with other chemicals to produce NO gas. The NO produced by heating or by reaction with other chemicals may be detected and quantified using the invention described here. Similarly, various substances containing nitrogen such as fertilizers and chemicals used as explosives will slowly decompose to release NO gas, and that NO gas can be detected and quantified using this invention. The detection of fertilizers and explosives may be enhanced by heating the sample to increase the rate of release of NO gas. The invention also applies to the detection and quantification of chemical compounds that do not contain nitrogen themselves but that will react with a nitrogen-containing compound to produce NO gas. An example is the detection and quantification of carbon monoxide (CO) where air containing CO is mixed with a nitrogen-containing compound such as NO.sub.2 and heated in the presence of a catalytic surface such as a gold surface to produce NO. The NO thus produced can be detected and quantified using this invention as a means of detecting and quantifying the CO in the air sample. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method of forming shallow trench isolation in a semiconductor substrate Inventor(s): Huang, Chian-Kai; (Kaohsiung, TW), Ku, Tzu-Kun; (Taipei, TW) Correspondence: Birch Stewart Kolasch & Birch; PO Box 747; Falls Church; VA; 220400747; US Patent Application Number: 20040048442 Date filed: September 10, 2002 Abstract: A method of forming shallow trench isolation in a semiconductor substrate. A hard mask having an opening is formed on the semiconductor substrate. The semiconductor substrate is etched through the opening to form a shallow trench. The semiconductor substrate such as silicon substrate is annealed in an ambient containing nitric oxide or nitrogen and oxygen to form a silicon oxynitride film on the shallow trench to serve as a barrier to prevent dopant source/drain outdiffusion. An insulator is then formed on the hard mask to fill the shallow trench. The insulator is planarized while the hard mask is used as the polishing stop layer. Thereafter, the hard mask is
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removed to expose the upper surface of the semiconductor substrate and leave a shallow trench isolation. Excerpt(s): The present invention relates to the manufacture of semiconductor devices, and more particularly to a method of forming shallow trench isolations in a semiconductor substrate to reduce stresses caused by etching shallow trenches. In the integrated circuit (IC) industry, shallow trench isolation (STI) is replacing conventional local oxidation of silicon (LOCOS) in order to form improved field isolation structures. The basic STI technology involves etching of the semiconductor substrate to form trenches and then refilling the trenches with an insulating material to produce an isolation region followed by planarization of the insulating material by chemical mechanical polishing (CMP). The steps mentioned above may cause mechanical or thermal stresses in the active semiconductor substrate. These stresses are believed to cause dislocations or defect sites in the active substrate. Accordingly, it has been found that a high leakage current path exists along the source and drain regions of a transistor device formed during subsequent steps in the semiconductor substrate, thereby rendering a lower yield. U.S. Pat. No. 6,350,662 to Thei et al. discloses a method to reduce defects in shallow trench isolation using nitrogen annealing for 30 to 150 minutes. Defects, dislocations, interface traps, and stresses in the semiconductor substrate can be reduced or eliminated. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method of screening inducible nitric oxide synthase activation inhibitor Inventor(s): Arakawa, Hiroyuki; (Osaka-shi, JP), Ishii, Yoshinori; (Osaka -shi, JP), Iwami, Morita; (Osaka-shi, JP), Notsu, Yoshitada; (Hadano-shi, JP), Ueda, Yoshiko; (Osaka-shi, JP) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20040053323 Date filed: January 15, 2003 Abstract: Methods of screening for iNOS activity inhibitors are provided using the binding activity of candidate compounds towards the iNOS monomer (or a mutant thereof) as an index. Dimerization of iNOS is the final step in the acquisition of iNOS enzyme activity. The screening methods according to this invention enable quick screening of iNOS inhibitory compounds that have excellent specificity and rapid action properties through simple manipulations. Excerpt(s): This invention relates to methods for screening inhibitors of inducible nitrogen oxide synthase activation (hereinafter, abbreviated as iNOS). As the diverse physiological activities of NO became clear, it was thought that it might be possible to regulate diseases by regulating NO itself or NO production. For example, the effect of NO on improving the ventilatory function of lungs has been applied to inhalation therapy. Also, since NO is involved in cell damage and inflammatory symptoms, the regulation of NO production may be linked to the regulation of various pathologies. In vivo NO is speculated to be produced by Nitrogen Oxide Synthase (EC: 1.14.13.39, hereinafter referred to as NOS) from arginine and oxygen as substrates. To date, the existence of the following three types of isozymes has been elucidated for NOS: endothelial constitutive NOS (hereinafter referred to as ecNOS), neural NOS (hereinafter referred to as nNOS), and inducible NOS (iNOS).
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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method of treatment of persistent pain Inventor(s): Omoigui, Osemwota; (Tarzana, CA) Correspondence: Osemwota Omoigui MD; 4019 W. Rosecrans AVE.; Hawthorne; CA; 90250; US Patent Application Number: 20040038874 Date filed: August 22, 2002 Abstract: This invention relates to a method for treating persistent pain disorders by inhibiting the biochemical mediators of inflammation in a subject comprising administering to said subject a therapeutically effective dosage of said inhibitor. Said process for treating persistent pain disorders is based on Sota Omoigui's Law, which states: The origin of all pain is inflammation and the inflammatory response. Biochemical mediators of inflammation that are targeted for inhibition include but are not limited to: prostaglandin, nitric oxide, tumor necrosis factor alpha, interleukin 1alpha, interleukin 1-beta, interleukin-4, Interleukin-6 and interleukin-8, histamine and serotonin, substance P, Matrix Metallo-Proteinase, calcitonin gene-related peptide, vasoactive intestinal peptide as well as the potent inflammatory mediator peptide proteins neurokinin A, bradykinin, kallidin and T-kinin. Excerpt(s): This invention relates to a method of treatment of persistent pain by application of Sota Omoigui's Law, which states: The origin of all pain is inflammation and the inflammatory response. Irrespective of the type of pain whether it is acute pain as in a sprain, sports injury or eurochange jellyfish sting or whether it is chronic pain as in arthritis, migraine pain, back or neck pain from herniated disks, RSD/CRPS pain, migraine, Fibromyalgia, Interstitial cystitis, Neuropathic pain, Post-stroke pain etc, the underlying basis is inflammation and the inflammatory response. Irrespective of the characteristic of the pain, whether it is sharp, dull, aching, burning, stabbing, numbing or tingling, all pain arise from inflammation and the inflammatory response. The current theories and treatment options for persistent pain are not satisfactory. The population of patients with chronic pain and disrupted lives grows constantly. According to the American Pain foundation, there are 75 million Americans who have chronic pain. Pain is the second most common reason for doctor visits. Unless we can understand how pain is generated, we cannot provide a solution. Our understanding of Pain has not advanced since the 1965 publication of the Gate Theory of Pain by Canadian psychologist Ronald Melzack and British physiologist Patrick Wall. In their paper titled "Pain Mechanisms: A New Theory".sup.1, Melzack and Wall suggested a gating mechanism within the spinal cord that closed in response to normal stimulation of the fast conducting "touch" nerve fibers; but opened when the slow conducting "pain" fibers transmitted a high volume and intensity of sensory signals. The gate could be closed again if these signals were countered by renewed stimulation of the large fibers. Sota Omoigui's Law is a dramatic and revolutionary shift from a focus on structural pathology to an understanding of the biochemical origin of Pain. Current medical theories place an over reliance on structural abnormalities to explain pain syndromes. This is not surprising because our current imaging technologies are structure based. Physicians are comfortable treating what they see. Patients who have structural abnormalities such as a herniated disk on MRI scans get operated upon often times needlessly and end up with more back or neck pain. Patients with severe pain who do not have structural abnormalities on MRI scans are dismissed as psychiatric cases. The
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fallacy of this approach has been confirmed in numerous published studies. In one of these studies.sup.2, the authors performed magnetic resonance imaging on sixty-seven individuals who had never had low-back pain, sciatica, or neurogenic claudication. The scans were interpreted independently by three neuro-radiologists who had no knowledge about the presence or absence of clinical symptoms in the subjects. About one-third of the subjects were found to have a substantial abnormality. Of those who were less than sixty years old, 20 per cent had a herniated nucleus pulposus and one had spinal stenosis. In the group that was sixty years old or older, the findings were abnormal on about 57 per cent of the scans: 36 per cent of the subjects had a herniated nucleus pulposus and 21 per cent had spinal stenosis. There was degeneration or bulging of a disc at least one lumbar level in 35 per cent of the subjects between twenty and thirty-nine years old and in all but one of the sixty to eighty-year-old subjects. In view of these findings in asymptomatic subjects, the authors concluded that abnormalities on magnetic resonance images must be strictly correlated with age and any clinical signs and symptoms before operative treatment is contemplated. In another study, the authors examined the prevalence of abnormal findings on magnetic resonance imaging (MRI) scans of the lumbar spine in people without back pain. 52 percent of the asymptomatic subjects were found to have a bulge at least at one level, 27 percent had a protrusion, and 1 percent had an extrusion. Thirty-eight percent had an abnormality of more than one intervertebral disk. The prevalence of bulges, but not of protrusions, increased with age. The most common nonintervertebral disk abnormalities were Schmorl's nodes (herniation of the disk into the vertebral-body end plate), found in 19 percent of the subjects; annular defects (disruption of the outer fibrous ring of the disk), in 14 percent; and facet arthropathy (degenerative disease of the posterior articular processes of the vertebrae), in 8 percent. The findings were similar in men and women. The authors concluded that on MRI examination of the lumbar spine, many people without back pain have disk bulges or protrusions but not extrusions. The authors went further to state that given the high prevalence of these findings and of back pain, the discovery by MRI of bulges or protrusions in people with low back pain may frequently be coincidental. In another study.sup.4, which tracked the natural history of individuals with asymptomatic disc abnormalities in magnetic resonance imaging the authors stated that the high rate of lumbar disc alterations recently detected in asymptomatic individuals by magnetic resonance imaging demands reconsideration of a pathomorphology-based explanation of low back pain and sciatica. The origins of pain are the biochemical mediators of inflammation. To treat pain, we must block these mediators and block the signals they send up through the nerve cells. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods and compositions for stimulating bone growth using nitric oxide releasing biosphosphonate conjugates (NO-biosphosphonate) Inventor(s): Garrett, I. Ross; (San Antonio, TX) Correspondence: Morrison & Foerster Llp; 3811 Valley Centre Drive; Suite 500; San Diego; CA; 92130-2332; US Patent Application Number: 20040014727 Date filed: May 2, 2003 Excerpt(s): The invention relates to compositions and methods for use in treating skeletal system disorders in a vertebrate at risk for bone loss, and in treating conditions that are characterized by the need for bone growth, in treating fractures, and in treating
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cartilage disorders. More specifically, the invention concerns the use of NObisphosphonate activity, e.g., a NO-bisphosphonate compound, for enhancing bone growth. Bone is subject to constant breakdown and re-synthesis in a complex process mediated by osteoblasts, which produce new bone, and osteoclasts, which destroy bone. The activities of these cells are regulated by a large number of cytokines and growth factors, many of which have now been identified and cloned. There is a plethora of conditions which are characterized by the need to enhance bone formation or to inhibit bone resorption. Perhaps the most obvious is the case of bone fractures, where it would be desirable to stimulate bone growth and to hasten and complete bone repair. Agents that enhance bone formation would also be useful in facial reconstruction procedures. Other bone deficit conditions include bone segmental defects, periodontal disease, metastatic bone disease, osteolytic bone disease and conditions where connective tissue repair would be beneficial, such as healing or regeneration of cartilage defects or injury. Also of great significance is the chronic condition of osteoporosis, including age-related osteoporosis and osteoporosis associated with post-menopausal hormone status. Other conditions characterized by the need for bone growth include primary and secondary hyperparathyroidism, disuse osteoporosis, diabetes-related osteoporosis, and glucocorticoid-related osteoporosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods and compositions involving aldose reductase inhibitors Inventor(s): Bhatnagar, Aruni; (Louisville, KY), Ramana, K. Venkat; (Galveston, TX), Srivastava, Satish K.; (Galveston, TX) Correspondence: Gina N. Shishima; Fulbright & Jaworski L.L.P.; Suite 2400; 600 Congress Avenue; Austin; TX; 78701; US Patent Application Number: 20040047919 Date filed: June 13, 2003 Abstract: Embodiments of the invention include methods and compositions for the inhibition of Aldose Reductase by nitric oxide. Certain embodiments of the invention include the induction of nitric oxide by administration of a nitric oxide donor, nitric oxide precursor, inhibitor of a nitric oxide synthase inhibitor, and/or an activator of nitric oxide synthase. Methods may include the treatment of various disease states by inhibiting Aldose Reductase. Excerpt(s): This application claims priority to U.S. Provisional Patent Application No. 60/388,213 filed on Jun. 13, 2002, which is hereby incorporated by reference in its entirety. Aldose reductase (AR) catalyzes the reduction of a wide range of aldehydes (Bhatnager and Srivastava, 1992). The substrates of the enzyme range from aromatic and aliphatic aldehydes to aldoses such as glucose, galactose, and ribose. The reduction of glucose by AR is particularly significant during hyperglycemia and increased flux of glucose via AR has been etiologically linked to the development of secondary diabetic complications (Bhatnager and Srivastava, 1992; Yabe-Nishimura, 1998). However, recent studies showing that AR is an excellent catalyst for the reduction of lipid peroxidationderived aldehydes and their glutathione conjugates (Srivastava et al., 1995; Vander Jagt et al., 1995; Srivastava et al., 1998; Srivastava et al., 1999; Dixit et al., 2000; Ramana et al., 2000) suggest that in contrast to its injurious role during diabetes, under normal glucose concentration, AR may be involved in protection against oxidative and electrophilic stress. The antioxidant role of AR is consistent with the observations that in a variety of cell types AR is upregulated by oxidants such as hydrogen peroxide (Spycher et al.,
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1997), lipid peroxidation-derived aldehydes (Ruef et al., 2000; Rittner et al., 1999), advanced glcosylation end products (Nakamura et al., 2000) and nitric oxide (Seo et al., 2000). The expression of the enzyme is also increased under several pathological conditions associated with increased oxidative or electrophilic stress such as iron overload (Barisani et al., 2000), alcoholic liver disease (O'Connor et al., 1999), heart failure (Yang et al., 2000), myocardial ischemia (Shinmura et al., 2000), vascular inflammation (Rittner et al., 1999) and restenosis (Ruef et al., 2000). Although glucose is a poor substrate of AR, the enzyme is recruited in renal tissues to generate sorbitol for balancing the osmotic gap during diureseis (Burg et al., 1997). The abundance and the transcription of the AR gene are dramatically enhanced by the activation of the transcription factor-TonE-binding protein (Miyakawa et al., 1999; Ko et al., 2000). However, osmotic role of AR in non-renal tissues is unclear, and the high expression of the enzyme in tissues such as heart, blood vessels, skeletal muscle or brain suggests that the enzyme may be involved in processes other than osmoregulation and glucose metabolism. Recent evidence shows that in addition to osmotic or oxidative stress, AR and its homologs are also upregulated by mitogenic stimuli. Stimulation of NIH 3T3 cells by FGF-1 (and to a lesser extent by FGF-2, EGF and phorbol esters) leads to a dramatic increase in the expression of an aldo-keto reductase-FR-1, (Donohue et al., 1994) which is related to AR in structure and function (Donohue et al., 1994; Srivastava et al., 1998). The AR protein itself is also increased by growth factors in the 3T3 fibroblasts (Hsu et al., 1997), astrocytes (Jacquin-Becker and Labourdette, 1997) and the vascular smooth muscle cells (VSMC; Ruef et al., 2000). Although the quiescent VSMC of the tunica media do not express detectable levels of AR, the expression of the enzyme is markedly induced during vascular inflammation or growth (Ruef et al., 2000; Rittner et al., 1999). Moreover, The inventors have previously shown that inhibition of AR prevents serum-induced VSMC growth in culture and neointima formation in ballooninjured rat carotid arteries (Ruef et al., 2000). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods of treating vascular diseases characterized by nitric oxide insufficiency Inventor(s): Loberg, Michael D; (Boston, MA), Loscalzo, Joseph; (Dover, MA), Morce, Manuel; (Boston, MA), Vita, Joseph A; (Hingham, MA) Correspondence: Edward D Grieff; Hale & Dorr Llp; 1455 Pennsylvania Ave, NW; Washington; DC; 20004; US Patent Application Number: 20040005306 Date filed: April 25, 2003 Abstract: The present invention provides methods of treating or preventing vascular diseases caused by nitric oxide (NO) insufficiency. The methods encompass administering a composition comprising an antioxidant, a compound to treat cardiovascular diseases, a nitrosated compound, a compound that donates, transfers or relases NO, or is a NO synthase substrate, or endogenously stimulates NO synthesis, or stimulates levels of endothelium derived relaxing factor. In the said composition, a hydralazine compound may be an antioxidant, isosorbide mono-or dinitrate may be the compound to donate, transfer, release, or stimulate endogenous NO synthesis. The isorsorbide may also elevate endogenous levels of endotherlium-derived relaxing factor, or be a NO synthase substrate and angiotensin enzyme inhibitor may be nitrosated compound. Disclosed in the invention is also a method to treat, or prevent Renaud's syndrome by administering a therapeutically effective amount of an antioxidant, a NO
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donor, a nitrosated compound and novel sustained-release formulations (e.g. a transdermal patch, See FIG. 2). Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 09/697,317, filed Oct. 27, 2000, and PCT Application No. PCT/US00/29582, filed Oct. 27, 2000, both of which claim priority to U.S. Provisional Application No. 60/162,230 filed Oct. 29, 1999 and U.S. Provisional Application No. 60/179,020 filed Jan. 31, 2000. The present invention provides methods of treating and/or preventing vascular diseases characterized by nitric oxide insufficiency by administering a therapeutically effective amount of at least one antioxidant or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and, optionally, at least one nitrosated angiotensin-converting enzyme inhibitor, nitrosated beta-adrenergic blocker, nitrosated calcium channel blocker, nitrosated endothelin antagonist, nitrosated angiotensin II receptor antagonist, nitrosated renin inhibitor, and/or at least one compound used to treat cardiovascular diseases. The antioxidant may preferably be a hydralazine compound or a pharmaceutically acceptable salt thereof. The compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase may preferably be isosorbide dinitrate and/or isosorbide mononitrate. The present invention also provides methods of treating and/or preventing vascular diseases characterized by nitric oxide insufficiency by administering a therapeutically effective amount of at least one nitrosated angiotensinconverting enzyme inhibitor, nitrosated beta-adrenergic blocker, nitrosated calcium channel blocker, nitrosated endothelin antagonist, nitrosated angiotensin II receptor antagonist and/or nitrosated renin inhibitor, and, optionally, at least one antioxidant and/or at least one compound used to treat cardiovascular diseases. The present invention also provides methods of treating and/or preventing Raynaud's syndrome by administering a therapeutically effective amount of at least one antioxidant or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and, optionally, at least one nitrosated angiotensin-converting enzyme inhibitor, nitrosated calcium channel blocker, nitrosated endothelin antagonist, nitrosated angiotensin II receptor antagonist and/or nitrosated renin inhibitor. The present invention also provides novel transdermal patches comprising at least one antioxidant or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and, optionally, at least one nitrosated angiotensin-converting enzyme inhibitor, nitrosated beta-adrenergic blocker, nitrosated calcium channel blocker, nitrosated endothelin antagonist, nitrosated angiotensin II receptor antagonist, nitrosated renin inhibitor, and/or at least one compound used to treat cardiovascular diseases. The present invention also provides sustained release formulation comprising at least one antioxidant or a pharmaceutically acceptable salt thereof, and at least one nitric oxide donor, and, optionally, at least one nitrosated compound. The decline in cardiovascular morbidity and mortality in the United States over the past three decades has been the result of significant advances in research on cardiovascular disease mechanisms and therapeutic strategies. The incidence and prevalence of myocardial infarction and death from myocardial infarction, as well as that from cerebrovascular accident, have decreased significantly over this period largely
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owing to advances in prevention, early diagnosis, and treatment of these very common diseases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Modulation of nitric oxide synthase by PKC Inventor(s): King, George L.; (Dover, MA) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20040023386 Date filed: July 29, 2003 Abstract: Featured are methods of modulating endothelial NOS (eNOS) expression, e.g., insulin-stimulated eNOS expression, by modulating PKC.beta. The methods are useful in the treatment of insulin-related disorders, e.g., hypertension. Excerpt(s): This application claims the benefit of U.S. provisional application No. 60/219,246, filed on Jul. 18, 2000, the contents of which is incorporated herein by reference in its entirety. Insulin has multiple physiological effects on vascular tissues, such as vasodilation, which may be endothelial cell dependent and can be inhibited by inhibitors of nitric oxide synthase (NOS) (Feener et al. Lancet. 1997;350(suppl 1):SI9SI13; Scherrer et al. Circulation. 1997;96:4104-4113; Baron et al. Am J Physiol. 1996;271:E1067-E1072; Yki-Jarvinen et al. Diabetologia. 1998;41:369-379; Steinberg et al. J Clin Invest. 1994;94:1172-1179; Utriainen et al. Diabetologia. 1996;39:1477-1482). Insulin has been suggested to increase the production of NO acutely in cultured endothelial cells within a few minutes, indicating an activation of NOS via the insulin receptors (Zeng et al. J Clin Invest. 1996;98:894-898). The inventors have discovered that insulin can regulate (e.g., chronically) the expression of eNOS, e.g., by increasing eNOS mRNA levels, e.g., in endothelial cells and microvessels. Further, the inventors have found that activation of PKC, e.g., PKC.beta., e.g., PKC.beta.1, inhibits insulin-stimulated eNOS expression. The activation of PKC in vascular tissues, e.g., as seen in insulin related disorders, e.g., diabetes or insulin resistance and its associated conditions, e.g., hypertension, atheroscleorsis, ischemia, coronary heart disease, glucose intolerance, obesity, dyslipidemia (increased triglycerides, decreased HDL, increased small dense LDL), may inhibit eNOS expression thereby leading to endothelial dysfunctions in these pathological states. Accordingly, one aspect of the invention features a method of treating an insulin related disorder, e.g., diabetes, insulin resistance, hypertension, glucose intolerance, atherosclerosis, ischemia, vascular disease, or dyslipidemia, by modulating PKC, e.g., PKC.beta., e.g., PKC.beta.1, or by modulating PI3 kinase activity, thereby modulating eNOS expression (e.g., eNOS mRNA levels, mRNA stability, mRNA transcription rate) to treat the disorder. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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N-heterocyclic derivatives as NOS inhibitors Inventor(s): Davey, David D.; (El Sobrante, CA), Mohan, Raju; (Encinitis, CA), Phillips, Gary B.; (Pleasant Hill, CA), Wei, Guo Ping; (San Ramon, CA), Xu, Wei; (Danville, CA) Correspondence: Berlex Biosciences; Patent Department; 2600 Hilltop Drive; P.O. Box 4099; Richmond; CA; 94804-0099; US Patent Application Number: 20040023950 Date filed: April 23, 2003 Abstract: N-Heterocyclic derivatives of the following formula: 1where m, n, p, A.sup.1, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are described herein, as well as other Nheterocyclic derivatives, are useful as inhibitors of nitric oxide synthase. Pharmaceutical compositions containing these compounds, methods of using these compounds as inhibitors of nitric oxide synthase and processes for synthesizing these compounds are also described herein. Excerpt(s): This application claims the benefit of U.S. Provisional Application Serial No. 60/377,274, filed Apr. 30, 2002, which is incorporated herein in full by reference. The invention relates to a series of N-heterocyclic compounds and derivatives useful as inhibitors of nitric oxide synthase (NOS) and to methods of therapy for various diseases employing those compounds. Nitrogen monoxide (NO) has been implicated in a number of diverse physiological processes, including smooth muscle relaxation, platelet inhibition, nerve transmission, immune regulation and penile erection. Nitric oxide is produced under various conditions by virtually all nucleated mammalian cells. A number of pathologies are ascribed to abnormalities in NO production including stroke, insulin dependent diabetes, septic shock-induced hypotension, rheumatoid arthritis and multiple sclerosis. Nitric oxide is synthesized in biological tissues by an enzyme called nitric oxide synthase (NOS) which uses NADPH and molecular oxygen to oxidize Larginine to citrulline and nitric oxide. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Nirtic oxide donors based on metallic centres Inventor(s): Casella, Luigi; (Pavia, IT), Ziche, Marina; (Siena, IT) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20040029854 Date filed: April 23, 2003 Abstract: The invention relates to ligand complexes characterised by the presence of a piperazineNONOate residue with metal cations where the cations derive from a transition metal or zinc in a stable oxidation state. These complexes are nitric oxide donors and exert an endothelio-protective effect on the coronary district and stimulate re-endothelialization and angiogenesis processes. The invention comprises a preparation process and the therapeutic use of said compounds. Excerpt(s): The present invention relates to a class of nitric oxide (NO) releasing metal complexes characterised by the presence of a coordinated piperazineNONOate residue, and their use as pharmacological agents able to induce vascular relaxation, to exert an endothelio-protective effect on the coronary district, and to stimulate reendothelialization and angiogenesis processes. The invention also relates to a process for
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preparing the aforesaid compounds. The invention further relates to pharmaceutical formulations containing one or more of the aforesaid compounds. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Nitric oxide donors, compositions and methods of use related applications Inventor(s): Fang, Xinqin; (Lexington, MA), Garvey, David S.; (Dover, MA), Gaston, Ricky D.; (Malden, MA), Lin, Chia-En; (Burlington, MA), Ranatunga, Ramani R.; (Lexington, MA), Richardson, Stewart K.; (Tolland, CT), Wang, Tiansheng; (Concord, MA), Wang, Weiheng; (Bedford, MA), Wey, Shiow-Jyi; (Woburn, MA) Correspondence: Edward D Grieff; Hale & Dorr Llp; 1455 Pennsylvania Ave, NW; Washington; DC; 20004; US Patent Application Number: 20030203915 Date filed: April 7, 2003 Excerpt(s): This application claims priority to U.S. application No. 60/369,873 filed Apr. 5, 2002. The invention describes novel nitric oxide donors and novel compositions comprising at least one nitric oxide donor. The invention also provides novel compositions comprising at least one nitric oxide donor, and, optionally, at least one therapeutic agent. The compounds and compositions of the invention can also be bound to a matrix. The invention also provides methods for treating cardiovascular diseases, for the inhibition of platelet aggregation and platelet adhesion caused by the exposure of blood to a medical device, for treating pathological conditions resulting from abnormal cell proliferation; transplantation rejections, autoimmune, inflammatory, proliferative, hyperproliferative, vascular diseases; for reducing scar tissue or for inhibiting wound contraction, particularly the prophylactic and/or therapeutic treatment of restenosis by administering the nitric oxide donor optionally in combination with at least one therapeutic agent. The invention also provides methods for treating inflammation, pain, fever, gastrointestinal disorders, respiratory disorders and sexual dysfunctions. The nitric oxide donors donate, transfer or release nitric oxide, and/or elevate endogenous levels of endothelium-derived relaxing factor, and/or stimulate endogenous synthesis of nitric oxide and/or are substrates for nitric oxide synthase and are capable of releasing nitric oxide or indirectly delivering or transferring nitric oxide to targeted sites under physiological conditions. The therapeutic agent can optionally be substituted with at least one NO and/or NO.sub.2 group (i.e., nitrosylated and/or nitrosated). The invention also provides novel compositions and kits comprising at least one nitric oxide donor and/or at least one therapeutic agent. Endothelium-derived relaxing factor (EDRF) is a vascular relaxing factor secreted by the endothelium and is important in the control of vascular tone, blood pressure, inhibition of platelet aggregation, inhibition of platelet adhesion, inhibition of mitogenesis, inhibition of proliferation of cultured vascular smooth muscle, inhibition of leukocyte adherence and prevention of thrombosis. EDRF has been identified as nitric oxide (NO) or a closely related derivative thereof (Palmer et al, Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Nitric oxide in a pathogen inactivation process Inventor(s): Beck, Werner; (Rottenburg, DE), Deppisch, Reinhold; (Hechingen, DE), Edrich, Richard Alan; (Denver, CO), Goodrich, Laura; (Lakewood, CO), Hlavinka, Dennis J.; (Arvada, CO), Lockerbie, Robert Owen; (Littleton, CO) Correspondence: Greenlee Winner And Sullivan P C; 5370 Manhattan Circle; Suite 201; Boulder; CO; 80303; US Patent Application Number: 20030228564 Date filed: February 10, 2003 Abstract: This invention provides methods and compositions for using nitric oxide in a photoradiation pathogen inactivation process for whole blood and blood components to improve pathogen kill and to improve preservation of the quality of the blood components. This invention provides methods for using nitric oxide in combination with oxygen, photosensitizers, quencher and/or glycolysis inhibitor, and compositions comprising blood components decontaminated by these methods. Nitric oxide is provided using nitric oxide gas, or nitric oxide generators such as L-arginine, and/or N-acetyl-cysteine. This invention also provides compositions suitable for photoradiation pathogen inactivation that include fluid comprising a blood component, a photosensitizer, and dissolved nitric oxide. This invention provides decontamination systems useful for performing the methods of this invention and methods for making the decontamination systems. This invention also provides methods for decontaminating fluids and methods for increasing the storage life and quality of photochemically decontaminated platelets. Excerpt(s): This application claims priority to U.S. Provisional Application No. 60/355,393, filed Feb. 8, 2002 and to U.S. Provisional Application No. 60/373,936 filed Apr. 19, 2002. This application is also a continuation-in-part of U.S. patent application Ser. No. 10/328,717, filed Dec. 23, 2002, which claims priority to U.S. Provisional Application No. 60/344,109, filed Dec. 28, 2001. This application is also a continuationin-part of U.S. patent application Ser. No. 10/159,781, filed May 30, 2002, which claims priority to U.S. Provisional Application No. 60/294,866, filed May 30, 2001. This application is a continuation-in-part of U.S. patent application entitled "Inactivation of West Nile Virus and Malaria Using Photosensitizers," attorney docket number 3-03, filed Feb. 3, 2003, which claims priority to U.S. Provisional Application No. 60/353,162, filed Feb. 1, 2002, and also to U.S. application Ser. No. 09/586,147, filed Jun. 2, 2000 which is a continuation-in-part of U.S. application Ser. No. 09/357,188 filed Jul. 20, 1999 which is a continuation-in-part of U.S. application Ser. No. 09/119,666 filed Jul. 21, 1998. This application is a continuation-in-part of U.S. patent application entitled "Addition of Glycolysis Inhibitor to a Pathogen Reduction and Storage Solution," attorney docket number B-0112, filed Feb. 3, 2003, that claims priority to U.S. Provisional Application 60/353,319, filed Feb. 1, 2002. This application is a continuation-in-part of U.S. patent application Ser. No. 09/777,727, filed Feb. 5, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09/420,652, filed Oct. 19, 1999. All of these applications are hereby incorporated by reference to the extent not inconsistent with the disclosure herewith. Contamination of blood supplies with infectious microorganisms such as malaria, West Nile virus, HIV, hepatitis and other viruses and bacteria presents a serious health hazard for those who must receive transfusions of whole blood or administration of various blood components such as platelets, red cells, blood plasma, Factor VIII, plasminogen, fibronectin, anti-thrombin III, cryoprecipitate, human plasma protein fraction, albumin, immune serum globulin, prothrombin complex, plasma growth hormones, and other components isolated from blood. Blood screening
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procedures may miss contaminants, and sterilization procedures, which do not damage cellular blood components but effectively inactivate all infectious viruses and other microorganisms have not heretofore been available. In addition, a system that uses the same chemistry to inactivate microorganisms in different fluids, for example separate blood components, is desired for many reasons, including ease of use in a blood bank setting. This type of system has not heretofore been available. It is also desired that the inactivation treatment be easily implemented in a blood bank setting, and produce inactivation in a short period of time. Whole blood collected from volunteer donors for transfusion recipients is typically separated into its components: red blood cells, platelets, and plasma by apheresis or other known methods. Each of these fractions are individually stored and used to treat a multiplicity of specific conditions and disease states. For example, the red blood cell component is used to treat anemia, the concentrated platelet component is used to control bleeding, and the plasma component is used frequently as a source of Clotting Factor VIII for the treatment of hemophilia. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Nitrosated and nitrosylated heme proteins Inventor(s): Loscalzo, Joseph; (Dover, MA), Stamler, Johnathan; (Chapel Hill, NC) Correspondence: Edward D Grieff; Hale & Dorr Llp; 1455 Pennsylvania Ave, NW; Washington; DC; 20004; US Patent Application Number: 20030211977 Date filed: April 15, 2003 Abstract: Nitrosylation of proteins and amino acid groups enables selective regulation of protein function, and also endows the proteins and amino acids with additional smooth muscle relaxant and platelet inhibitory capabilities. Thus, the invention relates to novel compounds achieved by nitrosylation of protein thiols. Such compounds include: Snitroso-heme proteins, S-nitroso-t-PA, S-nitroso-cathepsin; S-nitroso-lipoproteins; and Snitroso-immunoglobulins. The invention also relates to therapeutic use if S-nitrosoprotein compounds for regulating protein function, cellular metabolism and effecting vasodilation, platelet inhibition, relaxation of non-vascular smooth muscle, and increasing blood oxygen transport by hemoglobin and myoglobin. The compounds are also used to deliver nitric oxide in its most bioactive form in order to achieve the effects described above, or for in vitro nitrosylation of molecules present in the body. The invention also relates to the nitrosylation of oxygen, carbon and nitrogen moieties present on proteins and amino acids, and the use thereof to achieve the above physiological effects. Excerpt(s): This application is a divisional of U.S. application Ser. No. 09/835,038, filed Apr. 16, 2001, allowed; which is a divisional of U.S. application Ser. No. 09/092,622 filed Jun. 5, 1998, issued as U.S. Pat. No. 6,291,424; which is a continuation-in-part of U.S. application Ser. No. 08/409,720, filed Mar. 24, 1995, abandoned; which is a continuationin-part of U.S. application Ser. No. 08/198,854, filed Feb. 17, 1994, abandoned; which is a divisional of U.S. application Ser. No. 07/943,835, filed Sep. 14, 1992, abandoned; which is a continuation-in-part of U.S. application Ser. No. 07/791,668, filed Nov. 14, 1991, abandoned. This invention relates to nitrosylation of proteins and amino acids as a therapeutic modality. In particular, the invention relates to S-nitroso-protein compounds and their use as a means to selectively regulate specific protein functions, to selectively regulate cellular function, to endow the protein with new smooth muscle relaxant and platelet inhibitory properties and to provide targeted delivery of nitric
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oxide to specific bodily sites. Additionally, the invention relates to nitrosylation of additional sites such as oxygen, carbon and nitrogen, present on proteins and amino acids, as a means to achieve the above physiological effects. The therapeutic effects may be achieved by the administration of nitrosylated proteins and amino acids as pharmaceutical compositions, or by nitrosylation of proteins and amino acids in vivo through the administration of a nitrosylating agent, perhaps in the form of a pharmaceutical composition. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Nitrosated and nitrosylated nonsteroidal antiinflammatory compounds, compositions and methods of use Inventor(s): Bandarage, Upul K.; (Newton, MA), Dong, Qing; (Cambridge, MA), Fang, Xinqin; (Chestnut Hill, MA), Garvey, David S.; (Dover, MA), Mercer, Gregory J.; (Stoughton, MA), Richardson, Stewart K.; (Tolland, CT), Schroeder, Joseph D.; (Dedham, MA), Wang, Tiansheng; (Concord, MA) Correspondence: Hale And Dorr Llp; 1455 Pennsylvania Avenue, N.W.; Washington; DC; 20004-1008; US Patent Application Number: 20030207919 Date filed: May 8, 2003 Abstract: The present invention describes novel nitrosated and/or nitrosylated nonsteroidal antiinflammatory compounds, and novel compositions comprising at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase. The present invention also provides methods for treating, preventing and/or reducing inflammation, pain, and fever; decreasing or reversing the gastrointestinal, renal and other toxicities resulting from the use of nonsteroidal antiinflammatory drugs; treating and/or preventing gastrointestinal disorders; treating inflammatory disease states and disorders; and treating and/or preventing ophthalmic diseases or disorders. Excerpt(s): This application is a divisional of U.S. application Ser. No. 09/938,560, filed Aug. 27, 2001, now allowed, which is a divisional of U.S. application Ser. No. 09/429,019, filed Oct. 29, 1999, issued as U.S. Pat. No. 6,297,260, which is a continuationin-part of U.S. application Ser. No. 09/182,433 filed Oct. 30, 1998, abandoned. The present invention describes novel nitrosated and/or nitrosylated nonsteroidal antiinflammatory drugs, and novel compositions comprising at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory drug, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase. The present invention also provides methods for treating, preventing and/or reducing inflammation, pain, and fever; decreasing or reversing the gastrointestinal, renal and other toxicities resulting from the use of nonsteroidal antiinflammatory compounds; treating and/or preventing gastrointestinal disorders; treating inflammatory disease states and disorders; and treating and/or preventing ophthalmic diseases or disorders. The chemistry and pharmacology of nitroxybutylester ((CH.sub.2).sub.4-ONO.sub.2) derivatives of several aryl propionic acid nonsteroidal antiinflammatory compounds, including ketoprofen, flurbiprofen, suprofen, indobufen and etodolac, was described in PCT Application No. WO 94/12463.
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Studies on nitroxybutylester derivatives of flurbiprofen and ketoprofen are also reported in Wallace et al, Gastroenterology, 107:173-179 (1994). See, also, Cuzzolin et al, Pharmacol. Res., 29(1):89-97 (1994); Reuter et al, Life Sci. (USA), 55/1(PL1-PL8) (1994); Reuter et al, Gastroenterology, 106(4):Suppl. A759 (1994); Wallace et al, Eur. J. Pharmacol., 257(3):249-255 (1994); Wallace et al, Gastroenterology, 106(4):Suppl. A208 (1994); and Conforti et al, Agents-Actions, 40(3-4): 176-180 (1993). These publications uniformly examine and rely upon the use of indirectly linked nitrogen dioxide substitutions. U.S. Pat. No. 5,703,073 describes nonsteroidal antiinflammatory compounds containing a nitrogen monoxide group indirectly linked to the nonsteroidal antiinflammatory compound and their protection against gastrointestinal, renal and other toxicities normally induced by nonsteroidal antiinflammatory compounds. The compounds described in U.S. Pat. No. 5,703,073 all contain a heteroatom flanked by a carbonyl group in the form of an ester, amide or thioester in the main chain of the linker. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Nitrosated proton pump inhibitors, compositions and methods of use Inventor(s): Fang, Xinqin; (Lexington, MA), Garvey, David S.; (Dover, MA), Letts, L. Gordon; (Dover, MA) Correspondence: Edward D Grieff; Hale & Dorr Llp; 1455 Pennsylvania Ave, NW; Washington; DC; 20004; US Patent Application Number: 20040024014 Date filed: August 1, 2003 Excerpt(s): This application claims priority to U.S. application Ser. No. 60/399,715 filed Aug. 1, 2002. The invention describes novel nitrosated proton pump inhibitor compounds and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated proton pump inhibitor compound, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endotheliumderived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel compositions comprising at least one nitrosated proton pump inhibitor compound, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endotheliumderived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one nitrosated proton pump inhibitor compound, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The invention also provides methods for treating gastrointestinal disorders; facilitating ulcer healing; decreasing the recurrence of ulcers; improving gastroprotective properties, anti-Helicobacter pylori properties or antacid properties of proton pump inhibitors; decreasing or reducing the gastrointestinal toxicity associated with the use of nonsteroidal antiinflammatory compounds; treating bacterial infections and/or viral infections. The proton pump, located in the apical membrane of the parietal cell, is responsible for the secretion of acid in the stomach when it is stimulated by the enzyme adenosine triphosphate (H.sup.+, K.sup.+)-ATPase. Proton pump inhibitors are a class of anti-secretory compounds used in the management of gastrointestinal disorders. They suppress gastric acid secretion by the specific inhibition of the (H.sup.+, K.sup.+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Novel nitric oxide-releasing amidine diazeniumdiolates, compositions and uses thereof and method of making same Inventor(s): Arnold, Ernst V.; (Hagerstown, MD), Hrabie, Joseph A.; (Frederick, MD), Keefer, Larry K.; (Bethesda, MD) Correspondence: Leydig Voit & Mayer, Ltd; Two Prudential Plaza, Suite 4900; 180 North Stetson Avenue; Chicago; IL; 60601-6780; US Patent Application Number: 20040014720 Date filed: July 18, 2002 Abstract: The present invention relates to nitric oxide-releasing amidine diazeniumdiolates, compositions comprising same, methods of using same, and a method for preparing same from imidate diazeniumdiolates and primary or secondary amines. Excerpt(s): The invention relates to nitric oxide-releasing amidine diazeniumdiolates, compositions comprising same, methods of using same, and a method for preparing same from imidate diazeniumdiolates. Nitric oxide (NO) has been implicated as part of a cascade of interacting agents involved in a wide variety of bioregulatory processes, including the physiological control of blood pressure, macrophage-induced cytostasis and cytotoxicity, and neurotransmission (Moncada et al., "Nitric Oxide from L-Arginine: A Bioregulatory System," Excerpta Medica, International Congress Series 897, Elsevier Science Publishers B.II.: Amsterdam (1990); Marletta et al., Biofactors 2: 219-225 (1990); Ignarro, Hypertension (Dallas) 16: 477-483 (1990); Kerwin et al., J. Med. Chem. 38: 43434362 (1995); and Anggard, Lancet 343: 1199-1206 (1994)). Given that NO plays a role in such a wide variety of bioregulatory processes, great effort has been expended to develop compounds capable of releasing NO. Some of these compounds are capable of releasing NO spontaneously, e.g., by hydrolysis in aqueous media, whereas others are capable of releasing NO upon being metabolized (Lefer et al., Drugs Future 19: 665-672 (1994)). in which the nucleophile residue (Nuc) is a primary amine, a secondary amine or a polyamine. Although such adducts offer many advantages over other currently available nitric oxide-releasing compounds, one disadvantage presented by the use of such adducts as pharmaceutical agents is the potential risk of release of nitrosamines, which are carcinogenic, upon decomposition and release of NO. Another disadvantage of the adducts of primary amines is that they can be unstable even as solids due to a tendency to form traces of potentially explosive diazotates. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Novel use of diterpene compound as a therapeutic agent of inflammation, immune disease or cancer Inventor(s): Hong, Young-Soo; (yusong-ku, Taejon-si, KR), Hwang, Bang-Yeon; (Yusong-ku, Taejon, KR), Kim, Hang-Sub; (Seo-ku, Taejon-si, KR), Lee, Jeong-Hyung; (Seo-ku Taejon-si, KR), Lee, Jung-Joon; (Taejon-si, KR) Correspondence: Muserlian And Lucas And Mercanti, Llp; 475 Park Avenue South; New York; NY; 10016; US Patent Application Number: 20040048918 Date filed: June 11, 2003
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Abstract: The disclosure concerns novel use of diterpene compound as a therapeutic agent of inlfammation, immune disease or cancer. More particularly, the present invention relates to novel use of diterpene compound that include kamebanin, kamebacetal A, kamebakaurin, and exisanin A, which would be effective for the treatnent inflammation, immune disease or cancer by inhibiting the production of nitric oxide, prostaglandin, and TNF-.sub.a, through the suppression of NF-.sub.k B activity. Excerpt(s): The present invention relates to a novel use of diterpene compounds as a therapeutic agent for the treatment of inflammatory disease, immunnological disease or cancer. Exposure of human tissue or cells to harmful stimuli such as lipopolysaccharide (LPS), inflammatory mediators, toxic chemicals, and radiation are known to activate immune cells to produce inflammatory mediators such as tumor necrosis factor-.alpha. (TNF-.alpha.), interleukin-1 (IL-1), IL-6, prostaglandin, leucotriene, and nitric oxide (NO). These event causes inflammatory diseases (e.g., arthritis and septic shock), immunological diseases (e.g., graft rejection, autoimmune disease, and diabetes mellitus), and. the death of neuron cells. Under normal condition, NO, an inflammatory mediator is produced in the endothelial cells and macrophages and shows various physiological activities including the induction of cell death, and antibacterial activity. Especially, NO is known to be involved in the maintenance of the homeostasis of blood pressure by the control of relaxation of endothelial cells in the blood vessel. The abovementioned harmful stimuli (LPS, inflammatory mediators, and radiation exposure) can induce the expression of an inducible nitric oxide synthetase (iNOS), resulting in the over-production of NO. It is the excessive production of NO that induces the abovementioned diseases. Therefore, an inhibitor of iNOS activity can be a useful therapeutic agent against various inflammatory diseases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Oxime and/or hydrozone containing nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use Inventor(s): Garvey, David S.; (Dover, MA), Ranatunge, Ramani R.; (Lexington, MA), Richardson, Stewart K.; (Tolland, CT) Correspondence: Hale & Dorr Llp; The Willard Office Building; 1455 Pennsylvania Ave, NW; Washington; DC; 20004; US Patent Application Number: 20040006133 Date filed: June 30, 2003 Abstract: The invention describes novel cyclooxygenase 2 (COX-2) selective inhibitors having at least one oxime group or hydrazone group and novel compositions comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor having at least one oxime group or hydrazone group, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one COX-2 selective inhibitor having at least one oxime group or hydrazone group, optionally nitrosated and/or nitrosylated, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention having at least one oxime group or hydrazone group can be optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for
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facilitating wound healing; for treating and/or preventing renal and/or respiratory toxicity; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors. Excerpt(s): This application claims priority to U.S. application Ser. No. 60/392,044, filed Jun. 28,.2002, which is incorporated herein by reference. The invention describes novel nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent, wherein the nitrosated and/or nitrosylated COX-2 selective inhibitor must contain at least one oxime group or hydrazone group. The invention also provides novel compositions comprising at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one therapeutic agent, wherein the COX-2 selective inhibitor must contain at least one oxime group or hydrazone group. The invention also provides novel kits comprising at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent, wherein the COX-2 selective inhibitor must contain at least one oxime group or hydrazone group. The invention also provides methods for treating inflammation, pain and fever; for treating gastrointestinal disorders and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal and/or respiratory toxicities; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors. Nonsteroidal anti-inflammatory compounds (NSAIDs) are widely used for the treatment of pain, inflammation, and acute and chronic inflammatory disorders such as osteoarthritis and rheumatoid arthritis. These compounds inhibit the activity of the enzyme cyclooxygenase (COX), also known as prostaglandin G/H synthase, which is the enzyme that converts arachidonic acid into prostanoids. The NSAIDs also inhibit the production of other prostaglandins, especially prostaglandin G.sub.2, prostaglandin H.sub.2 and prostaglandin E.sub.2, thereby reducing the prostaglandin-induced pain and swelling associated with the inflammation process. The chronic use of NSAIDs has been associated with adverse effects, such as gastrointestinal ulceration and renal toxicity. The undesirable side effects are also due to the inhibition of prostaglandin in the affected organ. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Partially reduced nanoparticle additives to lower the amount of carbon monoxide and/or nitric oxide in the mainstream smoke of a cigarette Inventor(s): Hajaligol, Mohammad R.; (Midlothian, VA), Li, Ping; (Richmond, VA), Rasouli, Firooz; (Midlothian, VA) Correspondence: Burns, Doane, Swecker & MATHIS,L.L.P.; P. O. Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20040007241 Date filed: April 7, 2003 Abstract: Cut filler compositions, cigarettes, methods for making cigarettes and methods for smoking cigarettes which involve the use of partially reduced nanoparticle additives capable of acting as an oxidant for the conversion of carbon monoxide to carbon dioxide and/or as a catalyst for the conversion of carbon monoxide to carbon dioxide are provided. The compositions, articles and methods of the invention can be used to reduce the amount of carbon monoxide and/or nitric oxide present in mainstream smoke. The partially reduced additive can be formed by partially reducing Fe.sub.2O.sub.3, to produce a mixture of various reduced forms such as Fe.sub.3O.sub.4, FeO and/or Fe, along with unreduced Fe.sub.2O.sub.3. Excerpt(s): The invention relates generally to lowering the amount of carbon monoxide and/or nitric oxide in the mainstream smoke of a cigarette during smoking. More specifically, the invention relates to cut filler compositions, cigarettes, methods for making cigarettes and methods for smoking cigarettes, which involve the use of a partially reduced additive, in the form of nanoparticles, which acts as a catalyst for the conversion of carbon monoxide to carbon dioxide and/or a catalyst for the conversion of nitric oxide to nitrogen. Various methods for reducing the amount of carbon monoxide and/or nitric oxide in the mainstream smoke of a cigarette during smoking have been proposed. For example, British Patent No. 863,287 describes methods for treating tobacco prior to the manufacture of tobacco articles, such that incomplete combustion products are removed or modified during smoking of the tobacco article. This is said to be accomplished by adding a calcium oxide or a calcium oxide precursor to the tobacco. Iron oxide is also mentioned as an additive to the tobacco. Cigarettes comprising absorbents, generally in a filter tip, have been suggested for physically absorbing some of the carbon monoxide, but such methods are usually not completely efficient. A cigarette filter for removing byproducts formed during smoking is described in U.S. Reissue Patent No. RE 31,700, where the cigarette filter comprises dry and active green algae, optionally with an inorganic porous adsorbent such as iron oxide. Other filtering materials and filters for removing gaseous byproducts, such as hydrogen cyanide and hydrogen sulfide, are described in British Patent No. 973,854. These filtering materials and filters contain absorbent granules of a gas-adsorbent material, impregnated with finely divided oxides of both iron and zinc. In another example, an additive for smoking tobacco products and their filter elements, which comprises an intimate mixture of at least two highly dispersed metal oxides or metal oxyhydrates, is described in U.S. Pat. No. 4,193,412. Such an additive is said to have a synergistically increased absorption capacity for toxic substances in the tobacco smoke. British Patent No. 685,822 describes a filtering agent that is said to oxidize carbon monoxide in tobacco smoke to carbonic acid gas. This filtering agent contains, for example, manganese dioxide and cupric oxide, and slaked lime. The addition of ferric oxide in small amounts is said to improve the efficiency of the product. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Pharmaceutical composition for treating fecal incontinence and anal itch Inventor(s): Kamm, Michael A.; (London, GB), Phillips, Robin K.S.; (Northwood, GB) Correspondence: Birch Stewart Kolasch & Birch; PO Box 747; Falls Church; VA; 220400747; US Patent Application Number: 20030216420 Date filed: March 18, 2003 Abstract: Fecal incontinence and anal itch can be treated by administration, more particularly by local application to the anus, of an a adrenergic blocker, nitric oxide synthase inhibitor, prostaglandin F.sub.2.alpha., dopamine, morphine,.beta.-blockers, and 5-Hydroxytryptamine. The patients who benefit most from the invention are those who have a normal or low maximum anal resting pressure and a structurally intact internal anal sphincter muscle, and patients who have had major bowel resection and reanastomisis. Excerpt(s): This invention relates to the treatment of relief of fecal incontinence and anal itch (pruritis ani), particularly for patients who have had a major bowel resection and reanastomosis. Anal or fecal incontinence is the inability to voluntarily control the passage of feces or gas through the anus. It may occur either as fecal soiling or as rare episodes of incontinence for gas or watery stools. It is a very distressing condition that can result in self-inflicted social isolation and despair. Conventional treatments for fecal incontinence include drug therapy to improve stool consistency, such as morphine, loperamide and codeine phosphate to reduce gut motility, and laxatives to soften stools and relieve constipation. Biofeedback training is another treatment which involves muscle strengthening exercises to improve anal canal resting pressure, and squeeze pressure, and to teach symmetry of anal canal function. The most common form of treatment however, is surgical repair, such as the creation of a neo-sphincter which involves grafting on muscle from other parts of the anus, or a colostomy. (Gastroenterology in Practice, Summer 1995, p18-21; Dig Dis 1990; 8:179-188; and The New England Journal of Medicine, April 1992, p1002-1004). In mild cases of anal leakage, the patient will often try and plug the anus with a ball of cotton wall. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Pharmacotherapy for vascular dysfuntion associated with deficient nitric oxide bioactivity Inventor(s): Gross, Steven S.; (New York, NY), Jones, Caroline L.; (London, GB) Correspondence: Eric S Spector; Jones Tullar & Cooper; Eads Station; PO Box 2266; Arlington; VA; 22202; US Patent Application Number: 20030212135 Date filed: October 9, 2002 Abstract: A patient with a disorder involving endothelial dysfunction associated with deficient nitric oxide bioactivity, e.g., coronary artery disease, atherosclerosis, hypertension, diabetes or neurodegenerative condition stemming from ischemia and/or inflammation, is treated by administering nitric oxide bioactivity increasing hydroxyguanidine.
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Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/196,298, filed Apr. 12, 2000. This invention is directed at enhancing vascular function in patients with vascular diseases and conditions that are associated with deficient nitric oxide bioactivity, endothelial dysfunction, tetrahydrobiopterin insufficiency and/or oxidative stress. In an embodiment the oxidative stress triggers the tetrahydrobiopterin insufficiency which in turn triggers deficient nitric oxide bioactivity and endothelial dysfunction, and the invention is directed at treating the vascular diseases and conditions associated with the endothelial dysfunction. It is known that nitric oxide is constitutively produced by vascular endothelial cells where it plays a key physiological role in the moment-to-moment regulation of blood pressure and vascular tone. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Processes for preparing substituted aryl boronic acids Inventor(s): Caron, Stephane; (Groton, CT), Nowakowski, Jolanta; (Old Saybrook, CT) Correspondence: Pfizer Inc; 150 East 42nd Street; 5th Floor - Stop 49; New York; NY; 10017-5612; US Patent Application Number: 20040038940 Date filed: June 3, 2003 Abstract: The invention relates to processes for preparing a compound of the formula (V) 1and alkyl boronic esters thereof wherein R.sup.1 is attached at the 2 or 3 position of the benzene ring, R.sup.2 is attached at the 5 or 6 position, and R.sup.1, R.sup.2 and G are as defined herein. Said compound is a key synthetic intermediate in the preparation of 2-amino-6-(substituted-4-phe- noxy)-substituted-pyridines useful as nitric oxide synthase (NOS) inhibitors in a mammal. Excerpt(s): This application claims priority under 35 USC 119 of U.S. Provisional 60/393,501, filed Jul. 3, 2002. This invention relates to a new route for the preparation of substituted-aryl boronic acid derivatives which are useful intermediates in the preparation of 2-amino-6-(2-substituted-4-phenoxy)-substituted-pyr- idines that exhibit activity as nitric oxide synthase (NOS) inhibitors. Examples of 2-amino-6-(2-substituted4-phenoxy)-substituted-pyridines that are prepared from substituted-aryl boronic acid derivatives are disclosed in PCT international application publication number WO 98/34919, published Aug. 13, 1998, and incorporated herein by reference in its entirety. The 2-amino-6-(2-substituted-4-phenoxy)-substituted-pyridines disclosed in WO 98/34919 as nitric oxide synthase (NOS) inhibitors are useful in the treatment of migraine inflammatory diseases, stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Alzheimer's disease, chemical dependencies and addictions, emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine induced tolerance and withdrawal symptoms; inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington's disease, Parkinson's disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephsopathy and cancer in a mammal. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Pyrrolo[1,2-b][1,2,4]oxadiazine diones useful as nitric oxide synthase inhibitors Inventor(s): Awasthi, Alok K.; (Skokie, IL), Hallinan, E. Ann; (Evanston, IL), Hansen, Donald W. JR.; (Skokie, IL), Metz, Suzanne; (Chesterfield, MO), Scholten, Jeffrey A.; (Chesterfield, MO), Snyder, Jeffery S.; (Manchester, MO), Toth, Mihaly V.; (St. Louis, MO), Webber, Ronald Keith; (St. Charles, MO) Correspondence: Polster, Lieder, Woodruff & Lucchesi L.C.; 763 South New Ballas RD.; ST. Louis; MO; 63141; US Patent Application Number: 20040019019 Date filed: October 7, 2002 Abstract: The current invention discloses useful bicyclic and tricyclic amidino derivative compounds, pharmaceutical compositions containing these novel compounds, and to their use as nitric oxide synthase inhibitors. Excerpt(s): The present invention relates to heteroatom containing monocyclic and bicyclic compounds, pharmaceutical compositions containing these novel compounds, and to their use in therapy, in particular their use as nitric oxide synthase inhibitors. It has been known since the early 1980's that the vascular relaxation caused by acetylcholine is dependent on the presence of the vascular endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator has been known for well over 100 years. In addition, NO is the active component of amylnitrite, glyceryltrinitrate and other nitrovasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesized from the amino acid Larginine by the enzyme NO synthase. Nitric oxide is the endogenous stimulator of the soluble guanylate cyclase. In addition to endothelium-dependent relaxation, NO is involved in a number of biological actions including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al., Biochemical Pharmacology, 38, 1709-1715, 1989; Moncada et al., Pharmacological Reviews, 43, 109-142, 1991). Excess NO production appears to be involved in a number of pathological conditions, particularly conditions which involve systemic hypotension such as toxic shock, septic shock and therapy with certain cytokines (Kerwin et al., J. Medicinal Chemistry, 38, 4343-4362, 1995). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Skin acupoint/meridian nitric oxide collection kit and method thereof Inventor(s): Ma, Sheng-Xing; (Torrance, CA) Correspondence: Raymond Y. Chan; Suite 128; 108 N. Ynez AVE.; Monterey Park; CA; 91754; US Patent Application Number: 20040024332 Date filed: July 27, 2002 Abstract: A skin acupoint/meridian nitric oxide collection kit comprises a nitric oxide collecting solution; a collecting system comprising a guiding body having a collecting cavity and a skin window. When the nitric oxide collecting solution is received inside the collecting cavity of the guiding body and the collection kit is applied to the skin surface, the nitric oxide collecting solution is exposed to the skin surface through the skin window; an adhesive element made of adhesive material for attaching and
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positioning said guiding body on the skin surface such that said guiding body is provided on a predetermined position of the skin surface and the nitric oxide collecting solution is retained inside said collecting cavity on the predetermined position of the skin surface; means for injecting said nitric oxide collecting solution; and means for collecting said nitric oxide collecting solution. Excerpt(s): The present invention relates to a skin acupoint/meridian nitric oxide collection kit and method thereof, and more particularly to a skin acupoint/meridian nitric oxide collection kit and method for collecting nitric oxide, nitrite and nitrate for assaying nitric oxide concentration on a skin surface. Nitric oxide (NO) levels are predominantly increased in skin acupoints or meridians, and NO is an important meridian chemical. Collections of NO, nitrite, and nitrate from skin surface will make it possible to assay NO concentrations from the acupoints or meridians for research, diagnosis, and treatment of skin and related disorders using alternative therapies such as acupuncture, acupressure, chiropractic medicine, therapeutic touch, Reiki, Tuna, laying-on-of-hands, and Qi Gong. Recent studies have shown that NO is perhaps one of the most important messenger molecules in the human body, which is produced in many cell types including neurons and skin tissues. Nitric oxide concentrations and chemical messengers in human skin can be continuously monitored by using dermal microdialysis in vivo. (Clough G F, Bennett A R, Church M K: Measurement of nitric oxide concentration in human skin in vivo using dermal microdialysis. Exp Physiol 1998; 83: 431-434; Clough G, Bennett A R, Church M K: Relationship between nitric oxide, cyclic GMP and vasodilatation in human skin in vivo. J Physiol 1998; 513P). However, the procedure of such method requires a step of inserting a needle into the human's skin, which is painful. Thus, it may have possible side effects and cause infections through the needle. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
System for exsanguinous metabolic support of an organ or tissue Inventor(s): Brasile, Lauren; (Albany, NY) Correspondence: Heslin Rothenberg Farley & Mesiti PC; 5 Columbia Circle; Albany; NY; 12203; US Patent Application Number: 20040038192 Date filed: May 22, 2003 Abstract: An exsanguinous metabolic support system for maintaining an organ or tissue at a near normal metabolic rate is disclosed that employs a warm perfusion solution capable of altering the production of nitric oxide (NO) in an organ or tissue and supporting the metabolism of the organ or tissue at normothermic temperatures. Perfusion with the solution of the invention, therefore, can be used to regulate nitric oxide production in situations where it is desirable to do so, for example, to prevent reperfusion injury. The system also monitors parameters of the circulating perfusion solution, such as pH, temperature, osmolarity, flow rate, vascular pressure and partial pressure of respiratory gases, and nitric oxide (NO) concentration and regulates them to insure that the organ is maintained under near-physiologic conditions. Use of the system for long-term maintenance of organs for transplantation, for resuscitation and repair of organs having sustained warm ischemic damage, to treat cardiovascular disorders, to prevent reperfusion injury, as a pharmaceutical delivery system and prognosticator of posttransplantation organ function is also disclosed.
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Excerpt(s): This application is a continuation-in-part of co-pending U.S. Ser. No. 09/849,618 filed May 4, 2001 which is a continuation-in-part of co-pending U.S. Ser. No. 09/547,843 filed Apr. 12, 2000 which claims the priority of U.S. application Ser. No. 60/129,257 filed Apr. 14, 1999; the entire disclosures of which are incorporated herein by reference. The invention relates to a metabolic support system including a solution, method and apparatus for sustaining organs for transplantation under near-physiologic conditions. More particularly, the invention relates to use of the system for regulation of nitric oxide production in organs and tissues, repair and/or long-term maintenance of organs for transplantation, as a pharmaceutical delivery system and prognosticator of post-transplantation organ function. There continues to be an extreme shortage of organs for transplantation. Currently, the major limiting factor in clinical transplantation is the persistent shortage of organs. For example, kidney transplantation is largely dependent upon the availability of organs retrieved from heart-beating cadaver donors. There exists, however, a large and as yet untapped source of organs for transplantation, namely, non-heart-beating cadavers. Non-heart-beating cadavers are accident victims who succumb at the site of an injury and those having short post-trauma survival times. Additionally, non-heart-beating cadavers result when families are emotionally unable to make the decision to donate the organs of a loved one contemporaneously with making the decision to terminate life support. In these situations, the organs are not used because the lack of circulating blood supply (warm ischemia) once the heart stops beating, results in an injury cascade. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Therapeutic use of growth factor, and delivery device, especially for the treatment of intimal hyperplasia Inventor(s): Barker, Stephen George Edward; (London, GB), Martin, John Francis; (London, GB), Yla-Herttuala, Seppo; (Kuopio, FI) Correspondence: Saliwanchik Lloyd & Saliwanchik; A Professional Association; 2421 N.W. 41st Street; Suite A-1; Gainesville; FL; 326066669 Patent Application Number: 20030225020 Date filed: February 19, 2003 Abstract: The present invention concerns vascular endothelial growth factor (VEGF) which has utility in the treatment of intimal hyperplasia, hypertension and atherosclerosis, and of conditions susceptible to treatment with agents that produce nitric oxide or prostacyclin. Instead of VEGF, an equivalent agent such as an agonist of VEGF receptors may be given, as may nucleic acid encoding such an agonist. The agent may successfully be administered via the adventitial surface of a blood vessel, e.g., using a device which defines a reservoir between the body wall and the vessel's adventitial surface, the reservoir being at least part-filled by a pharmaceutical formulation containing the agent to be delivered. Excerpt(s): The present invention relates to the therapeutic use of a growth factor, and particularly to the treatment and prevention of intimal hyperplasia of blood vessels and other conditions, especially hypertension. The invention relates also to a device that can be used for delivering the active agent. Intimal hyperplasia is the increase in the number of cells between the endothelium and internal elastic lamina of a blood vessel, particularly in the intimal layer found there, or in an artery. Intimal hyperplasia is often caused by smooth muscle cell (SMC) proliferation in the blood vessel wall. When
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intimal hyperplasia occurs, de novo thickening of the intimal layer or of the vessel wall, i.e. stenosis, may result. Thus, the blood vessel may become occluded. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Topical pharmaceutical composition comprising a cholinergic agent or a calcium channel blocker Inventor(s): Kamm, Michael A.; (London, GB), Phillips, Robin K.S.; (Northwood, GB) Correspondence: Birch Stewart Kolasch & Birch; PO Box 747; Falls Church; VA; 220400747; US Patent Application Number: 20040028752 Date filed: August 8, 2002 Abstract: A method and composition are provided for the treatment of an anorectal disorder and for controlling the pain associated therewith. The method comprises administering to a subject in need of such treatment therapeutically effective amounts of a calcium channel blocker either alone or together with a nitric oxide donor. Amlodipine, anipamil, barnidipine, benidipine, bepridil, darodipine, diltiazem, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, lidoflazine, manidipine, mepirodipine, nicardipine, nifedipine, niludipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, perhexiline, tiapamil, verapamil and pharmaceutically acceptable salts thereof, are suitable calcium channel blockers. Excerpt(s): This invention relates to the use of a calcium channel blocker or a cholinegic agent, particularly diltiazem and bethanechol, alone and in combination for the treatment of benign anal diseases where there is an associated anal sphincter spasm. The invention particularly relates to the treatment of anal fissures and painful haemorrhoidal conditions. A fissure is a split in the skin of the distal anal canal. It is a common complaint in young adults with a roughly equal incidence in both sexes. Acute fissures are very common and most heal spontaneously, but a proportion progress to form a chronic linear ulcer in the anal canal and show great reluctance to heal without intervention. Treatment has remained largely unchanged for over 150 years and the pathogenesis of anal fissure is not fully understood. The passage of a hard stool bolus has traditionally been thought to cause anal fissure. Thus for acute fissures the avoidance of constipation, such as involving a high bran diet, has been used as treatment for many years. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Transdermal pharmaceutical delivery composition Inventor(s): Benjamin, Nigel; (London, GB), Tucker, Arthur T.; (London, GB) Correspondence: Dilworth Paxson Llp; 3200 Mellon Bank Center; 1735 Market Street; Philadelphia; PA; 19103; US Patent Application Number: 20040013747 Date filed: June 16, 2003 Abstract: A pharmaceutically delivery system is described comprising a pharmaceutically active agent and acidified nitrite as an agent to produce local production of nitric oxide at the skin surface. The dosage form may be in any
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pharmaceutically acceptable carrier means and comprises an acidifying agent adapted to reduce the pH at the environment. In one embodiment, a barrier consisting of a membrane allows diffusions of the anaesthetic and nitrite ions while preventing direct contact of the skin and acidifying agent. Excerpt(s): The present invention relates to a new composition for transdermal delivery of topically applied pharmaceutical preparations. The system comprises the use of the pharmaceutical agent and acidified nitrite contained within a delivery system to allow passage of both the specific pharmaceutical agent and nitric oxide to the skin. The penetration of substances through the skin is important from both toxicological and therapeutic viewpoints. Passive delivery of most compounds across different epithelia is limited due to the excellent barrier properties afforded by these epithelia. The stratum corneum is the principal barrier to penetration of most chemicals. Conventional topical delivery systems are therefore restricted to either substances for local effects or to highly potent, small, lipophilic substances for systemic effects. It is also difficult to deliver ionic and high-molecular-weight drugs in therapeutically sufficient amounts by conventional systems. By way of example, many medical and surgical procedures require topical anaesthesia. The use of local anaesthetics requires an agent possessing the following general properties. It should not be irritating to the tissue to which it is applied, nor should it cause any permanent damage to nerve structure. Its systemic toxicity should be low because it is eventually absorbed from its site of administration. It is usually important that the time required for the onset of anaesthesia should be as short as possible. Furthermore, the action must last long enough to allow time for the contemplated medical or surgical intervention, yet not so long as to entail an extended period of recovery (J. Murdoch Ritchie & N. M. Greene Local Anaesthetics in Goodman & Gilman's: The Pharmacological Basis of Therapeutics, pages 311-331, McGraw-Hill Inc, (1992)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Tricyclic-bis-enone derivatives and methods of use thereof Inventor(s): Favaloro, Frank G.; (Norfolk, MA), Gribble, Gordon W.; (Lebanon, NH), Honda, Tadashi; (Hanover, NH), Sporn, Michael B.; (Tunbridge, VT), Suh, Nanjoo; (White River Junction, VT) Correspondence: Fulbright & Jaworski L.L.P.; A Registered Limited Liability Partnership; Suite 2400; 600 Congress Avenue; Austin; TX; 78701-3271; US Patent Application Number: 20030232786 Date filed: January 15, 2003 Abstract: Novel tricyclic-bis-enone derivatives (TBEs) as well as the process for the preparation of such TBEs are provided. Also provided are methods for prevention and/or treatment of cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotropic lateral sclerosis, rheumatoid arthritis, inflammatory bowel disease, and all other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide (NO) or prostaglandins or the overexpression of iNOS or COX-2 genes or gene products. Further, methods for the synthesis of the TBE compounds of the invention utilize cheap commercially available reagents and are highly cost effective and amenable to scale-up. Additional high efficiency synthetic methods that utilize novel intermediates as well as the synthesis of these intermediates are also provided. Furthermore, the invention also provides methods for designing novel and watersoluble TBEs.
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Excerpt(s): The present application claims priority to provisional U.S. Patent Application Serial No. 60/348,594 filed Jan. 15, 2002; provisional U.S. Patent Application Serial No. 60/376,040, filed Apr. 26, 2002 and provisional U.S. Patent Application Serial No. 60/402,966, filed Aug. 13, 2002. The entire text of each of the above referenced applications is incorporated herein by reference and without disclaimer. The present invention provides novel tricyclic-bis-enone derivatives (TBEs), as well as the process for the preparation of such TBEs, for prevention and/or treatment of cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotropic lateral sclerosis, rheumatoid arthritis, inflammatory bowel disease, and other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide (NO) or prostaglandins. One of the major needs in clinical oncology is the development of effective and safe new agents for chemoprevention. In particular, there is a need for chemopreventative agents targeted at mechanisms known to be involved in the process of carcinogenesis. In recent years, there has been a resurgence of interest in the study of mechanisms of inflammation that relate to carcinogenesis and in the use of such mechanisms as the basis for development of new chemopreventative agents. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Two dimensional polymer that generates nitric oxide Inventor(s): Koren, Amy B.; (Lansing, MI), McDonald, William F.; (Utica, OH) Correspondence: Foley & Lardner; Firstar Center; 777 East Wisconsin Avenue; Milwaukee; WI; 53202-5367; US Patent Application Number: 20040033242 Date filed: August 16, 2002 Abstract: A polymeric composition that generates nitric oxide and a process for rendering the surface of a substrate nonthrombogenic by applying a coating of the polymeric composition to the substrate are disclosed. The composition comprises: (1) a crosslinked chemical combination of (i) a polymer having amino group-containing side chains along a backbone forming the polymer, and (ii) a crosslinking agent containing functional groups capable of reacting with the amino groups; and (2) a plurality of nitric oxide generating functional groups associated with the crosslinked chemical combination. Once exposed to a physiological environment, the coating generates nitric oxide thereby inhibiting platelet aggregation. In one embodiment, the nitric oxide generating functional groups are provided by a nitrated compound (e.g., nitrocellulose) imbedded in the polymeric composition. In another embodiment, the nitric oxide generating functional groups comprise N.sub.2O.sub.2.sup.- groups covalently bonded to amino groups on the polymer. Excerpt(s): This invention relates to a polymeric composition that generates nitric oxide, and more particularly to a two dimensional polymer having nitric oxide generating functional groups or compounds including nitric oxide generating functional groups bound to the polymer for generating nitric oxide. It is well known that when blood comes into contact with a surface other than the natural wall of a blood vessel, the activation of certain circulating substances results in the coagulation of the blood. If thrombi are formed on portions of the surface which contact blood flow, there is a risk that the thrombi will be released and cause serious blood circulation disturbances called thrombosis. As a result, extensive investigations have been undertaken over many years to find materials having a reduced tendency to form thrombosis. This area of research has become increasingly important with the development of various objects and articles
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which can be in contact with blood, such as artificial organs, vascular grafts, probes, cannulas, catheters and the like. Synthetic polymeric materials have come to the fore as preferred materials for such articles. However, these polymeric materials have the major drawback of being thrombogenic. Accordingly, numerous procedures for rendering a polymeric surface non-thrombogenic have been proposed. (As used herein, "nonthrombogenic" and "antithrombogenic" refer to any material which inhibits thrombus formation on a surface.) One known approach for counteracting thrombogenicity of a polymeric surface has been the use of polymer treatments or polymer coatings that serve to inhibit platelet aggregation on the polymeric surface. For instance, functional groups or compounds that inhibit platelet aggregation may be bound to or imbedded in a polymer matrix, or bound to or imbedded in a polymer coating that is applied to the polymer matrix. Typically, antithrombogenic polymer coatings can also be applied to other materials such as metals and ceramics. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Use of nitric oxide adducts Inventor(s): Folts, John D.; (Madison, WI), Loscalzo, Joseph; (Dover, MA), Stamler, Jonathan; (Chapel Hill, NC) Correspondence: Hollie L. Baker; Hale And Dorr, Llp; 60 State Street; Boston; MA; 02109; US Patent Application Number: 20040037836 Date filed: August 25, 2003 Abstract: A method for preventing adverse effects associated with the use of a medical device in a patient by introducing into the patient a device of which at least a portion includes a prophylactic or therapeutic amount of a nitric oxide adduct. The nitric oxide adduct can be present in a matrix coating on a surface of the medical device; can be coated per se on a surface of the medical device; can be directly or indirectly bound to reactive sites on a surface of the medical device; or at least a portion of the medical device can be formed of a material, such as a polymer, which includes the nitric oxide adduct. Also disclosed is a method for preventing adverse effects associated with the use of a medical device in a patient by introducing the device during a medical procedure and before or during said procedure locally administering a nitric oxide adduct to the site of contact of said device with any internal tissue. Excerpt(s): This application is a continuation of U.S. application Ser. No. 10/253,977 filed Jul. 11, 2002, which is a continuation of U.S. application Ser. No. 09/621,610 filed Jul. 21, 2000, issued as U.S. Pat. No. 6,471,978, which is a continuation of U.S. application Ser. No. 09/433,550 filed Nov. 4, 1999, issued as U.S. Pat. No. 6,174,539, which is a continuation of U.S. application Ser. No. 08/460,465 filed Jun. 2, 1995, issued as U.S. Pat. No. 6,087,479, which is a continuation-in-part of U.S. application Ser. No. 08/123,331 filed Sep. 17, 1993, abandoned. This application is related to U.S. Pat. No. 6,255,277 and U.S. Pat. No. 6,352,709. This invention relates to the use of medical devices and to the treatment of damaged vasculature. More particularly, the invention relates to the use of medical devices which are inserted into a patient wherein at least a portion of the device includes a surface which exposes and delivers a form of nitric oxide to vascular surfaces with which it comes in contact. Alternatively the invention relates to the field of preventing the adverse effects which result from medical procedures which involve the use of such a medical device and which include administering a source of nitric oxide to the cite of vasculature contact of such medical devices. The vascular endothelium
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participates in many homeostatic mechanisms important for the regulation of vascular tone and the prevention of thrombosis. A primary mediator of these functions is endothelium-derived relaxing factor (EDRF). First described in 1980 by Furchgott and Zawadzki (Furchgott and Zawadzki, Nature (Lond.) 288:373-376, 1980), EDRF is either nitric oxide (Moncada et al., Pharmacol Rev. 43:109-142, 1991.) (NO) or a closely related No-containing molecule (Myers et al., Nature (Lond.), 345:161-163, 1990). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Uses for medical devices having a lubricious, nitric oxide-releasing coating Inventor(s): Shah, Chirag B.; (North Attleboro, MA), Tedeschi, Eugene; (Santa Rosa, CA) Correspondence: Stradling Yocco Carlson & Rauth; Suite 1600; 660 Newport Center Drive; P.O. Box 7680; Newport Beach; CA; 92660; US Patent Application Number: 20040043068 Date filed: September 4, 2003 Abstract: Methods are provided for delivering nitric oxide to the vascular tissue of a patient to inhibit or prevent restenosis or improve vascular function following various surgical procedures or associated with various NO-related conditions. The disclosed methods comprise contacting the vascular tissue of a patient with a medical device coated with a coating comprising nitric oxide associated with and releaseable from a polyurea network formed from the reaction on said medical device of a polyisocyanate; an amine donor and/or hydroxyl donor; an isocyanatosilane adduct having terminal isocyanate groups and at least one hydrolyzable alkoxy group bonded to silicon; and optionally a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 09/405,024, filed Sep. 27, 1999, which is a continuation-in-part of U.S. application Ser. No. 09/163,038, filed Sep. 29, 1998, which applications are herein incorporated by reference in their entirety. This invention relates generally to the uses for a drug-coating complex which is drug-releasing in physiological media. More particularly, the invention relates to methods of using medical devices coated with a lubricious, nitric oxide-releasing coating for the treatment of vascular disorders, including restenosis, and the induction of angiogenesis. It has long been known that hydrophilic coatings with low friction (coefficient of friction of 0.3 or less) are useful for a variety of medical devices such as catheters, catheter introducers and the like. When low friction surfaces are used, the devices, upon introduction into the body, slide easily within arteries, veins and other body orifices and passageways. There have been a wide variety of methods used to provide the surfaces desired. In some cases the material of the catheter or medical device is formed of a material having good anti-friction properties such as poly(tetrafluoroethylene) or other plastics which tend to avoid abrasion with the body. However, in many cases the selection of materials does not provide the anti-slip properties desired in conjunction with other desirable properties for the particular medical device. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Keeping Current In order to stay informed about patents and patent applications dealing with nitric oxide, 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 “nitric oxide” (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 nitric oxide. You can also use this procedure to view pending patent applications concerning nitric oxide. 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 NITRIC OXIDE Overview This chapter provides bibliographic book references relating to nitric oxide. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on nitric oxide 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 “nitric oxide” (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 nitric oxide: •
Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment Source: Malden, MA: Blackwell Science, Inc. 1999. 568 p. Contact: Available from Blackwell Science, Inc. 350 Main Street, Malden, MA 02148. (800) 215-1000 or (781)-388-8250. Fax (781) 388-8270. E-mail:
[email protected]. Website: www.blackwellscience.com. PRICE: $125.00 plus shipping and handling. ISBN: 0632043423. Summary: Cirrhosis (liver scarring) is a very prevalent disease and ascites (fluid accumulation) is the most frequent complication. The development of ascites in cirrhosis is the consequence of the simultaneous occurrence of very complex processes leading to impairment in hepatic, circulatory, and renal function. The textbook offers 32 chapters on the pathogenesis, diagnosis and treatment of ascites and renal dysfunction in liver disease. Topics include historical notes on ascites in cirrhosis; characteristics of ascites;
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clinical disorders of renal function in cirrhosis with ascites; clinical disorders of renal function in acute liver failure; renal dysfunction and postoperative renal failure in obstructive jaundice; spontaneous bacterial peritonitis; the etiology, diagnosis, and management of noncirrhotic ascites; extracellular fluid volume homeostasis; physiology of the renal circulation; physiology of the gastrointestinal and liver circulation; the renin angiotensin aldosterone system in cirrhosis; the sympathetic nervous system in cirrhosis; arginine vasopressin in cirrhosis; atrial natriuretic peptide and other natriuretic factors in cirrhosis; arachidonic acid metabolites and the kidney in cirrhosis; nitric oxide and systemic and renal hemodynamic disturbances in cirrhosis; endothelin and systemic, renal, and hepatic hemodynamic disturbances in cirrhosis; the systemic circulation in cirrhosis; the splanchnic circulation in cirrhosis; alterations of hepatic and splanchnic microvascular exchange in cirrhosis (local factors in the formation of ascites); experimental models in the investigation of portal hypertension; renal dysfunction and ascites in carbon tetrachloride induced cirrhosis in rates; bacterial infection of the ascitic fluid in rates with carbon tetrachloride induced cirrhosis; the arterial vasodilation hypothesis of ascites formation in cirrhosis; prognosis of cirrhosis with ascites; the medical treatment of ascites in cirrhosis; treatment of ascites by paracentesis; the treatment of refractory ascites in cirrhosis; the treatment of hepatorenal syndrome in cirrhosis; drug induced renal failure in cirrhosis; liver transplantation in cirrhotic patients with ascites; and the treatment and prophylaxis of spontaneous bacterial peritonitis. Each chapter is written by experts in the field and includes extensive references. The text concludes with a subject index. •
Diabetes and Cardiovascular Disease Source: Totowa, NJ: The Humana Press, Inc. 2001. 458 p. 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 textbook offers practicing physicians the day to day practical knowledge about cardiovascular disease and diabetes. The 24 chapters in the book focus on either clinical or basic aspects of diabetes and cardiovascular disease. Part I, pathophysiology, reviews the mechanisms and risk factors for diabetic cardiovascular disease. Specific topics include the effects of insulin on the vascular system, vascular abnormalities in the prediabetic state, diabetes and advanced glycation end products, diabetes and hypertension (high blood pressure), the renin-angiotensin system, diabetes and dyslipidemia (disordered levels of fats in the blood), diabetes and thrombosis (blood clotting), diabetes and atherosclerosis (hardening and narrowing of the arteries), and nitric oxide and its role in diabetes mellitus. Part II focuses on the heart in diabetes mellitus, including coronary artery disease and congestive heart failure, including the preoperative assessment and perioperative management of the surgical patient with diabetes mellitus. Part III, the peripheral vascular system, addresses epidemiology (incidence and prevalence), mechanisms, methods of assessment, and treatment of this macrovascular disease. Specific topics include diabetes and arterial stiffness, methods for assessing large vessel pathophysiology, and peripheral vascular disease in patients with diabetes mellitus. And Part IV reviews the different microvascular effects in individuals with diabetes mellitus, including retinopathy (eye disease), nephropathy (kidney disease), neuropathy
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(nerve disease), and microcirculation of the diabetic foot. Each chapter includes extensive references and a subject index concludes the text.
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 “nitric oxide” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “nitric oxide” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “nitric oxide” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
Active chlorine and nitric oxide formation from chemical rocket plume afterburning (SuDoc NAS 1.26:197503) by D. M. Leone; ISBN: B00010RQUG; http://www.amazon.com/exec/obidos/ASIN/B00010RQUG/icongroupinterna
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Airway Responsiveness and Exhaled Nitric Oxide: Studies in Asthma and Sjogren's Syndrome by Dora Ludviksdottir; ISBN: 9155445128; http://www.amazon.com/exec/obidos/ASIN/9155445128/icongroupinterna
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Biochemical, Pharmacological, and Clinical Aspects of Nitric Oxide by Ben Avi Weissman (Editor), et al; ISBN: 0306451131; http://www.amazon.com/exec/obidos/ASIN/0306451131/icongroupinterna
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Biology of Nitric Oxide by S. Moncada (Editor); ISBN: 1855781425; http://www.amazon.com/exec/obidos/ASIN/1855781425/icongroupinterna
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Cellular and Molecular Biology of Nitric Oxide by Jeffrey D. Laskin, Debra L. Laskin; ISBN: 0824719654; http://www.amazon.com/exec/obidos/ASIN/0824719654/icongroupinterna
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Development of UV optical measurements of nitric oxide and hydroxyl radical at the exit of high pressure gas turbine combustors final report (March 1995 to March 1998) (SuDoc NAS 1.26:208869) by D. S. Liscinsky; ISBN: B000110POY; http://www.amazon.com/exec/obidos/ASIN/B000110POY/icongroupinterna
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Endothelial Nitric Oxide in the Control of Glomular Hemodynamics (Comprehensive Summaries of Uppsala Dissertations from the Faculty of mediciNe, 1166) by Janos Pittner; ISBN: 9155453511; http://www.amazon.com/exec/obidos/ASIN/9155453511/icongroupinterna
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Endothelium, Nitric Oxide, and Atherosclerosis: From Basic Mechanisms to Clinical Implications by Julio A., Md. Panza (Editor), Richard O. Cannon (Editor); ISBN: 0879934360; http://www.amazon.com/exec/obidos/ASIN/0879934360/icongroupinterna
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Experimental assessment and enhancement of planar laser-induced fluorescence measurements of nitric oxide in an inverse diffusion flame (SuDoc NAS 1.26:202329) by William P. Partridge; ISBN: B00010YFK0; http://www.amazon.com/exec/obidos/ASIN/B00010YFK0/icongroupinterna
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Free Radicals, Nitric Oxide and Inflammation: Molecular, Biochemical, and Clinical Aspects (Nato: Life and Behavioural Sciences, 344) by Aldo Tomasi (Editor), et al;
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ISBN: 1586032437; http://www.amazon.com/exec/obidos/ASIN/1586032437/icongroupinterna •
Functional Neuroanatomy of the Nitric Oxide System by Hendrik Wilhelm Maria Steinbusch (Editor), et al; ISBN: 0444502858; http://www.amazon.com/exec/obidos/ASIN/0444502858/icongroupinterna
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Headache Pathogenesis: Monoamines, Neuropeptides, Purines, and Nitric Oxide (Frontiers in Headache Research, Vol. 7) by Jes Olesen (Editor), Lars Edvinsson (Editor); ISBN: 0781712084; http://www.amazon.com/exec/obidos/ASIN/0781712084/icongroupinterna
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Induction of nitric oxide synthase in channel catfish Ictalurus punctatus by Edwardsiella ictaluri (SuDoc EP 1.23/6:600/J-94/438) by W. Peter Schoor; ISBN: B00010NJ5C; http://www.amazon.com/exec/obidos/ASIN/B00010NJ5C/icongroupinterna
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Laser-induced fluorescence measurements and modeling of nitric oxide in counterflow diffusion flames (SuDoc NAS 1.26:209805) by Rayavarapu V. Ravikrishna; ISBN: B000112WD6; http://www.amazon.com/exec/obidos/ASIN/B000112WD6/icongroupinterna
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Life, Death and Nitric Oxide by A. R. Butler, R. Nicholson; ISBN: 0854046860; http://www.amazon.com/exec/obidos/ASIN/0854046860/icongroupinterna
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Macula Densa Derived Nitric Oxide & Kidney Function (Comprehensive Summaries of Uppsala Dissertations from the Faculty of mediciNe, 1144) by Anna Ollerstam; ISBN: 9155452930; http://www.amazon.com/exec/obidos/ASIN/9155452930/icongroupinterna
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Measurements and modeling of nitric oxide formation in counterflow, premixed CH b4 s/O b2 s/N b2 s flames (SuDoc NAS 1.26:209804) by D. Douglas Thomsen; ISBN: B000112WCM; http://www.amazon.com/exec/obidos/ASIN/B000112WCM/icongroupinterna
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Measurements of Nitric Oxide and Nitrogen Dioxide in Ambient Air at Harwell, Jan.Dec. 1985 by F.J. Sandalls, A.W. Leonard; ISBN: 0705810348; http://www.amazon.com/exec/obidos/ASIN/0705810348/icongroupinterna
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Measurements of Ozone, Nitric Oxide and Nitrogen Dioxide in Ambient Air at Harwell, January - December 1987 by F.J. Sandalls, et al; ISBN: 0705812588; http://www.amazon.com/exec/obidos/ASIN/0705812588/icongroupinterna
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Measurements of Ozone, Nitric Oxide and Nitrogen Dioxide in Ambient Air at Harwell, January-December 1986 by F.J. Sandalls, S.L. Gaudern; ISBN: 0705810364; http://www.amazon.com/exec/obidos/ASIN/0705810364/icongroupinterna
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Methods in Enzymology, Volume 301: Nitric Oxide, Part C: Biological and Antioxidant Activities by John Abelson (Author), et al; ISBN: 0121822028; http://www.amazon.com/exec/obidos/ASIN/0121822028/icongroupinterna
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Methods in Enzymology, Volume 359: Nitric Oxide, Part D: Oxide Detection, Mitochondria and Cell Functions, and Peroxynitrite Reactions by Enrique Cadenas (Author), Lester Packer (Author); ISBN: 0121822621; http://www.amazon.com/exec/obidos/ASIN/0121822621/icongroupinterna
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Methods in Nitric Oxide Research by Martin Feelisch (Editor), Jonathan S. Stamler (Editor); ISBN: 0471955248; http://www.amazon.com/exec/obidos/ASIN/0471955248/icongroupinterna
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Nitric Oxide; ISBN: 4762277703; http://www.amazon.com/exec/obidos/ASIN/4762277703/icongroupinterna
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Nitric Oxide & the Cell: Proliferation, Differentiation & Death by S. Moncada (Editor), et al; ISBN: 1855781204; http://www.amazon.com/exec/obidos/ASIN/1855781204/icongroupinterna
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Nitric Oxide (Handbook of Experimental Pharmacology, V. 143) by J.-L Balligand, et al; ISBN: 3540661220; http://www.amazon.com/exec/obidos/ASIN/3540661220/icongroupinterna
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Nitric Oxide : Biology and Pathobiology by Louis Ignarro (Author); ISBN: 0123704200; http://www.amazon.com/exec/obidos/ASIN/0123704200/icongroupinterna
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Nitric Oxide : Principles and Actions by Jack Jr. Lancaster (Author); ISBN: 0124355552; http://www.amazon.com/exec/obidos/ASIN/0124355552/icongroupinterna
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Nitric Oxide and Endothelin in the Pathogenesis of Glaucoma by Ivan O. Haefliger (Editor), J. Flammer (Editor); ISBN: 0781716004; http://www.amazon.com/exec/obidos/ASIN/0781716004/icongroupinterna
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Nitric Oxide and Free Radicals in Peripheral Neurotransmission by Stanley Kalsner (Editor), Stanley Kaslner (Editor); ISBN: 0817640703; http://www.amazon.com/exec/obidos/ASIN/0817640703/icongroupinterna
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Nitric Oxide and Infection by Ferric C. Fang (Editor); ISBN: 0306461471; http://www.amazon.com/exec/obidos/ASIN/0306461471/icongroupinterna
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Nitric Oxide and Inflammation by Daniela Salvemini (Editor), et al; ISBN: 3764361646; http://www.amazon.com/exec/obidos/ASIN/3764361646/icongroupinterna
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Nitric Oxide and Radicals in the Pulmonary Vasculature by E. Kenneth Weir (Editor), et al; ISBN: 0879936312; http://www.amazon.com/exec/obidos/ASIN/0879936312/icongroupinterna
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Nitric Oxide and the Cardiovascular System (Contemporary Cardiology) by Joseph Loscalzo (Editor), Joseph A. Vita (Editor); ISBN: 0896036200; http://www.amazon.com/exec/obidos/ASIN/0896036200/icongroupinterna
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Nitric Oxide and the Kidney: Physiology and Pathophysiology by Michael S. Goligorsky (Editor), Steven S. Gross (Editor); ISBN: 0412080613; http://www.amazon.com/exec/obidos/ASIN/0412080613/icongroupinterna
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Nitric Oxide and the Lung by Warren M. Zapol (Editor), Kenneth D. Bloch (Editor); ISBN: 0824797256; http://www.amazon.com/exec/obidos/ASIN/0824797256/icongroupinterna
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Nitric Oxide and the Peripheral Nervous System by Toda; ISBN: 1855781395; http://www.amazon.com/exec/obidos/ASIN/1855781395/icongroupinterna
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Nitric Oxide and the Regulation of the Peripheral Circulation by Philip J. Kadowitz (Editor), D. B. McNamara (Editor); ISBN: 0817640460; http://www.amazon.com/exec/obidos/ASIN/0817640460/icongroupinterna
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Nitric Oxide as a Mediator by Barbul; ISBN: 187970224X; http://www.amazon.com/exec/obidos/ASIN/187970224X/icongroupinterna
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Nitric oxide formation in a lean, premixed-prevaporized jet A/air flame tube an experimental and analytical study (SuDoc NAS 1.15:105722) by NASA; ISBN: B00010JBZE; http://www.amazon.com/exec/obidos/ASIN/B00010JBZE/icongroupinterna
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Nitric Oxide from L-Arginine: A Bioregulatory System: Proceedings of a Symposium Held at the Royal Society, London, 14-15 September, 1989 by Salvador Moncada, E. Annie Higgs; ISBN: 0444811540; http://www.amazon.com/exec/obidos/ASIN/0444811540/icongroupinterna
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Nitric Oxide in Bone and Joint Disease by Mika V. J. Hukkanen (Editor), et al; ISBN: 0521592208; http://www.amazon.com/exec/obidos/ASIN/0521592208/icongroupinterna
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Nitric Oxide in Brain Development, Plasticity, and Disease by R. Ranney Mize (Editor), et al; ISBN: 0444828850; http://www.amazon.com/exec/obidos/ASIN/0444828850/icongroupinterna
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Nitric Oxide in Plants - Occurrence and Function by Ya'Acov Y. Leshem, et al; ISBN: 0792360885; http://www.amazon.com/exec/obidos/ASIN/0792360885/icongroupinterna
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Nitric Oxide in Pulmonary Processes: Role in Physiology and Pathophysiology of Lung Disease (Respiratory Pharmacology and Pharmacotherapy) by M. G. Belvisi (Editor); ISBN: 0817657185; http://www.amazon.com/exec/obidos/ASIN/0817657185/icongroupinterna
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Nitric Oxide in the Eye by S. Kashii (Editor), et al; ISBN: 4431702873; http://www.amazon.com/exec/obidos/ASIN/4431702873/icongroupinterna
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Nitric Oxide in the Inner Ear With Particular Regard to Neurotransmission & Pharmacotherapy (Comprehensive Summaries of Uppsala Dissertations from the Faculty of mediciNe, 1159) by Raul Popa; ISBN: 9155453252; http://www.amazon.com/exec/obidos/ASIN/9155453252/icongroupinterna
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Nitric Oxide in the Nervous System by Stephen Vincent (Author); ISBN: 0127219854; http://www.amazon.com/exec/obidos/ASIN/0127219854/icongroupinterna
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Nitric Oxide in Transplant Rejection and Anti-Tumor Defense by Stanislaw Lukiewicz (Editor), et al; ISBN: 0792383893; http://www.amazon.com/exec/obidos/ASIN/0792383893/icongroupinterna
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Nitric Oxide Part B: Physiological and Pathological Processes by John Abelson (Author), et al; ISBN: 0121821706; http://www.amazon.com/exec/obidos/ASIN/0121821706/icongroupinterna
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Nitric Oxide Protocols (Methods in Molecular Biology (Clifton, N.J.), 279.) by Aviv Hassid (Editor); ISBN: 1588292371; http://www.amazon.com/exec/obidos/ASIN/1588292371/icongroupinterna
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Nitric Oxide Protocols hardbound NOT published this is paper ed. by Michael A. Titheradge (Editor); ISBN: 0896035379; http://www.amazon.com/exec/obidos/ASIN/0896035379/icongroupinterna
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Nitric Oxide Research from Chemistry to Biology: Epr Spectroscopy of Nitrosylated Compounds (Molecular Biology Intelligence Unit Series) by Yann A. Henry, et al; ISBN: 0412135612; http://www.amazon.com/exec/obidos/ASIN/0412135612/icongroupinterna
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Nitric Oxide Synthase: Characterization and Functional Analysis : Characterization and Functional Analysis by P. Michael Conn (Author), Mahin Maines (Author); ISBN: 0121853012; http://www.amazon.com/exec/obidos/ASIN/0121853012/icongroupinterna
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Nitric Oxide, Cytochromes P450, and Sexual Steroid Hormones (Ernst Schering Research Foundation Workshop, 21) by J. R., Jr. Lancaster (Editor), J. F. Parkinson (Editor); ISBN: 3540630503; http://www.amazon.com/exec/obidos/ASIN/3540630503/icongroupinterna
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Nitric Oxide: A Modulator of Cell-Cell Interactions in the Microcirculation by Kubes; ISBN: 3540600361; http://www.amazon.com/exec/obidos/ASIN/3540600361/icongroupinterna
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Nitric Oxide: A Modulator of Cell-Cell Interactions in the Microcirulation (Molecular Biology Intelligence Unit) by Paul Kubes (Editor); ISBN: 1570592802; http://www.amazon.com/exec/obidos/ASIN/1570592802/icongroupinterna
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Nitric Oxide: Basic Research and Clinical Applications (Nato: Life Sciences, 317) by R. J. Gryglewski (Editor), et al; ISBN: 1586031643; http://www.amazon.com/exec/obidos/ASIN/1586031643/icongroupinterna
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Nitric Oxide: Biochemistry, Molecular Biology, and Therapeutic Implications (Advances in Pharmacology, Vol 34) by Louis Ignarro (Editor), et al; ISBN: 0120329352; http://www.amazon.com/exec/obidos/ASIN/0120329352/icongroupinterna
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Nitric Oxide: Brain & Immune System by S. Moncada (Editor), et al; ISBN: 1855780461; http://www.amazon.com/exec/obidos/ASIN/1855780461/icongroupinterna
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Nitric Oxide: Novel Actions, Deleterious Effects, and Clinical Potential (Annals of the New York Academy of Sciences, V. 962) by Chuang C. Chiueh (Editor), et al; ISBN: 157331367X; http://www.amazon.com/exec/obidos/ASIN/157331367X/icongroupinterna
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Nitric Oxide: Roles in Neuronal Communication and Neurotoxicity (Taniguchi Symposia on Brain Sciences, No. 17) by Hiroshi Takagi, et al; ISBN: 0849377765; http://www.amazon.com/exec/obidos/ASIN/0849377765/icongroupinterna
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Nitric oxide-stimulated ADP-ribosylation by Stefanie Dimmeler; ISBN: 3861113554; http://www.amazon.com/exec/obidos/ASIN/3861113554/icongroupinterna
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Pathophysiology and Clinical Applications of Nitric Oxide (Endothelial Cell Research Series) by Gabor M. Rubanyi (Editor); ISBN: 9057024152; http://www.amazon.com/exec/obidos/ASIN/9057024152/icongroupinterna
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Pathophysiology of Blood-Brain Barrier, Brain Edema and Cell Injury Following Hyperthermia: New Role of Heat Shock Protein, Nitric Oxide and Carbon: An Experimental Study in Rat Using Light and Electron Microscopy (Comprehensive Summaries of Uppsala Dissertations, 830) by Hari Shanker Sharma; ISBN: 9155444296; http://www.amazon.com/exec/obidos/ASIN/9155444296/icongroupinterna
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Recent Advances in Nitric Oxide Research by A. Kitabatake (Editor), et al; ISBN: 443170230X; http://www.amazon.com/exec/obidos/ASIN/443170230X/icongroupinterna
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Role of Nitric Oxide in Sepsis and Ards (Update in Intensive Care and Emergency Medicine, No 24) by M. P. Fink (Editor), D. Payen (Editor); ISBN: 3540601287; http://www.amazon.com/exec/obidos/ASIN/3540601287/icongroupinterna
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Sex & Nitric Oxide: Index of New Information & Research Bible by Kristine; ISBN: 078830206X; http://www.amazon.com/exec/obidos/ASIN/078830206X/icongroupinterna
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Shock, Sepsis, and Organ Failure: Nitric Oxide by Gunther Schlag, Heinz Redl; ISBN: 0387585494; http://www.amazon.com/exec/obidos/ASIN/0387585494/icongroupinterna
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Shock, Sepsis, and Organ Failure: Scavenging of Nitric Oxide and Inhibition of Its Production by Austria)/ Redl, H. Wiggers Bernard Conference 1997 Vienna (Editor), et al; ISBN: 3540645446; http://www.amazon.com/exec/obidos/ASIN/3540645446/icongroupinterna
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Synchronized Delivery of Inspired Nitric Oxide: Effects on Oxygenation & Pulmonary Tension During Artificial Ventillation (Comprehensive Summaries of Uppsala Dissertations from the Faculty of mediciNe, 1162) by Erkki Heinonen; ISBN: 9155453376; http://www.amazon.com/exec/obidos/ASIN/9155453376/icongroupinterna
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The Biology of Nitric Oxide: Part 1 Physiological and Clinical Aspects: Proceedings of the 2nd International Meeting on the Biology of Nitric Oxide (Part 1) by M.A. Marletta, et al; ISBN: 1855780127; http://www.amazon.com/exec/obidos/ASIN/1855780127/icongroupinterna
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The Biology of Nitric Oxide: Proceedings of the 4th International Meeting on the Biology of Nitric Oxide, Amelia Island, Florida, U.S.A. (Part 5) by S. Moncada (Editor), et al; ISBN: 1855781026; http://www.amazon.com/exec/obidos/ASIN/1855781026/icongroupinterna
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The Hyperosmolar Airway: Mechanisms of Reduced Response to Nitric Oxide by Josephine Hjoberg; ISBN: 9155445888; http://www.amazon.com/exec/obidos/ASIN/9155445888/icongroupinterna
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The Role of Nitric Oxide in Heart Failure by Bodh I. Jugdutt (Editor); ISBN: 140207736X; http://www.amazon.com/exec/obidos/ASIN/140207736X/icongroupinterna
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The Role of Nitric Oxide in Physiology and Pathophysiology (Current Topics in Microbiology and Immunology, Vol 196) by H. Maeda (Editor), et al; ISBN: 0387582142; http://www.amazon.com/exec/obidos/ASIN/0387582142/icongroupinterna
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Thermospheric nitric oxide from the ATLAS 1 and Spacelab 1 missions (SuDoc NAS 1.26:200032) by NASA; ISBN: B00010RQJ2; http://www.amazon.com/exec/obidos/ASIN/B00010RQJ2/icongroupinterna
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Understanding the latitude structure of nitric oxide in the mesosphere and lower thermosphere final report (SuDoc NAS 1.26:206778) by T. J. Fuller-Rowell; ISBN: B000110ENQ; http://www.amazon.com/exec/obidos/ASIN/B000110ENQ/icongroupinterna
Chapters on Nitric Oxide In order to find chapters that specifically relate to nitric oxide, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and nitric oxide 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 “nitric oxide” (or
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synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on nitric oxide: •
Free Radicals, Nitric Oxide, and Diabetic Complications Source: in LeRoith, D.; Taylor, S.I.; Olefsky, J.M., eds. Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia, PA: Lippincott-Raven Publishers. 1996. p. 840-847. Contact: Available from Lippincott-Raven Publishers. 12107 Insurance Way, Hagerstown, MD 21740-5184. (800) 777-2295. Fax (301) 824-7390. PRICE: $199.00. ISBN: 0397514565. Summary: Increasing evidence suggests that increased oxidative stress and changes in nitric oxide (NO) formation or activity play major roles in the complications of diabetes. In this chapter, from a medical textbook on diabetes, the authors present an overview of free radical and NO pathways. The potential mechanisms underlying diabetes-induced alterations of the activity of these pathways are reviewed in the context of the relevance of these changes to the development of vascular complications of diabetes. Finally, the authors discuss the practical application of this information and future considerations for the prevention of diabetes complications. They conclude that the experimental and human evidence supports a clear role for increased oxidant stress in many of the proposed biochemical pathways linked to the microvascular and macrovascular complications of diabetes. In particular, recent evidence has underscored the role elevated glucose plays in oxidative modification of LDL by a superoxide-dependent pathway, and has demonstrated that, in people with poorly controlled IDDM, there is increased LDL oxidation associated with reduced antioxidant defenses. The particular role of NO in insulin's metabolic functions remains to be evaluated. The authors also stress that the role of nutrition should be considered as a factor related to increased oxidative stress in diabetes. 4 figures. 4 tables. 121 references.
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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,
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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. PERIODICALS AND NEWS ON NITRIC OXIDE Overview In this chapter, we suggest a number of news sources and present various periodicals that cover nitric oxide.
News Services and Press Releases One of the simplest ways of tracking press releases on nitric oxide 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 “nitric oxide” (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 nitric oxide. 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 “nitric oxide” (or synonyms). The following was recently listed in this archive for nitric oxide: •
Little benefit seen with early nitric oxide therapy for neonatal respiratory failure Source: Reuters Industry Breifing Date: March 04, 2004
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Exhaled nitric oxide a quick and accurate way to diagnose asthma Source: Reuters Medical News Date: February 25, 2004
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Elevated exhaled nitric oxide linked to increased airway responsiveness in children Source: Reuters Medical News Date: December 25, 2003
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M. tuberculosis proteasome needed for nitric oxide resistance Source: Reuters Medical News Date: December 11, 2003
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Nitric oxide may reduce lung disease and death in premature infants with RDS Source: Reuters Medical News Date: November 26, 2003
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Nitric oxide may help preemies with lung disease Source: Reuters Health eLine Date: November 26, 2003
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Steroid iontophoresis, topical nitric oxide relieve pain of epicondylitis Source: Reuters Medical News Date: July 30, 2003
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Nitric oxide synthase 3 gene polymorphism influences exhaled NO levels Source: Reuters Medical News Date: July 22, 2003
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Nitric oxide donating aspirins inhibit thrombosis and restenosis in early trials Source: Reuters Industry Breifing Date: May 26, 2003
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Inhaled nitric oxide improves pulmonary hemodynamics in severe COPD Source: Reuters Medical News Date: April 08, 2003
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Overexpression of nitric oxide gene improves survival in mice with heart failure Source: Reuters Medical News Date: March 31, 2003
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Nitric oxide therapy may relieve vaso-occlusive crisis in sickle cell disease Source: Reuters Industry Breifing Date: March 04, 2003
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Red wine increases endothelial nitric oxide synthase expression Source: Reuters Medical News Date: February 17, 2003
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NicOx cleared by FDA to start phase I study of nitric oxide product Source: Reuters Industry Breifing Date: February 05, 2003
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Nitric oxide may contribute to melanoma progression via MMP upregulation Source: Reuters Medical News Date: January 28, 2003
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NitroMed to collaborate with Merck on nitric oxide medicines Source: Reuters Industry Breifing Date: January 07, 2003
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Perhexiline normalizes platelet aggregation in response to nitric oxide in coronary patients Source: Reuters Industry Breifing Date: January 02, 2003
Periodicals and News
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Nitric oxide donor shows potential to reverse impaired healing in diabetics Source: Reuters Industry Breifing Date: December 27, 2002
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Newly identified protein influences production of nitric oxide Source: Reuters Medical News Date: November 22, 2002
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Short-acting nitric oxide donors appear safe for pregnancy-associated hypertension Source: Reuters Medical News Date: November 12, 2002
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Effects of cell-free hemoglobin on nitric oxide may explain sickle-cell pain crisis Source: Reuters Medical News Date: November 11, 2002
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Nasal nitric oxide levels significantly increase during humming Source: Reuters Medical News Date: July 26, 2002
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Mutations of nitric oxide synthase gene linked to high-altitude pulmonary edema Source: Reuters Medical News Date: July 26, 2002
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Nitrate ingestion may generate mutagenic levels of nitric oxide at GE junction Source: Reuters Medical News Date: June 05, 2002
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The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. 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 “nitric oxide” (or synonyms) into the search box, and click on “Search News.” As this service is technology
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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 “nitric oxide” (or synonyms). If you know the name of a company that is relevant to nitric oxide, 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 “nitric oxide” (or synonyms).
Newsletters on Nitric Oxide Find newsletters on nitric oxide 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 “nitric oxide.” 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 “nitric oxide” (or synonyms) into the “For these words:” box. The following list was generated using the options described above: •
Use of Low-Dose Prednisone in the Management of Rheumatoid Arthritis, The Source: Bulletin on the Rheumatic Diseases. 50(12): 1-4. 2001. Contact: Available from Arthritis Foundation. 1330 West Peachtree Street, Atlanta, GA 30309. (800) 268-6942 or (404) 872-7100. Fax (404) 872-9559. Website: www.arthritis.org. Summary: This newsletter provides health professionals with information on the use of low dose prednisone, a glucocorticoid, in the management of rheumatoid arthritis (RA). RA, a chronic, symmetric polyarthritis that can lead to joint deformity and destruction, is associated with a significant increase in economic loss, morbidity, and mortality. Glucocorticoids have been used in the treatment of RA since 1948. These 21 carbon steroid molecules activate a cytoplasmic glucocorticoid receptor that ultimately results in the prevention of gene expression of various proinflammatory proteins and the inhibition of class I and II major histocompatibility complexes, adhesion molecules, inducible nitric oxide, and cyclooxygenase 2 enzyme. The side effects of glucocorticoids are well known. However, side effects can be minimized by using low doses. Potential side effects of low dose prednisone are osteopenia, bruising, weight gain, and formation of either cataracts or glaucoma. The article reviews evidence demonstrating the effectiveness of low dose corticosteroids in managing RA and suggests appropriate dosing. The article recommends that prednisone, at a dose not to exceed 10 milligrams
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per day be initiated as early as possible in the treatment of RA, usually with another disease modifying antirheumatic drug. 1 table and 22 references.
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 “nitric oxide” (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 nitric oxide: •
Role of Nitric Oxide in Hirschsprung's Disease Source: Messenger. 8(2): 10. 1996. Contact: Available from American Pseudo-obstruction and Hirschsprung's Disease Society (APHS). 158 Pleasant Street, North Andover, MA 01845. (978) 685-4477. Fax (978) 685-4488. E-mail:
[email protected]. Summary: During the past decade, the understanding of gastrointestinal motility has been changed tremendously by the discovery of a neurotransmitter, nitric oxide (NO). This brief article explores the role of nitric oxide in Hirschsprung's disease. The authors first review the diverse roles that NO plays in human physiology; it relaxes vessels, promotes fatal hypotension in septic shock, protects against stomach ulcers (by keeping the gastric mucosal blood flow intact), and prevents atherosclerosis. Hirschsprung's disease is characterized by the lack of ganglion cells and impaired relaxation of the colon (less frequently in other parts of the gut). Researchers have investigated the effect of NO in Hirschsprung's disease. Some of the data support the idea that Hirschsprung's disease is characterized by a deficiency of NO producing nerves in the gut. The study confirms NO dependent relaxation in the human colon, so the absence of NO in the gastrointestinal smooth muscle may be responsible for the spasticity of the aganglionic segment in Hirschsprung's disease.
Academic Periodicals covering Nitric Oxide Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to nitric oxide. In addition to these sources, you can search for articles covering nitric oxide that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical
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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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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 Institute11: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
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These publications are typically written by one or more of the various NIH Institutes.
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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 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:13 •
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
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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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
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Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
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Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
12
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). 13 See http://www.nlm.nih.gov/databases/databases.html.
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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
The NLM Gateway14 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.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “nitric oxide” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total
Items Found 35307 141 395 67 167 36077
HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 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.18 Simply search by “nitric oxide” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
14
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
15
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). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18
The HSTAT URL is http://hstat.nlm.nih.gov/.
Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.
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Coffee Break: Tutorials for Biologists19 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.20 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.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
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Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
The Genome Project and Nitric Oxide In the following section, we will discuss databases and references which relate to the Genome Project and nitric oxide. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).22 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 19 Adapted 20
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 21 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. 22 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.
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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “nitric oxide” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for nitric oxide: •
Nitric Oxide Synthase 1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=163731 Genes and Disease (NCBI - Map)
The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •
Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html
•
Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html
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Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html
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Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html
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Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html
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•
Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html
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Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez
Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •
3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books
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Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome
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NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/
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Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide
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OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
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PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset
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ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein
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PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure
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Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy
To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then
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select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “nitric oxide” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database23 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database24 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “nitric oxide” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).
23
Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 24 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.
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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 nitric oxide 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 nitric oxide. 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 nitric oxide. 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 “nitric oxide”:
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Other guides Asthma http://www.nlm.nih.gov/medlineplus/asthma.html Asthma in Children http://www.nlm.nih.gov/medlineplus/asthmainchildren.html Coronary Disease http://www.nlm.nih.gov/medlineplus/coronarydisease.html Pulmonary Hypertension http://www.nlm.nih.gov/medlineplus/pulmonaryhypertension.html Sickle Cell Anemia http://www.nlm.nih.gov/medlineplus/sicklecellanemia.html
You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on nitric oxide. 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: •
Photosensitivity and Lupus Source: Washington, DC: Lupus Foundation of America. 2003. 6 p. Contact: Available from Lupus Foundation of America. 2000 L. St., Suite 710, Washington, DC 20036-4916. (202) 349-1155 or (800) 558-0121. (800) 558-0231 (information in Spanish). Fax: (202) 349-1156. Website: www.lupus.org. Summary: This brochure discusses photosensitivity, a major feature in systemic lupus erythematosus (SLE) (a form of lupus that may affect any organ or system of the body) and cutaneous lupus (a form of lupus that is mainly limited to the skin). Sunlight is associated with the development of new skin lesions and flares of internal disease including joint pain and fatigue. Patients who are prescribed photosensitizing antibiotics may also develop phototoxic reactions such as sunburning. Both UVA and UVB rays cause photosensitivity in lupus. Inflammation and skin redness in individuals with lupus are thought to be caused by a higher occurrence of apoptosis (programmed death of skin cells) than in individuals without lupus. Apoptosis promotes the development of inflammation, and too much nitric oxide (an inflammation-promoting substance) made in the skin of individuals with lupus causes further redness and inflammation. A 'butterfly rash' on the face and rash on the back, chest, and arms may occur after sun
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exposure. Individuals can protect themselves from the harmful effects of ultraviolet light by avoiding tropical and midday sunlight. If avoidance is not possible, individuals should wear broad-brimmed hats and tightly-woven clothing and use sunblocks or sunscreens. Fluorescent lights and photocopiers also emit UV light and precautions for their use is described. The National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “nitric oxide” (or synonyms). The following was recently posted: •
Allergic rhinitis and its impact on asthma Source: Allergic Rhinitis and its Impact on Asthma Workshop Group - Independent Expert Panel; 2001 November; 188 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3421&nbr=2647&a mp;string=nitric+AND+oxide
•
Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock Source: American College of Critical Care Medicine - Professional Association; 2002 June; 14 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3433&nbr=2659&a mp;string=nitric+AND+oxide
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Global initiative for asthma. Global strategy for asthma management and prevention Source: National Heart, Lung, and Blood Institute (U.S.) - Federal Government Agency [U.S.]; 1995 January (revised 2002); 176 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3203&nbr=2429&a mp;string=nitric+AND+oxide
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Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease Source: National Heart, Lung, and Blood Institute (U.S.) - Federal Government Agency [U.S.]; 2001; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=2779&nbr=2005&a mp;string=nitric+AND+oxide
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Guidelines on diagnosis and management of acute pulmonary embolism Source: European Society of Cardiology - Medical Specialty Society; 2000 August; 36 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2592&nbr=1818&a mp;string=nitric+AND+oxide
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Management of preterm labour Source: Chapter of Obstetricians and Gynaecologists, Academy of Medicine (Singapore) - Medical Specialty Society; 2001 May; 28 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2889&nbr=2115&a mp;string=nitric+AND+oxide
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Use of inhaled nitric oxide Source: American Academy of Pediatrics - Medical Specialty Society; 2000 August; 2 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2598&nbr=1824&a mp;string=nitric+AND+oxide 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 nitric oxide. 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
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
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WebMDHealth: http://my.webmd.com/health_topics
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to nitric oxide. By consulting all of associations listed in
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this chapter, you will have nearly exhausted all sources for patient associations concerned with nitric oxide. 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 nitric oxide. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “nitric oxide” (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 “nitric oxide”. 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 “nitric oxide” (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 “nitric oxide” (or a synonym) into the search box, and click “Submit Query.”
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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.25
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
25
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)26: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
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California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
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California: Gateway Health Library (Sutter Gould Medical Foundation)
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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
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Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
26
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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•
Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
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Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm
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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp
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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm
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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
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MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
•
Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
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Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
•
MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
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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
299
NITRIC OXIDE DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine: A dopaminergic neurotoxic compound which produces irreversible clinical, chemical, and pathological alterations that mimic those found in Parkinson disease. [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 Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Ablation: The removal of an organ by surgery. [NIH] Abrasion: 1. The wearing away of a substance or structure (such as the skin or the teeth) through some unusual or abnormal mechanical process. 2. An area of body surface denuded of skin or mucous membrane by some unusual or abnormal mechanical process. [EU] Abscisic Acid: Abscission-accelerating plant growth substance isolated from young cotton fruit, leaves of sycamore, birch, and other plants, and from potatoes, lemons, avocados, and other fruits. [NIH] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] 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] Acid Rain: Acidic water usually pH 2.5 to 4.5, which poisons the ecosystem and adversely affects plants, fishes, and mammals. It is caused by industrial pollutants, mainly sulfur oxides and nitrogen oxides, emitted into the atmosphere and returning to earth in the form of acidic rain water. [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] Acrosome: Cap-like structure covering the nucleus and anterior part of the sperm head. [NIH]
Acrosome Reaction: Changes that occur to liberate the enzymes of the acrosome of spermatozoa that allow the entry of a spermatozoon into the ovum. [NIH]
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Acrylonitrile: A highly poisonous compound used widely in the manufacture of plastics, adhesives and synthetic rubber. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acupuncture Points: Designated locations along nerves or organ meridians for inserting acupuncture needles. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [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] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] 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 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] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH] Adhesives: Substances that cause the adherence of two surfaces. They include glues (properly collagen-derived adhesives), mucilages, sticky pastes, gums, resins, or latex. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [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] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH]
Dictionary 301
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 Agonists: Drugs that bind to and activate adrenergic receptors. [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 Metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, oxidative metabolism, or cell respiration. [NIH] Aerobic Respiration: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as oxidative metabolism, cell respiration, or aerobic metabolism. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]
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] Affinity Chromatography: In affinity chromatography, a ligand attached to a column binds specifically to the molecule to be purified. [NIH] Afterload: The tension produced by the heart muscle after contraction. [EU] Agarose: A polysaccharide complex, free of nitrogen and prepared from agar-agar which is produced by certain seaweeds (red algae). It dissolves in warm water to form a viscid solution. [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] 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] Air Sacs: Thin-walled sacs or spaces which function as a part of the respiratory system in birds, fishes, insects, and mammals. [NIH] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions
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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] Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Aldose Reductase Inhibitor: A class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes. Aldose reductase is an enzyme that is normally present in the eye and in many other parts of the body. It helps change glucose (sugar) into a sugar alcohol called sorbitol. Too much sorbitol trapped in eye and nerve cells can damage these cells, leading to retinopathy and neuropathy. Drugs that prevent or slow (inhibit) the action of aldose reductase are being studied as a way to prevent or delay these complications of diabetes. [NIH] 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] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Allopurinol: A xanthine oxidase inhibitor that decreases uric acid production. [NIH] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial fibrosis or cardiac decompensation. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha 1-Antitrypsin: Plasma glycoprotein member of the serpin superfamily which inhibits trypsin, neutrophil elastase, and other proteolytic enzymes. Commonly referred to as alpha 1-proteinase inhibitor (A1PI), it exists in over 30 different biochemical variant forms known collectively as the PI (protease inhibitor) system. Hereditary A1PI deficiency is associated with pulmonary emphysema. [NIH] Alpha 1-Antitrypsin Deficiency: A disease caused by single gene defects. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-Defensins: Defensins found in azurophilic granules of neutrophils and in the secretory granules of intestinal paneth cells. [NIH]
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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] Alum: A type of immune adjuvant (a substance used to help boost the immune response to a vaccine). Also called aluminum sulfate. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Amebiasis: Infection with any of various amebae. It is an asymptomatic carrier state in most individuals, but diseases ranging from chronic, mild diarrhea to fulminant dysentery may occur. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino 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] Aminolevulinic Acid: A compound produced from succinyl-CoA and glycine as an intermediate in heme synthesis. [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] Ammonium Sulfate: Sulfuric acid diammonium salt. It is used in fractionation of proteins. [NIH]
Amphetamines: Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopression, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular
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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] 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] Anaesthetic: 1. Pertaining to, characterized by, or producing anaesthesia. 2. A drug or agent that is used to abolish the sensation of pain. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Anal Fissure: A small tear in the anus that may cause itching, pain, or bleeding. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] 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]
Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anastomosis: A procedure to connect healthy sections of tubular structures in the body after the diseased portion has been surgically removed. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] 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] 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
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the coronary circulation to supply it. [NIH] Anginal: Pertaining to or characteristic of angina. [EU] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [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] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]
Anode: Electrode held at a positive potential with respect to a cathode. [NIH] Anorectal: Pertaining to the anus and rectum or to the junction region between the two. [EU] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Anthracycline: A member of a family of anticancer drugs that are also antibiotics. [NIH] Anthraquinones: An anthracene ring which contains two ketone moieties in any position. Can be substituted in any position except on the ketone groups. [NIH] Antiallergic: Counteracting allergy or allergic conditions. [EU] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [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] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood
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thinner. [NIH] Antidepressant: A drug used to treat depression. [NIH] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [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] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-infective: An agent that so acts. [EU] Anti-Infective Agents: Substances that prevent infectious agents or organisms from spreading or kill infectious agents in order to prevent the spread of infection. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] 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] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]
Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antithrombotic: Preventing or interfering with the formation of thrombi; an agent that so acts. [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] Apheresis: Components plateletpheresis. [NIH]
being
separated
out,
as
leukapheresis,
plasmapheresis,
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]
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Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aqueous: Having to do with water. [NIH] Arachidonate 12-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 12-hydroperoxyarachidonate (12-HPETE) which is itself rapidly converted by a peroxidase to 12-hydroxy-5,8,10,14-eicosatetraenoate (12-HETE). The 12-hydroperoxides are preferentially formed in platelets. EC 1.13.11.31. [NIH] Arachidonate 15-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 15-hydroperoxyarachidonate (15-HPETE) which is rapidly converted to 15-hydroxy5,8,11,13-eicosatetraenoate (15-HETE). The 15-hydroperoxides are preferentially formed in neutrophils and lymphocytes. EC 1.13.11.33. [NIH] Arachidonate Lipoxygenases: Enzymes catalyzing the oxidation of arachidonic acid to hydroperoxyarachidonates (HPETES). These products are then rapidly converted by a peroxidase to hydroxyeicosatetraenoic acids (HETES). The positional specificity of the enzyme reaction varies from tissue to tissue. The final lipoxygenase pathway leads to the leukotrienes. EC 1.13.11.- . [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginase: A ureahydrolase that catalyzes the hydrolysis of arginine or canavanine to yield L-ORNITHINE and urea. Deficiency of this enzyme causes hyperargininemia. EC 3.5.3.1. [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] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] 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] Arteriosus: Circle composed of anastomosing arteries derived from two long posterior ciliary and seven anterior ciliary arteries, located in the ciliary body about the root of the iris.
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[NIH]
Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Arteriovenous Fistula: An abnormal communication between an artery and a vein. [NIH] Arthropathy: Any joint disease. [EU] Articular: Of or pertaining to a joint. [EU] Artificial Eye: Usually made of artificial plastic material or glass to which small quantities of metallic oxides have been added in order to imitate the features and coloring of the various parts of t he human eye; a prosthesis made of glass, plastic, or similar material. [NIH] Artificial Limbs: Prosthetic replacements for arms, legs, and parts therof. [NIH] Artificial Organs: Devices intended to replace non-functioning organs. They may be temporary or permanent. Since they are intended always to function as the natural organs they are replacing, they should be differentiated from prostheses and implants and specific types of prostheses which, though also replacements for body parts, are frequently cosmetic (artificial eye) as well as functional (artificial limbs). [NIH] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [NIH] Ascitic Fluid: The serous fluid which accumulates in the peritoneal cavity in ascites. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspartate: A synthetic amino acid. [NIH] Asphyxia: A pathological condition caused by lack of oxygen, manifested in impending or actual cessation of life. [NIH] Aspirate: Fluid withdrawn from a lump, often a cyst, or a nipple. [NIH] Aspiration: The act of inhaling. [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] Astigmatism: A condition in which the surface of the cornea is not spherical; causes a blurred image to be received at the retina. [NIH] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures.
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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] Atmospheric Pressure: The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. [NIH] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] Atrial: Pertaining to an atrium. [EU] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [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] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]
Axillary Artery: The continuation of the subclavian artery; it distributes over the upper limb, axilla, chest and shoulder. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Back Pain: Acute or chronic pain located in the posterior regions of the trunk, including the thoracic, lumbar, sacral, or adjacent regions. [NIH] Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [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 Infections: Infections by bacteria, general or unspecified. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacterial Translocation: The passage of viable bacteria from the gastrointestinal tract to extra-intestinal sites, such as the mesenteric lymph node complex, liver, spleen, kidney, and blood. Factors that promote bacterial translocation include overgrowth with gram-negative enteric bacilli, impaired host immune defenses, and injury to the intestinal mucosa resulting in increased intestinal permeability. These mechanisms can act in concert to promote synergistically the systemic spread of indigenous translocating bacteria to cause lethal sepsis. [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] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [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] Basilar Artery: The artery formed by the union of the right and left vertebral arteries; it runs from the lower to the upper border of the pons, where it bifurcates into the two posterior cerebral arteries. [NIH] Basophil: A type of white blood cell. Basophils are granulocytes. [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 Rays: A stream of positive or negative electrons ejected with high energy from a
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disintegrating atomic nucleus; most biomedically used isotopes emit negative particles (electrons or negatrons, rather than positrons). Cathode rays are low-energy negative electrons produced in cathode ray tubes, also called television tubes or oscilloscopes. [NIH] Beta-Defensins: Defensins found mainly in epithelial cells. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Beta-Thromboglobulin: A platelet-specific protein which is released when platelets aggregate. Elevated plasma levels have been reported after deep venous thrombosis, preeclampsia, myocardial infarction with mural thrombosis, and myeloproliferative disorders. Measurement of beta-thromboglobulin in biological fluids by radioimmunoassay is used for the diagnosis and assessment of progress of thromboembolic disorders. [NIH] Bethanechol: A slowly hydrolyzed muscarinic agonist with no nicotinic effects. Bethanechol is generally used to increase smooth muscle tone, as in the GI tract following abdominal surgery or in urinary retention in the absence of obstruction. It may cause hypotension, cardiac rate changes, and bronchial spasms. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile Ducts: Tubes that carry bile from the liver to the gallbladder for storage and to the small intestine for use in digestion. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biochemical Phenomena: Biochemical functions, activities, and processes at organic and molecular levels in humans, animals, microorganisms, and plants. [NIH] Biochemical reactions: In living cells, chemical reactions that help sustain life and allow cells to grow. [NIH]
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Biological Phenomena: Biological functions and activities at the organic and molecular levels in humans, animals, microorganisms, and plants. For biochemical and metabolic processes, biochemical phenomena is available. [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] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopterin: A natural product that has been considered as a growth factor for some insects. [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] Biphasic: Having two phases; having both a sporophytic and a gametophytic phase in the life cycle. [EU] 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] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Coagulation Factors: Endogenous substances, usually proteins, that are involved in the blood coagulation process. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelet Disorders: Disorders caused by abnormalities in platelet count or function. [NIH]
Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber.
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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 Substitutes: Substances that can carry oxygen to and carbon dioxide away from the tissues when introduced into the blood stream. They are used to replace hemoglobin in severe hemorrhage and also to perfuse isolated organs. The best known are perfluorocarbon emulsions and various hemoglobin solutions. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blotting and transferred to strips of nitrocellulose paper. The blots are then detected by radiolabeled antibody probes. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bone Development: Gross development of bones from fetus to adult. It includes osteogenesis, which is restricted to formation and development of bone from the undifferentiated cells of the germ layers of the embryo. It does not include osseointegration. [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 Resorption: Bone loss due to osteoclastic activity. [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] Boronic Acids: Inorganic or organic compounds that contain the basic structure RB(OH)2. [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]
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Brachial Artery: The continuation of the axillary artery; it branches into the radial and ulnar arteries. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Ischemia: Localized reduction of blood flow to brain tissue due to arterial obtruction or systemic hypoperfusion. This frequently occurs in conjuction with brain hypoxia. Prolonged ischemia is associated with brain infarction. [NIH] Brain Neoplasms: Neoplasms of the intracranial components of the central nervous system, including the cerebral hemispheres, basal ganglia, hypothalamus, thalamus, brain stem, and cerebellum. Brain neoplasms are subdivided into primary (originating from brain tissue) and secondary (i.e., metastatic) forms. Primary neoplasms are subdivided into benign and malignant forms. In general, brain tumors may also be classified by age of onset, histologic type, or presenting location in the brain. [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] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchial Provocation Tests: Tests involving inhalation of allergens (nebulized or in dust form), nebulized pharmacologically active solutions (e.g., histamine, methacholine), or control solutions, followed by assessment of respiratory function. These tests are used in the diagnosis of asthma. [NIH] Bronchial Spasm: Spasmodic contraction of the smooth muscle of the bronchi. [NIH] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchiseptica: A small, gram-negative, motile bacillus. A normal inhabitant of the respiratory tract in man, dogs, and pigs, but is also associated with canine infectious tracheobronchitis and atrophic rhinitis in pigs. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchoconstriction: Diminution of the caliber of a bronchus physiologically or as a result of pharmacological intervention. [NIH] Bronchodilatation: A dilated state of a bronchus or the site at which a bronchus is dilated. [EU]
Bronchodilator: A drug that relaxes the smooth muscles in the constricted airway. [NIH] Bronchopulmonary: Pertaining to the lungs and their air passages; both bronchial and pulmonary. [EU] Bronchopulmonary Dysplasia: A chronic lung disease appearing in certain newborn infants
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treated for respiratory distress syndrome with mechanical ventilation and elevated concentration of inspired oxygen. [NIH] Bronchoscopy: Endoscopic examination, therapy or surgery of the bronchi. [NIH] Bronchus: A large air passage that leads from the trachea (windpipe) to the lung. [NIH] Brucellosis: Infection caused by bacteria of the genus Brucella mainly involving the reticuloendothelial system. This condition is characterized by fever, weakness, malaise, and weight loss. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Budesonide: A glucocorticoid used in the management of asthma, the treatment of various skin disorders, and allergic rhinitis. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cadaver: A dead body, usually a human body. [NIH] Calcitonin Gene-Related Peptide: Calcitonin gene-related peptide. A 37-amino acid peptide derived from the calcitonin gene. It occurs as a result of alternative processing of mRNA from the calcitonin gene. The neuropeptide is widely distributed in neural tissue of the brain, gut, perivascular nerves, and other tissue. The peptide produces multiple biological effects and has both circulatory and neurotransmitter modes of action. In particular, it is a potent endogenous vasodilator. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium channel blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools. Since they are inducers of vascular and other smooth muscle relaxation, they are used in the drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms. [NIH] Calcium Signaling: Signal transduction mechanisms whereby calcium mobilization (from outside the cell or from intracellular storage pools) to the cytoplasm is triggered by external stimuli. Calcium signals are often seen to propagate as waves, oscillations, spikes or puffs. The calcium acts as an intracellular messenger by activating calcium-responsive proteins. [NIH]
Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Calpain: Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including neuropeptides, cytoskeletal proteins, proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. [NIH]
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Cannula: A tube for insertion into a duct or cavity; during insertion its lumen is usually occupied by a trocar. [EU] 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 Permeability: Property of blood capillary walls that allows for the selective exchange of substances. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (tight junctions) which may limit large molecule movement. [NIH] Capsaicin: Cytotoxic alkaloid from various species of Capsicum (pepper, paprika), of the Solanaceae. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carbon Monoxide Poisoning: Toxic asphyxiation due to the displacement of oxygen from oxyhemoglobin by carbon monoxide. [NIH] Carboxypeptidases: Enzymes that act at a free C-terminus of a polypeptide to liberate a single amino acid residue. They are further divided based on their catalytic mechanism into serine-type carboxypeptidases EC 3.4.16; metallocarboxypeptidases, EC 3.4.17; and cysteinetype carboxypeptidases, EC 3.4.18. EC 3.4.-. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] 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] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiology: The study of the heart, its physiology, and its functions. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiopulmonary Bypass: Diversion of the flow of blood from the entrance of the right atrium directly to the aorta (or femoral artery) via an oxygenator thus bypassing both the heart and lungs. [NIH] Cardiotonic: 1. Having a tonic effect on the heart. 2. An agent that has a tonic effect on the heart. [EU]
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Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carotid Arteries: Either of the two principal arteries on both sides of the neck that supply blood to the head and neck; each divides into two branches, the internal carotid artery and the external carotid artery. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] 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] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cassia: Leguminous plants Cassia senna L. (or C. acutifolia) and C. angustifolia that contain anthraquinones which are used as laxatives. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catfish: Common name to express the order Siluriformes. This order contains many families and over 2,000 species, including venomous species. Heteropneustes and Plotosus genera have dangerous stings and are aggressive. Most species are passive stingers. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH]
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Cathode: An electrode, usually an incandescent filament of tungsten, which emits electrons in an X-ray tube. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Cauda Equina: The lower part of the spinal cord consisting of the lumbar, sacral, and coccygeal nerve roots. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] 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 Communication: Any of several ways in which living cells of an organism communicate with one another, whether by direct contact between cells or by means of chemical signals carried by neurotransmitter substances, hormones, and cyclic AMP. [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 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 proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Cellobiose: A disaccharide consisting of two glucose units in beta (1-4) glycosidic linkage. Obtained from the partial hydrolysis of cellulose. [NIH] Cellular metabolism: The sum of all chemical changes that take place in a cell through which energy and basic components are provided for essential processes, including the synthesis of new molecules and the breakdown and removal of others. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief
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constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] 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] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Aqueduct: Narrow channel in the mesencephalon that connects the third and fourth ventricles. [NIH] Cerebral Arteries: The arteries supplying the cerebral cortex. [NIH] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] 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]
Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrovascular Circulation: The circulation of blood through the vessels of the brain. [NIH] Cerebrovascular Disorders: A broad category of disorders characterized by impairment of blood flow in the arteries and veins which supply the brain. These include cerebral infarction; brain ischemia; hypoxia, brain; intracranial embolism and thrombosis; intracranial arteriovenous malformations; and vasculitis, central nervous system. In common usage, the term cerebrovascular disorders is not limited to conditions that affect the cerebrum, but refers to vascular disorders of the entire brain including the diencephalon; brain stem; and cerebellum. [NIH] 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
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controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervical Ripening: A change in the cervix with respect to its readiness to relax. The cervix becomes softer, more flexible, more distensible, and shorter in the final weeks of pregnancy. Though naturally occurring during normal pregnancy, it can also be induced for certain cases of prolonged or high-risk pregnancy by administration of hormones. [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] Chemical Warfare: Tactical warfare using incendiary mixtures, smokes, or irritant, burning, or asphyxiating gases. [NIH] Chemical Warfare Agents: Chemicals that are used to cause the disturbance, disease, or death of humans during war. [NIH] Chemoprevention: The use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the development or recurrence of, cancer. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chest Pain: Pressure, burning, or numbness in the chest. [NIH] Chiropractic: A system of treating bodily disorders by manipulation of the spine and other parts, based on the belief that the cause is the abnormal functioning of a nerve. [NIH] Chlorine: A greenish-yellow, diatomic gas that is a member of the halogen family of elements. It has the atomic symbol Cl, atomic number 17, and atomic weight 70.906. It is a powerful irritant that can cause fatal pulmonary edema. Chlorine is used in manufacturing, as a reagent in synthetic chemistry, for water purification, and in the production of chlorinated lime, which is used in fabric bleaching. [NIH] Cholelithiasis: Presence or formation of gallstones. [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] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] 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]
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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 lymphocytic leukemia: A slowly progressing disease in which too many white blood cells (called lymphocytes) are found in the body. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [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] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] Citrus: Any tree or shrub of the Rue family or the fruit of these plants. [NIH] C-kit receptor: A protein on the surface of some cells that binds to stem cell factor (a substance that causes certain types of cells to grow). Altered forms of this receptor may be associated with some types of cancer. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Claudication: Limping or lameness. [EU] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] 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] 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
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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] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] Cochlea: The part of the internal ear that is concerned with hearing. It forms the anterior part of the labyrinth, is conical, and is placed almost horizontally anterior to the vestibule. [NIH]
Codeine: An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. [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] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] 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] Colloids: Two-phase systems in which one is uniformly dispersed in another as particles small enough so they cannot be filtered or will not settle out. The dispersing or continuous phase or medium envelops the particles of the discontinuous phase. All three states of matter can form colloids among each other. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colostomy: An opening into the colon from the outside of the body. A colostomy provides a new path for waste material to leave the body after part of the colon has been removed. [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH]
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Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] 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]
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Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Cone: One of the special retinal receptor elements which are presumed to be primarily concerned with perception of light and color stimuli when the eye is adapted to light. [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] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] 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] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Contractility: Capacity for becoming short in response to a suitable stimulus. [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] Contralateral: Having to do with the opposite side of the body. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]
Conus: A large, circular, white patch around the optic disk due to the exposing of the sclera as a result of degenerative change or congenital abnormality in the choroid and retina. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a
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single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Cor pulmonale: Heart disease that results from resistance to the passage of blood through the lungs; it often leads to right heart failure. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneal Transplantation: Partial or total replacement of the cornea from one human or animal to another. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] 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] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] 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]
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Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Critical Care: Health care provided to a critically ill patient during a medical emergency or crisis. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cross-Linking Reagents: Reagents with two reactive groups, usually at opposite ends of the molecule, that are capable of reacting with and thereby forming bridges between side chains of amino acids in proteins; the locations of naturally reactive areas within proteins can thereby be identified; may also be used for other macromolecules, like glycoproteins, nucleic acids, or other. [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] Cryptosporidiosis: Parasitic intestinal infection with severe diarrhea caused by a protozoan, Cryptosporidium. It occurs in both animals and humans. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Curcumin: A dye obtained from tumeric, the powdered root of Curcuma longa Linn. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. [NIH] Cutaneous: Having to do with the skin. [NIH] Cyanide: An extremely toxic class of compounds that can be lethal on inhaling of ingesting in minute quantities. [NIH] Cyanosis: A bluish or purplish discoloration of the skin and mucous membranes due to an increase in the amount of deoxygenated hemoglobin in the blood or a structural defect in the hemoglobin molecule. [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 A: A 33-kD protein identical to adenovirus E1A-associated protein p60. Cyclin A regulates p33cdk2 and p34cdc2, and is necessary for progression through the S phase of the cell cycle. [NIH] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active
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aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyclosporins: A group of closely related cyclic undecapeptides from the fungi Trichoderma polysporum and Cylindocarpon lucidum. They have some antineoplastic and antifungal action and significant immunosuppressive effects. Cyclosporins have been proposed as adjuvants in tissue and organ transplantation to suppress graft rejection. [NIH] Cyproterone: An anti-androgen that, in the form of its acetate, also has progestational properties. It is used in the treatment of hypersexuality in males, as a palliative in prostatic carcinoma, and, in combination with estrogen, for the therapy of severe acne and hirsutism in females. [NIH] Cyst: A sac or capsule filled with fluid. [NIH] Cystathionine beta-Synthase: A multifunctional pyridoxal phosphate enzyme. In the second stage of cysteine biosynthesis it catalyzes the reaction of homocysteine with serine to form cystathionine with the elimination of water. Deficiency of this enzyme leads to hyperhomocysteinemia and homocystinuria. EC 4.2.1.22. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]
Cystitis: Inflammation of the urinary bladder. [EU] 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] Cytochrome b: Cytochromes (electron-transporting proteins) with protoheme or a related heme as the prosthetic group. The prosthetic group is not covalently bound to the protein moiety. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] 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] Cytostatic: An agent that suppresses cell growth and multiplication. [EU]
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Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Cytotoxins: Substances elaborated by microorganisms, plants or animals that are specifically toxic to individual cells; they may be involved in immunity or may be contained in venoms. [NIH]
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] 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] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Decongestant: An agent that reduces congestion or swelling. [EU] Decontamination: The removal of contaminating material, such as radioactive materials, biological materials, or chemical warfare agents, from a person or object. [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] Defensins: Family of antimicrobial peptides that have been identified in humans, animals, and plants. They are thought to play a role in host defenses against infections, inflammation, wound repair, and acquired immunity. Based on the disulfide pairing of their characteristic six cysteine residues, they are divided into alpha-defensins and beta-defensins. [NIH] Deferoxamine: Natural product isolated from Streptomyces pilosus. It forms iron complexes and is used as a chelating agent, particularly in the form of its mesylate. [NIH] Defibrillation: The act to arrest the fibrillation of (heart muscle) by applying electric shock across the chest, thus depolarizing the heart cells and allowing normal rhythm to return. [EU] 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]
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Delusions: A false belief regarding the self or persons or objects outside the self that persists despite the facts, and is not considered tenable by one's associates. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [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] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermal: Pertaining to or coming from the skin. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detoxification: Treatment designed to free an addict from his drug habit. [EU] 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] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [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 Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU]
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Diastolic blood pressure: The minimum pressure that remains within the artery when the heart is at rest. [NIH] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Dietitian: An expert in nutrition who helps people plan what and how much food to eat. [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] Dilate: Relax; expand. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [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] Dilator: A device used to stretch or enlarge an opening. [NIH] Diltiazem: A benzothiazepine derivative with vasodilating action due to its antagonism of the actions of the calcium ion in membrane functions. It is also teratogenic. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Diploid: Having two sets of chromosomes. [NIH] Dipyridamole: A drug that prevents blood cell clumping and enhances the effectiveness of fluorouracil and other chemotherapeutic agents. [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] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate
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objects. [EU] Disposition: A tendency either physical or mental toward certain diseases. [EU] 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] DNA Polymerase beta: A DNA repair enzyme that catalyzes DNA synthesis during base excision DNA repair. EC 2.7.7.7. [NIH] DNA Topoisomerase: An enzyme catalyzing ATP-independent breakage of single-stranded DNA, followed by passage and rejoining of another single-stranded DNA. This enzyme class brings about the conversion of one topological isomer of DNA into another, e.g., the relaxation of superhelical turns in DNA, the interconversion of simple and knotted rings of single-stranded DNA, and the intertwisting of single-stranded rings of complementary sequences. (From Enzyme Nomenclature, 1992) EC 5.99.1.2. [NIH] Dobutamine: A beta-2 agonist catecholamine that has cardiac stimulant action without evoking vasoconstriction or tachycardia. It is proposed as a cardiotonic after myocardial infarction or open heart surgery. [NIH] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] 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] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Delivery Systems: Systems of administering drugs through controlled delivery so that an optimum amount reaches the target site. Drug delivery systems encompass the carrier, route, and target. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity
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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] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] 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] Dynamometer: An instrument for measuring the force of muscular contraction. [NIH] 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] Dyspepsia: Impaired digestion, especially after eating. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]
Ecosystem: A dynamic complex of plant, animal and micro-organism communities and their non-living environment interacting as a functional unit. [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] 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] Electric shock: A dangerous patho-physiological effect resulting from an electric current passing through the body of a human or animal. [NIH]
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Electroacupuncture: A form of acupuncture using low frequency electrically stimulated needles to produce analgesia and anesthesia and to treat disease. [NIH] Electrocardiogram: Measurement of electrical activity during heartbeats. [NIH] Electrochemistry: The study of chemical changes resulting from electrical action and electrical activity resulting from chemical changes. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [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] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Emesis: Vomiting; an act of vomiting. Also used as a word termination, as in haematemesis. [EU]
Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Emulsions: Colloids of two immiscible liquids where either phase may be either fatty or aqueous; lipid-in-water emulsions are usually liquid, like milk or lotion and water-in-lipid emulsions tend to be creams. [NIH] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]
Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of
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this condition. [NIH] Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord, often used to indicate an infectious process, but also applicable to a variety of autoimmune and toxic-metabolic conditions. There is significant overlap regarding the usage of this term and encephalitis in the literature. [NIH] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [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] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]
Endometriosis: A condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. [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] Endotoxemia: A condition characterized by the presence of endotoxins in the blood. If endotoxemia is the result of gram-negative rod-shaped bacteria, shock may occur. [NIH] 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] Enteric Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Enteritis: Inflammation of the intestine, applied chiefly to inflammation of the small intestine; see also enterocolitis. [EU] Enterocolitis: Inflammation of the intestinal mucosa of the small and large bowel. [NIH]
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Enterocytes: Terminally differentiated cells comprising the majority of the external surface of the intestinal epithelium (see intestinal mucosa). Unlike goblet cells, they do not produce or secrete mucins, nor do they secrete cryptdins as do the paneth cells. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [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] 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] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Eosinophilic: A condition found primarily in grinding workers caused by a reaction of the pulmonary tissue, in particular the eosinophilic cells, to dust that has entered the lung. [NIH] Epicondylitis: Inflammation of the epicondyle or of the tissues adjoining the epicondyle of the humerus. [EU] 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] 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] Epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epoprostenol: A prostaglandin that is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. It is a potent inhibitor of platelet aggregation. The sodium salt has been also used to treat primary pulmonary hypertension. [NIH] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also
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called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [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. [NIH]
Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]
Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethidium: A trypanocidal agent and possible antiviral agent that is widely used in experimental cell biology and biochemistry. Ethidium has several experimentally useful properties including binding to nucleic acids, noncompetitive inhibition of nicotinic acetylcholine receptors, and fluorescence among others. It is most commonly used as the bromide. [NIH] Etodolac: A nonsteroidal anti-inflammatory agent with potent analgesic and antiarthritic properties. It has been shown to be effective in the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and in the alleviation of postoperative pain. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excipients: Usually inert substances added to a prescription in order to provide suitable consistency to the dosage form; a binder, matrix, base or diluent in pills, tablets, creams, salves, etc. [NIH]
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Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excitotoxicity: Excessive exposure to glutamate or related compounds can kill brain neurons, presumably by overstimulating them. [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 Tolerance: The exercise capacity of an individual as measured by endurance (maximal exercise duration and/or maximal attained work load) during an exercise test. [NIH]
Exhaustion: The feeling of weariness of mind and body. [NIH] Exocytosis: Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exotoxin: Toxic substance excreted by living bacterial cells. [NIH] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Expiratory: The volume of air which leaves the breathing organs in each expiration. [NIH] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extracorporeal: Situated or occurring outside the body. [EU] Extracorporeal Circulation: Diversion of blood flow through a circuit located outside the body but continuous with the bodily circulation. [NIH] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. [EU]
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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] Facial: Of or pertaining to the face. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fascioliasis: Helminth infection of the liver caused by species of Fasciola. [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] 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] Felodipine: A dihydropyridine calcium antagonist with positive inotropic effects. It lowers blood pressure by reducing peripheral vascular resistance through a highly selective action on smooth muscle in arteriolar resistance vessels. [NIH] 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] Femoral Vein: The vein accompanying the femoral artery in the same sheath; it is a continuation of the popliteal vein and becomes the external iliac vein. [NIH] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fertilizers: Substances or mixtures that are added to the soil to supply nutrients or to make available nutrients already present in the soil, in order to increase plant growth and productivity. [NIH] Fetal Hemoglobin: The major component of hemoglobin in the fetus. This hemoglobin has two alpha and two gamma polypeptide subunits in comparison to normal adult hemoglobin, which has two alpha and two beta polypeptide subunits. Fetal hemoglobin concentrations can be elevated (usually above 0.5%) in children and adults affected by leukemia and several types of anemia. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrillation: A small, local, involuntary contraction of muscle, invisible under the skin, resulting from spontaneous activation of single muscle cells or muscle fibres. [EU] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of
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other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filler: An inactive substance used to make a product bigger or easier to handle. For example, fillers are often used to make pills or capsules because the amount of active drug is too small to be handled conveniently. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Finasteride: An orally active testosterone 5-alpha-reductase inhibitor. It is used as a surgical alternative for treatment of benign prostatic hyperplasia. [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] Flatus: Gas passed through the rectum. [NIH] Flavoring Agents: Substances added to foods and medicine to improve the quality of taste. [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] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Fluoxetine: The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants. [NIH] Flurbiprofen: An anti-inflammatory analgesic and antipyretic of the phenylalkynoic acid series. It has been shown to reduce bone resorption in periodontal disease by inhibiting carbonic anhydrase. [NIH] Flushing: A transient reddening of the face that may be due to fever, certain drugs, exertion, stress, or a disease process. [NIH] Flutamide: An antiandrogen with about the same potency as cyproterone in rodent and canine species. [NIH] Foam Cells: Lipid-laden macrophages originating from monocytes or from smooth muscle cells. [NIH] Focal Adhesions: An anchoring junction of the cell to a non-cellular substrate. It is composed of a specialized area of the plasma membrane where bundles of microfilaments
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terminate and attach to the transmembrane linkers, integrins, which in turn attach through their extracellular domains to extracellular matrix proteins. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Food Additives: Substances which are of little or no nutritive value, but are used in the processing or storage of foods or animal feed, especially in the developed countries; includes antioxidants, food preservatives, food coloring agents, flavoring agents, anti-infective agents (both plain and local), vehicles, excipients and other similarly used substances. Many of the same substances are pharmaceutic aids when added to pharmaceuticals rather than to foods. [NIH]
Food Coloring Agents: Natural or synthetic dyes used as coloring agents in processed foods. [NIH] Food Preservatives: Substances capable of inhibiting, retarding or arresting the process of fermentation, acidification or other deterioration of foods. [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] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Functional Residual Capacity: The volume of air remaining in the lungs at the end of a normal, quiet expiration. It is the sum of the residual volume and the expiratory reserve volume. Common abbreviation is FRC. [NIH] Fungemia: The presence of fungi circulating in the blood. Opportunistic fungal sepsis is seen most often in immunosuppressed patients with severe neutropenia or in postoperative patients with intravenous catheters and usually follows prolonged antibiotic therapy. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites,
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including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungicide: An agent that destroys fungi. [EU] Gallate: Antioxidant present in tea. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] 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 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] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [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 Acid: Hydrochloric acid present in gastric juice. [NIH] Gastric Mucosa: Surface epithelium in the stomach that invaginates into the lamina propria, forming gastric pits. Tubular glands, characteristic of each region of the stomach (cardiac, gastric, and pyloric), empty into the gastric pits. The gastric mucosa is made up of several different kinds of cells. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastroenteritis: An acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhoea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Called also enterogastritis. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH]
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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] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genistein: An isoflavonoid derived from soy products. It inhibits protein-tyrosine kinase and topoisomerase-ii (dna topoisomerase (atp-hydrolysing)) activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 phase arrest in human and murine cell lines. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Layers: The three layers of cells comprising the early embryo. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Giardiasis: An infection of the small intestine caused by the flagellated protozoan Giardia lamblia. It is spread via contaminated food and water and by direct person-to-person contact. [NIH] Ginkgo biloba: Exclusive species of the genus Ginkgo, family Ginkgoacea. It produces extracts of medicinal interest. Ginkgo may refer to the genus or species. [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] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [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] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glottis: The vocal apparatus of the larynx, consisting of the true vocal cords (plica vocalis)
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and the opening between them (rima glottidis). [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] 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] Glutamate-Cysteine Ligase: One of the enzymes active in the gamma-glutamyl cycle. It catalyzes the synthesis of gamma-glutamylcysteine from glutamate and cysteine in the presence of ATP with the formation of ADP and orthophosphate. EC 6.3.2.2. [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]
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] 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 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] Goblet Cells: Cells of the epithelial lining that produce and secrete mucins. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU]
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Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Graft Survival: The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] 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] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Granulomatous Disease, Chronic: A recessive X-linked defect of leukocyte function in which phagocytic cells ingest but fail to digest bacteria, resulting in recurring bacterial infections with granuloma formation. [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] Guanosine Triphosphate: Guanosine 5'-(tetrahydrogen triphosphate). A guanine nucleotide containing three phosphate groups esterified to the sugar moiety. [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] Haematemesis: The vomiting of blood. [EU] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [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]
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Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart Catheterization: Procedure which includes placement of catheter, recording of intracardiac and intravascular pressure, obtaining blood samples for chemical analysis, and cardiac output measurement, etc. Specific angiographic injection techniques are also involved. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heat Stroke: A condition characterized by cessation of sweating, hot dry skin, delirium, collapse, and coma and resulting from prolonged exposure to high environmental temperature. [NIH] Hematocrit: Measurement of the volume of packed red cells in a blood specimen by centrifugation. The procedure is performed using a tube with graduated markings or with automated blood cell counters. It is used as an indicator of erythrocyte status in disease. For example, anemia shows a low hematocrit, polycythemia, high values. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Hematopoietic tissue: Tissue in which new blood cells are formed. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemicrania: An ache or a pain in one side of the head, as in migraine. [NIH] Hemocytes: Any blood or formed element especially in invertebrates. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains. [NIH]
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Hemoglobin E: An abnormal hemoglobin that results from the substitution of lysine for glutamic acid at position 26 of the beta chain. It is most frequently observed in southeast Asian populations. [NIH] Hemoglobin H: An abnormal hemoglobin composed of four beta chains. It is caused by the reduced synthesis of the alpha chain. This abnormality results in alpha-thalassemia. [NIH] Hemoglobin M: A group of abnormal hemoglobins in which amino acid substitutions take place in either the alpha or beta chains but near the heme iron. This results in facilitated oxidation of the hemoglobin to yield excess methemoglobin which leads to cyanosis. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemoperfusion: Removal of toxins or metabolites from the circulation by the passing of blood, within a suitable extracorporeal circuit, over semipermeable microcapsules containing adsorbents (e.g., activated charcoal) or enzymes, other enzyme preparations (e.g., gel-entrapped microsomes, membrane-free enzymes bound to artificial carriers), or other adsorbents (e.g., various resins, albumin-conjugated agarose). [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis A: Hepatitis caused by hepatovirus. It can be transmitted through fecal contamination of food or water. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hepatorenal Syndrome: Renal failure in those with liver disease, usually liver cirrhosis or obstructive jaundice. Historically called Heyd disease, urohepatic syndrome, or bile nephrosis. [NIH] Hepatovirus: A genus of Picornaviridae causing infectious hepatitis naturally in humans and experimentally in other primates. It is transmitted through fecal contamination of food or water. [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] Herniated: Protrusion of a degenerated or fragmented intervertebral disc into the intervertebral foramen compressing the nerve root. [NIH] Hesperidin: Predominant flavonoid in lemons and sweet oranges. [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]
Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous
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chromosomes. [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] 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] Histamine Release: The secretion of histamine from mast cell and basophil granules by exocytosis. This can be initiated by a number of factors, all of which involve binding of IgE, cross-linked by antigen, to the mast cell or basophil's Fc receptors. Once released, histamine binds to a number of different target cell receptors and exerts a wide variety of effects. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [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] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] 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] Hyaline membrane disease: A respiratory disease of newborns, especially premature infants, in which a membrane composed of proteins and dead cells forms and lines the alveoli making gas exchange difficult or impossible. [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] Hydra: A genus of freshwater cnidarians, of interest because of their complex organization and because their adult organization corresponds roughly to the gastrula of higher animals. [NIH]
Hydralazine: A direct-acting vasodilator that is used as an antihypertensive agent. [NIH] Hydrocephalus: Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial hypertension; headache; lethargy; urinary incontinence; and ataxia (and in infants macrocephaly). This condition may be caused by obstruction of cerebrospinal fluid pathways due to neurologic abnormalities, intracranial hemorrhages; central nervous system infections; brain neoplasms; craniocerebral trauma; and other conditions. Impaired resorption of
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cerebrospinal fluid from the arachnoid villi results in a communicating form of hydrocephalus. Hydrocephalus ex-vacuo refers to ventricular dilation that occurs as a result of brain substance loss from cerebral infarction and other conditions. [NIH] Hydrofluoric Acid: A solution of hydrogen fluoride in water. It is a colorless fuming liquid which can cause painful burns. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Cyanide: HCN. A toxic liquid or colorless gas. It is found in the smoke of various tobacco products and released by combustion of nitrogen-containing organic materials. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] 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] Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. [NIH] Hyperbaric: Characterized by greater than normal pressure or weight; applied to gases under greater than atmospheric pressure, as hyperbaric oxygen, or to a solution of greater specific gravity than another taken as a standard of reference. [EU] Hyperbaric oxygen: Oxygen that is at an atmospheric pressure higher than the pressure at sea level. Breathing hyperbaric oxygen to enhance the effectiveness of radiation therapy is being studied. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercapnia: A clinical manifestation of abnormal increase in the amount of carbon dioxide in arterial blood. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperhomocysteinemia: An inborn error of methionone metabolism which produces an excess of homocysteine in the blood. It is often caused by a deficiency of cystathionine betasynthase and is a risk factor for coronary vascular disease. [NIH]
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Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypotensive: Characterized by or causing diminished tension or pressure, as abnormally low blood pressure. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypothyroidism: Deficiency of thyroid activity. In adults, it is most common in women and is characterized by decrease in basal metabolic rate, tiredness and lethargy, sensitivity to cold, and menstrual disturbances. If untreated, it progresses to full-blown myxoedema. In infants, severe hypothyroidism leads to cretinism. In juveniles, the manifestations are intermediate, with less severe mental and developmental retardation and only mild symptoms of the adult form. When due to pituitary deficiency of thyrotropin secretion it is called secondary hypothyroidism. [EU] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Hypoxemia: Deficient oxygenation of the blood; hypoxia. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Ibuprofen: A nonsteroidal anti-inflammatory agent with analgesic properties used in the therapy of rheumatism and arthritis. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH]
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Iliac Vein: A vein on either side of the body which is formed by the union of the external and internal iliac veins and passes upward to join with its fellow of the opposite side to form the inferior vena cava. [NIH] Iloprost: An eicosanoid, derived from the cyclooxygenase pathway of arachidonic acid metabolism. It is a stable and synthetic analog of epoprostenol, but with a longer half-life than the parent compound. Its actions are similar to prostacyclin. Iloprost produces vasodilation and inhibits platelet aggregation. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] 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] 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] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulins: Glycoproteins present in the blood (antibodies) and in other tissue. They are classified by structure and activity into five classes (IgA, IgD, IgE, IgG, IgM). [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] 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] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH]
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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] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
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]
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] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH]
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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] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Inspiratory Capacity: The maximum volume of air that can be inspired after reaching the end of a normal, quiet expiration. It is the sum of the tidal volume and the inspiratory reserve volume. Common abbreviation is IC. [NIH] Inspiratory Reserve Volume: The extra volume of air that can be inspired with maximal effort after reaching the end of a normal, quiet inspiration. Common abbreviation is IRV. [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] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]
Intensive Care Units: Hospital units providing continuous surveillance and care to acutely ill patients. [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
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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-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-12: A heterodimeric cytokine that stimulates the production of interferon gamma from T-cells and natural killer cells, and also induces differentiation of Th1 helper cells. It is an initiator of cell-mediated immunity. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-4: Soluble factor produced by activated T-lymphocytes that causes proliferation and differentiation of B-cells. Interleukin-4 induces the expression of class II major histocompatibility complex and Fc receptors on B-cells. It also acts on T-lymphocytes, mast cell lines, and several other hematopoietic lineage cells including granulocyte, megakaryocyte, and erythroid precursors, as well as macrophages. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Interleukin-8: A cytokine that activates neutrophils and attracts neutrophils and Tlymphocytes. It is released by several cell types including monocytes, macrophages, Tlymphocytes, fibroblasts, endothelial cells, and keratinocytes by an inflammatory stimulus. IL-8 is a member of the beta-thromboglobulin superfamily and structurally related to platelet factor 4. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intervertebral: Situated between two contiguous vertebrae. [EU] Intervertebral Disk Displacement: An intervertebral disk in which the nucleus pulposus has protruded through surrounding fibrocartilage. This occurs most frequently in the lower lumbar region. [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] Intracranial Embolism: The sudden obstruction of a blood vessel by an embolus. [NIH] Intracranial Embolism and Thrombosis: Embolism or thrombosis involving blood vessels which supply intracranial structures. Emboli may originate from extracranial or intracranial
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sources. Thrombosis may occur in arterial or venous structures. [NIH] Intracranial Hemorrhages: Bleeding within the intracranial cavity, including hemorrhages in the brain and within the cranial epidural, subdural, and subarachnoid spaces. [NIH] Intracranial Hypertension: Increased pressure within the cranial vault. This may result from several conditions, including hydrocephalus; brain edema; intracranial masses; severe systemic hypertension; pseudotumor cerebri; and other disorders. [NIH] Intrathecal: Describes the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. Drugs can be injected into the fluid or a sample of the fluid can be removed for testing. [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] Intubation: Introduction of a tube into a hollow organ to restore or maintain patency if obstructed. It is differentiated from catheterization in that the insertion of a catheter is usually performed for the introducing or withdrawing of fluids from the body. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion 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] Ion Exchange: Reversible chemical reaction between a solid, often an ION exchange resin, and a fluid whereby ions may be exchanged from one substance to another. This technique is used in water purification, in research, and in industry. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] 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 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] Iontophoresis: Therapeutic introduction of ions of soluble salts into tissues by means of electric current. In medical literature it is commonly used to indicate the process of increasing the penetration of drugs into surface tissues by the application of electric current.
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It has nothing to do with ion exchange, air ionization nor phonophoresis, none of which requires current. [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] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Ischemic stroke: A condition in which the blood supply to part of the brain is cut off. Also called "plug-type" strokes. Blocked arteries starve areas of the brain controlling sight, speech, sensation, and movement so that these functions are partially or completely lost. Ischemic stroke is the most common type of stroke, accounting for 80 percent of all strokes. Most ischemic strokes are caused by a blood clot called a thrombus, which blocks blood flow in the arteries feeding the brain, usually the carotid artery in the neck, the major vessel bringing blood to the brain. When it becomes blocked, the risk of stroke is very high. [NIH] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Isoproterenol: Isopropyl analog of epinephrine; beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract, etc. It is used mainly as bronchodilator and heart stimulant. [NIH] Isosorbide: 1,4:3,6-Dianhydro D-glucitol. Chemically inert osmotic diuretic used mainly to treat hydrocephalus; also used in glaucoma. [NIH] Isosorbide Dinitrate: A vasodilator used in the treatment of angina. Its actions are similar to nitroglycerin but with a slower onset of action. [NIH] Isozymes: The multiple forms of a single enzyme. [NIH] Isradipine: 4-(4-Benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methyl ethyl ester. A potent calcium channel antagonist that is highly selective for vascular smooth muscle. It is effective in the treatment of chronic stable angina pectoris, hypertension, and congestive cardiac failure. [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]
Jellyfish: Free swimming marine cnidarians. Most of the large jellyfish are in the class Scyphozoa; the small jellyfish are in the class Hydrozoa (hydra). [NIH] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kallidin: A decapeptide bradykinin homolog produced by the action of tissue and glandular kallikreins on low-molecular-weight kininogen. It is a smooth-muscle stimulant
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and hypotensive agent that functions through vasodilatation. [NIH] Kallikrein-Kinin System: A system produced in the distal nephron of the kidney. Its components are kallikrein, kinins, kininase I and II, and enkephalinase. It is involved in mediation and modulation of the renin-angiotensin-aldosterone system, prostaglandins, vasopressins, and in the regulation of sodium-water balance, renal hemodynamics, and particularly blood pressure. The system participates in the control of renal functions and the physiopathology of renal diseases. [NIH] Kallikreins: Proteolytic enzymes from the serine endopeptidase family found in normal blood and urine. Specifically, Kallikreins are potent vasodilators and hypotensives and increases vascular permeability and affects smooth muscle. They act as infertility agents in men. Three forms are recognized, plasma kallikrein (EC 3.4.21.34), tissue kallikrein (EC 3.4.21.35), and prostate-specific antigen (EC 3.4.21.77). [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Keratoconus: A disorder characterized by an irregular corneal surface (cone-shaped) resulting in blurred and distorted images. [NIH] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH] Ketoprofen: An ibuprofen-type anti-inflammatory analgesic and antipyretic. It is used in the treatment of rheumatoid arthritis and osteoarthritis. [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
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that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kidney stone: A stone that develops from crystals that form in urine and build up on the inner surfaces of the kidney, in the renal pelvis, or in the ureters. [NIH] Kidney Transplantation: The transference of a kidney from one human or animal to another. [NIH] Killer Cells: Lymphocyte-like effector cells which mediate antibody-dependent cell cytotoxicity. They kill antibody-coated target cells which they bind with their Fc receptors. [NIH]
Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Lactation: The period of the secretion of milk. [EU] 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] Laryngeal: Having to do with the larynx. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Lavage: A cleaning of the stomach and colon. Uses a special drink and enemas. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]
Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Left ventricular assist device: A mechanical device used to increase the heart's pumping ability. [NIH] Leishmaniasis: A disease caused by any of a number of species of protozoa in the genus Leishmania. There are four major clinical types of this infection: cutaneous (Old and New World), diffuse cutaneous, mucocutaneous, and visceral leishmaniasis. [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] 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]
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Lethargy: Abnormal drowsiness or stupor; a condition of indifference. [EU] 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]
Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] 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] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]
Lidoflazine: Coronary vasodilator with some antiarrhythmic action. [NIH] Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkages: 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] Linoleic Acids: Eighteen-carbon essential fatty acids that contain two double bonds. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives.
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Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [NIH] Lisinopril: An orally active angiotensin-converting enzyme inhibitor that has been used in the treatment of hypertension and congestive heart failure. [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 Circulation: The circulation of blood through the vessels of the liver. [NIH] Liver Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. [NIH] 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] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Long-Term Potentiation: A persistent increase in synaptic efficacy, usually induced by appropriate activation of the same synapses. The phenomenological properties of long-term potentiation suggest that it may be a cellular mechanism of learning and memory. [NIH] Loperamide: 4-(p-Chlorophenyl)-4-hydroxy-N.N-dimethyl-alpha,alpha-diphenyl-1piperidine butyramide hydrochloride. Synthetic anti-diarrheal agent with a long duration of action; it is not significantly absorbed from the gut, has no effect on the adrenergic system or central nervous system, but may antagonize histamine and interfere with acetylcholine release locally. [NIH] Lordosis: The anterior concavity in the curvature of the lumbar and cervical spine as viewed from the side. The term usually refers to abnormally increased curvature (hollow back, saddle back, swayback). It does not include lordosis as normal mating posture in certain animals ( = posture + sex behavior, animal). [NIH] Low Back Pain: Acute or chronic pain in the lumbar or sacral regions, which may be associated with musculo-ligamentous sprains and strains; intervertebral disk displacement; and other conditions. [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
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cholesterol and both are directly correlated with CHD risk. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Luminol: 5-Amino-2,3-dihydro-1,4-phthalazinedione. Substance that emits light on oxidation. It is used in chemical determinations. [NIH] Lung Transplantation: The transference of either one or both of the lungs from one human or animal to another. [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] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokine: A soluble protein produced by some types of white blood cell that stimulates other white blood cells to kill foreign invaders. [NIH] Lymphokine-activated killer cells: White blood cells that are stimulated in a laboratory to kill tumor cells. Also called LAK cells. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macula: A stain, spot, or thickening. Often used alone to refer to the macula retinae. [EU] Macula Lutea: An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the superior pole of the eye and slightly below the level of the optic disk. [NIH] Macular Degeneration: Degenerative changes in the macula lutea of the retina. [NIH]
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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] Malaise: A vague feeling of bodily discomfort. [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] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammary: Pertaining to the mamma, or breast. [EU] Mandibular Nerve: A branch of the trigeminal (5th cranial) nerve. The mandibular nerve carries motor fibers to the muscles of mastication and sensory fibers to the teeth and gingivae, the face in the region of the mandible, and parts of the dura. [NIH] Maneb: Manganese derivative of ethylenebisdithiocarbamate. It is used in agriculture as a fungicide and has been shown to cause irritation to the eyes, nose, skin, and throat. [NIH] Manic: Affected with mania. [EU] Manic-depressive psychosis: One of a group of psychotic reactions, fundamentally marked by severe mood swings and a tendency to remission and recurrence. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mastication: The act and process of chewing and grinding food in the mouth. [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]
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Maxillary: Pertaining to the maxilla : the irregularly shaped bone that with its fellow forms the upper jaw. [EU] Mechanical ventilation: Use of a machine called a ventilator or respirator to improve the exchange of air between the lungs and the atmosphere. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane 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] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the
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adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]
Mesencephalic: Ipsilateral oculomotor paralysis and contralateral tremor, spasm. or choreic movements of the face and limbs. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metalloporphyrins: Porphyrins which are combined with a metal ion. The metal is bound equally to all four nitrogen atoms of the pyrrole rings. They possess characteristic absorption spectra which can be utilized for identification or quantitative estimation of porphyrins and porphyrin-bound compounds. [NIH] 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] Metaphase: The second phase of cell division, in which the chromosomes line up across the equatorial plane of the spindle prior to separation. [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] Metastasize: To spread from one part of the body to another. When cancer cells metastasize and form secondary tumors, the cells in the metastatic tumor are like those in the original (primary) tumor. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Metronidazole: Antiprotozoal used in amebiasis, trichomoniasis, giardiasis, and as treponemacide in livestock. It has also been proposed as a radiation sensitizer for hypoxic cells. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985, p133), this substance may reasonably be anticipated to be a carcinogen (Merck, 11th ed). [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]
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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] Microfilaments: The smallest of the cytoskeletal filaments. They are composed chiefly of actin. [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] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]
labeled
with
Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] 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] 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] Mitogen-Activated Protein Kinase Kinases: A serine-threonine protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate mitogen-activated protein kinases and are themselves phosphorylated by MAP kinase kinase kinases. JNK kinases (also known as SAPK kinases) are a subfamily. EC 2.7.10.- [NIH] Mitogen-Activated Protein Kinases: A superfamily of protein-serine-threonine kinases that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by mitogen-activated protein kinase kinases which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP kinase kinase kinases). Families of these mitogen-activated protein kinases (MAPKs) include extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs) (also known as c-jun terminal kinases (JNKs)), and p38-mitogen-activated protein kinases. EC 2,7,1.- [NIH] Mitomycin: An antineoplastic antibiotic produced by Streptomyces caespitosus. It acts as a
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bi- or trifunctional alkylating agent causing cross-linking of DNA and inhibition of DNA synthesis. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] 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 cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monophosphate: So called second messenger for neurotransmitters and hormones. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]
Morphological: Relating to the configuration or the structure of live organs. [NIH] Motility: The ability to move spontaneously. [EU] Motor Neurons: Neurons which activate muscle cells. [NIH] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief
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constituent of mucus. [NIH] Mucociliary: Pertaining to or affecting the mucus membrane and hairs (including eyelashes, nose hair, .): mucociliary clearing: the clearance of mucus by ciliary movement ( particularly in the respiratory system). [EU] Mucocutaneous: Pertaining to or affecting the mucous membrane and the skin. [EU] 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 Organ Failure: A progressive condition usually characterized by combined failure of several organs such as the lungs, liver, kidney, along with some clotting mechanisms, usually postinjury or postoperative. [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 Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [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] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, 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] Mutagenic: Inducing genetic mutation. [EU] Mycophenolate mofetil: A drug that is being studied for its effectiveness in preventing graft-versus-host disease and autoimmune disorders. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelodysplastic syndrome: Disease in which the bone marrow does not function normally. Also called preleukemia or smoldering leukemia. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary
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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]
Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myofibrils: Highly organized bundles of actin, myosin, and other proteins in the cytoplasm of skeletal and cardiac muscle cells that contract by a sliding filament mechanism. [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] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [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] Narcosis: A general and nonspecific reversible depression of neuronal excitability, produced by a number of physical and chemical aspects, usually resulting in stupor. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nasal Cavity: The proximal portion of the respiratory passages on either side of the nasal septum, lined with ciliated mucosa, extending from the nares to the pharynx. [NIH] Nasal Septum: The partition separating the two nasal cavities in the midplane, composed of cartilaginous, membranous and bony parts. [NIH] Natural killer cells: NK cells. A type of white blood cell that contains granules with enzymes that can kill tumor cells or microbial cells. Also called large granular lymphocytes (LGL). [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH]
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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] Neck Pain: Discomfort or more intense forms of pain that are localized to the cervical region. This term generally refers to pain in the posterior or lateral regions of the neck. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephron: A tiny part of the kidneys. Each kidney is made up of about 1 million nephrons, which are the working units of the kidneys, removing wastes and extra fluids from the blood. [NIH] Nephropathy: Disease of the kidneys. [EU] Nephrosis: Descriptive histopathologic term for renal disease without an inflammatory component. [NIH] 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] 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] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [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] Neurogenic: Loss of bladder control caused by damage to the nerves controlling the bladder. [NIH] Neurogenic Inflammation: Inflammation caused by an injurious stimulus of peripheral neurons and resulting in release of neuropeptides which affect vascular permeability and help initiate proinflammatory and immune reactions at the site of injury. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU]
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Neuromuscular Junction: The synapse between a neuron and a muscle. [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] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]
Neurotoxins: Toxic substances from microorganisms, plants or animals that interfere with the functions of the nervous system. Most venoms contain neurotoxic substances. Myotoxins are included in this concept. [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 unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] New Guinea: Originally an island of the Malay Archipelago, the second largest island in the world. It divided, West New Guinea becoming part of Indonesia and East New Guinea becoming Papua New Guinea. [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] Nicardipine: 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl) methyl 2(methyl(phenylmethyl)amino)-3,5-pyridinecarboxylic acid ethyl ester. A potent calcium channel blockader with marked vasodilator action. It has antihypertensive properties and is effective in the treatment of angina and coronary spasms without showing cardiodepressant effects. It has also been used in the treatment of asthma and enhances the action of specific antineoplastic agents. [NIH] Nickel: A trace element with the atomic symbol Ni, atomic number 28, and atomic weight 58.69. It is a cofactor of the enzyme urease. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful anti-
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anginal agent that also lowers blood pressure. The use of nifedipine as a tocolytic is being investigated. [NIH] Nimodipine: A calcium channel blockader with preferential cerebrovascular activity. It has marked cerebrovascular dilating effects and lowers blood pressure. [NIH] Nisoldipine: 1,4-Dihydro-2,6-dimethyl-4 (2-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-methylpropyl ester. Nisoldipine is a dihydropyridine calcium channel antagonist that acts as a potent arterial vasodilator and antihypertensive agent. It is also effective in patients with cardiac failure and angina. [NIH] Nitrates: Inorganic or organic salts and esters of nitric acid. These compounds contain the NO3- radical. [NIH] Nitrendipine: Ethyl methyl 2,4-dihydro-2,6-dimethyl-4(3-nitrophenyl)-3,5pyridinedicarboxylate. A calcium channel blocker with marked vasodilator action. It is an effective antihypertensive agent and differs from other calcium channel blockers in that it does not reduce glomerular filtration rate and is mildly natriuretic, rather than sodium retentive. [NIH] Nitric acid: A toxic, corrosive, colorless liquid used to make fertilizers, dyes, explosives, and other chemicals. [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]
Nitric-Oxide Synthase: An enzyme that catalyzes the conversion of L-arginine, NADPH, and oxygen to citrulline, nitric oxide, and NADP+. The enzyme found in brain, but not that induced in lung or liver by endotoxin, requires calcium. (From Enzyme Nomenclature, 1992) EC 1.14.13.39. [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] Nitrogen Dioxide: Nitrogen oxide (NO2). A highly poisonous gas. Exposure produces inflammation of lungs that may only cause slight pain or pass unnoticed, but resulting edema several days later may cause death. (From Merck, 11th ed) It is a major atmospheric pollutant that is able to absorb UV light that does not reach the earth's surface. [NIH] Nitrogen Oxides: Inorganic oxides that contain nitrogen. [NIH] Nitroglycerin: A highly volatile organic nitrate that acts as a dilator of arterial and venous smooth muscle and is used in the treatment of angina. It provides relief through improvement of the balance between myocardial oxygen supply and demand. Although total coronary blood flow is not increased, there is redistribution of blood flow in the heart when partial occlusion of coronary circulation is effected. [NIH] Nitroprusside: (OC-6-22)-Pentakis(cyano-C)nitrosoferrate(2-). A powerful vasodilator used in emergencies to lower blood pressure or to improve cardiac function. It is also an indicator for free sulfhydryl groups in proteins. [NIH] Nitrosamines: A class of compounds that contain a -NH2 and a -NO radical. Many members of this group have carcinogenic and mutagenic properties. [NIH]
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Nitrosation: Conversion into nitroso compounds. An example is the reaction of nitrites with amino compounds to form carcinogenic N-nitrosamines. [NIH] Nitrous Oxide: Nitrogen oxide (N2O). A colorless, odorless gas that is used as an anesthetic and analgesic. High concentrations cause a narcotic effect and may replace oxygen, causing death by asphyxia. It is also used as a food aerosol in the preparation of whipping cream. [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] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritive Value: An indication of the contribution of a food to the nutrient content of the diet. This value depends on the quantity of a food which is digested and absorbed and the amounts of the essential nutrients (protein, fat, carbohydrate, minerals, vitamins) which it contains. This value can be affected by soil and growing conditions, handling and storage, and processing. [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] Oculomotor: Cranial nerve III. It originate from the lower ventral surface of the midbrain and is classified as a motor nerve. [NIH] Odour: A volatile emanation that is perceived by the sense of smell. [EU] 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] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oncology: The study of cancer. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Ophthalmic: Pertaining to the eye. [EU]
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Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]
Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [NIH]
Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Optic nerve head: The circular area (disc) where the optic nerve connects to the retina. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [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] Osmolarity: The concentration of osmotically active particles expressed in terms of osmoles of solute per litre of solution. [EU] Osmoles: The standard unit of osmotic pressure. [NIH] 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] Osseointegration: The growth action of bone tissue, as it assimilates surgically implanted devices or prostheses to be used as either replacement parts (e.g., hip) or as anchors (e.g., endosseous dental implants). [NIH] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteoblasts: Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. [NIH]
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Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Osteogenesis: The histogenesis of bone including ossification. It occurs continuously but particularly in the embryo and child and during fracture repair. [NIH] Osteolytic: Causing the breakdown of bone. [NIH] 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] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] 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 metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [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]
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Oxides: Binary compounds of oxygen containing the anion O(2-). The anion combines with metals to form alkaline oxides and non-metals to form acidic oxides. [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Oxygenator: An apparatus by which oxygen is introduced into the blood during circulation outside the body, as during open heart surgery. [NIH] Oxytocin: A nonapeptide posterior pituitary hormone that causes uterine contractions and stimulates lactation. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palladium: A chemical element having an atomic weight of 106.4, atomic number of 46, and the symbol Pd. It is a white, ductile metal resembling platinum, and following it in abundance and importance of applications. It is used in dentistry in the form of gold, silver, and copper alloys. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Paneth Cells: Epithelial cells found in the basal part of the intestinal glands (crypts of Lieberkuhn). Paneth cells synthesize and secrete lysozyme and cryptdins. [NIH] Paracentesis: A procedure in which fluid is withdrawn from a body cavity via a trocar and cannula, needle, or other hollow instrument. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Paranasal Sinuses: Air-filled extensions of the respiratory part of the nasal cavity into the frontal, ethmoid, sphenoid, and maxillary cranial bones. They vary in size and form in different individuals and are lined by the ciliated mucous membranes of the nasal cavity. [NIH]
Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH]
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Paratuberculosis: An infectious disease caused by Mycobacterium paratuberculosis. Characteristics include chronic debilitation and weight loss. [NIH] Parenchyma: The essential elements of an organ; used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework, or stroma. [EU] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parietal Lobe: Upper central part of the cerebral hemisphere. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Particle: A tiny mass of material. [EU] Parturition: The act or process of given birth to a child. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] 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 Education: The teaching or training of patients concerning their own health needs. [NIH]
Pelvic: Pertaining to the pelvis. [EU] Penile Erection: The state of the penis when the erectile tissue becomes filled with blood and causes the penis to become rigid and elevated. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] 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] 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] Perhexiline: 2-(2,2-Dicyclohexylethyl)piperidine. Coronary vasodilator used especially for angina of effort. It may cause neuropathy and hepatitis. [NIH] Periaqueductal Gray: Central gray matter surrounding the cerebral aqueduct in the
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mesencephalon. Physiologically it is probably involved in rage reactions, the lordosis reflex, feeding responses, bladder tonus, and pain. [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] 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 Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [NIH] Peristalsis: The rippling motion of muscles in the intestine or other tubular organs characterized by the alternate contraction and relaxation of the muscles that propel the contents onward. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] 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] 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] Perivascular: Situated around a vessel. [EU] Perspiration: Sweating; the functional secretion of sweat. [EU] Pertussis: An acute, highly contagious infection of the respiratory tract, most frequently affecting young children, usually caused by Bordetella pertussis; a similar illness has been
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associated with infection by B. parapertussis and B. bronchiseptica. It is characterized by a catarrhal stage, beginning after an incubation period of about two weeks, with slight fever, sneezing, running at the nose, and a dry cough. In a week or two the paroxysmal stage begins, with the characteristic paroxysmal cough, consisting of a deep inspiration, followed by a series of quick, short coughs, continuing until the air is expelled from the lungs; the close of the paroxysm is marked by a long-drawn, shrill, whooping inspiration, due to spasmodic closure of the glottis. This stage lasts three to four weeks, after which the convalescent stage begins, in which paroxysms grow less frequent and less violent, and finally cease. Called also whooping cough. [EU] 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] Pharmaceutic Aids: Substances which are of little or no therapeutic value, but are necessary in the manufacture, compounding, storage, etc., of pharmaceutical preparations or drug dosage forms. They include solvents, diluting agents, and suspending agents, and emulsifying agents. Also, antioxidants; preservatives, pharmaceutical; dyes (coloring agents); flavoring agents; vehicles; excipients; ointment bases. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenylephrine: An alpha-adrenergic agonist used as a mydriatic, nasal decongestant, and cardiotonic agent. [NIH] Phonophoresis: Use of ultrasound to increase the percutaneous adsorption of drugs. [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] 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]
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Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylate: Attached to a phosphate group. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] 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] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] 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] Phototransduction: The transducing of light energy to afferent nerve impulses, such as takes place in the retinal rods and cones. After light photons are absorbed by the photopigments, the signal is transmitted to the outer segment membrane by the cyclic GMP second messenger system, where it closes the sodium channels. This channel gating ultimately generates an action potential in the inner retina. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [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] 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]
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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] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] 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] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [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 Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelet Count: A count of the number of platelets per unit volume in a sample of venous blood. [NIH]
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Platelet Factor 4: A high-molecular-weight proteoglycan-platelet factor complex which is released from blood platelets by thrombin. It acts as a mediator in the heparin-neutralizing capacity of the blood and plays a role in platelet aggregation. At high ionic strength (I=0.75), the complex dissociates into the active component (molecular weight 29,000) and the proteoglycan carrier (chondroitin 4-sulfate, molecular weight 350,000). The molecule exists in the form of a dimer consisting of 8 moles of platelet factor 4 and 2 moles of proteoglycan. [NIH]
Plateletpheresis: The preparation of platelet concentrates with the return of red cells and platelet-poor plasma to the donor. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]
Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] Pneumonectomy: An operation to remove an entire lung. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Pollen: The male fertilizing element of flowering plants analogous to sperm in animals. It is released from the anthers as yellow dust, to be carried by insect or other vectors, including wind, to the ovary (stigma) of other flowers to produce the embryo enclosed by the seed. The pollens of many plants are allergenic. [NIH] Polyarthritis: An inflammation of several joints together. [EU] 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] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]
Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polymyxin: Basic polypeptide antibiotic group obtained from Bacillus polymyxa. They affect the cell membrane by detergent action and may cause neuromuscular and kidney damage. At least eleven different members of the polymyxin group have been identified, each designated by a letter. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called
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tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] Polyvinyl Alcohol: A polymer prepared from polyvinyl acetates by replacement of the acetate groups with hydroxyl groups. It is used as a pharmaceutic aid and ophthalmic lubricant as well as in the manufacture of surface coatings artificial sponges, cosmetics, and other products. [NIH] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] Pontine: A brain region involved in the detection and processing of taste. [NIH] Popliteal: Compression of the nerve at the neck of the fibula. [NIH] Popliteal Vein: The vein formed by the union of the anterior and posterior tibial veins; it courses through the popliteal space and becomes the femoral vein. [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] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] 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] Potentiating: 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
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convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] 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] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Preeclampsia: A toxaemia of late pregnancy characterized by hypertension, edema, and proteinuria, when convulsions and coma are associated, it is called eclampsia. [EU] Pre-Eclampsia: Development of hypertension with proteinuria, edema, or both, due to pregnancy or the influence of a recent pregnancy. It occurs after the 20th week of gestation, but it may develop before this time in the presence of trophoblastic disease. [NIH] Preleukemia: Conditions in which the abnormalities in the peripheral blood or bone marrow represent the early manifestations of acute leukemia, but in which the changes are not of sufficient magnitude or specificity to permit a diagnosis of acute leukemia by the usual clinical criteria. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Priapism: Persistent abnormal erection of the penis, usually without sexual desire, and accompanied by pain and tenderness. It is seen in diseases and injuries of the spinal cord, and may be caused by vesical calculus and certain injuries to the penis. [EU] 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] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH]
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Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Propidium: Quaternary ammonium analog of ethidium; an intercalating dye with a specific affinity to certain forms of DNA and, used as diiodide, to separate them in density gradients; also forms fluorescent complexes with cholinesterase which it inhibits. [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 D: Physiologically active prostaglandins found in many tissues and organs. They show pressor activity, are mediators of inflammation, and have potential antithrombotic effects. [NIH] Prostaglandins E: (11 alpha,13E,15S)-11,15-Dihydroxy-9-oxoprost-13-en-1-oic acid (PGE(1)); (5Z,11 alpha,13E,15S)-11,15-dihydroxy-9-oxoprosta-5,13-dien-1-oic acid (PGE(2)); and (5Z,11 alpha,13E,15S,17Z)-11,15-dihydroxy-9-oxoprosta-5,13,17-trien-1-oic acid (PGE(3)). Three of the six naturally occurring prostaglandins. They are considered primary in that no one is derived from another in living organisms. Originally isolated from sheep seminal fluid and
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vesicles, they are found in many organs and tissues and play a major role in mediating various physiological activities. [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] Prostheses and Implants: Artificial substitutes for body parts, and materials inserted into tissue for functional, cosmetic, or therapeutic purposes. Prostheses can be functional, as in the case of artificial arms and legs, or cosmetic, as in the case of an artificial eye. Implants, all surgically inserted or grafted into the body, tend to be used therapeutically. Experimental implants is available for those used experimentally. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent. [NIH]
Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Kinase C: An enzyme that phosphorylates proteins on serine or threonine residues in the presence of physiological concentrations of calcium and membrane phospholipids. The additional presence of diacylglycerols markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by phorbol esters and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. EC 2.7.1.-. [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors. EC 2.7.10. [NIH] Protein-Tyrosine Kinase: An enzyme that catalyzes the phosphorylation of tyrosine residues in proteins with ATP or other nucleotides as phosphate donors. EC 2.7.1.112. [NIH]
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Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]
Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Proton Pump: Integral membrane proteins that transport protons across a membrane against a concentration gradient. This transport is driven by hydrolysis of ATP by H(+)transporting ATP synthase. [NIH] Proton Pump Inhibitors: Medicines that stop the stomach's acid pump. Examples are omeprazole (oh-MEH-prah-zol) (Prilosec) and lansoprazole (lan-SOH-prah-zol) (Prevacid). [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] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Proto-Oncogenes: Normal cellular genes homologous to viral oncogenes. The products of proto-oncogenes are important regulators of biological processes and appear to be involved in the events that serve to maintain the ordered procession through the cell cycle. Protooncogenes have names of the form c-onc. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] 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
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psychotic. [EU] 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 Circulation: The circulation of blood through the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulmonary Ventilation: The total volume of gas per minute inspired or expired measured in liters per minute. [NIH] Pulposus: Prolapse of the nucleus pulposus into the body of the vertebra; necrobacillosis of rabbits. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Pupil: The aperture in the iris through which light passes. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Pyrogenic: Inducing fever. [EU] Quercetin: Aglucon of quercetrin, rutin, and other glycosides. It is widely distributed in the plant kingdom, especially in rinds and barks, clover blossoms, and ragweed pollen. [NIH] 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]
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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] Radiculopathy: Disease involving a spinal nerve root (see spinal nerve roots) which may result from compression related to intervertebral disk displacement; spinal cord injuries; spinal diseases; and other conditions. Clinical manifestations include radicular pain, weakness, and sensory loss referable to structures innervated by the involved nerve root. [NIH]
Radioactive: Giving off radiation. [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Rage: Fury; violent, intense anger. [NIH] Ramipril: A long-acting angiotensin-converting enzyme inhibitor. It is a prodrug that is transformed in the liver to its active metabolite ramiprilat. [NIH] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU]
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Reality Testing: The individual's objective evaluation of the external world and the ability to differentiate adequately between it and the internal world; considered to be a primary ego function. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] 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] Reflux: The term used when liquid backs up into the esophagus from the stomach. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] 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] Relaxant: 1. Lessening or reducing tension. 2. An agent that lessens tension. [EU] 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
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cancer in the body. [NIH] Renal Artery: A branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters. [NIH] Renal Circulation: The circulation of the blood through the vessels of the kidney. [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] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Residual Volume: The volume of air remaining in the lungs at the end of a maximal expiration. Common abbreviation is RV. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] 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] Respirator: A mechanical device that helps a patient breathe; a mechanical ventilator. [NIH] Respiratory Burst: A large increase in oxygen uptake by neutrophils and most types of tissue macrophages through activation of an NADPH-cytochrome b-dependent oxidase that reduces oxygen to a superoxide. Individuals with an inherited defect in which the oxidase that reduces oxygen to superoxide is decreased or absent (granulomatous disease, chronic) often die as a result of recurrent bacterial infections. [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] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Respiratory Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [NIH]
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Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [NIH] Restitution: The restoration to a normal state. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Resuscitation: The restoration to life or consciousness of one apparently dead; it includes such measures as artificial respiration and cardiac massage. [EU] Reticular: Coarse-fibered, netlike dermis layer. [NIH] Reticular Formation: A region extending from the pons & medulla oblongata through the mesencephalon, characterized by a diversity of neurons of various sizes and shapes, arranged in different aggregations and enmeshed in a complicated fiber network. [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] Retinae: A congenital notch or cleft of the retina, usually located inferiorly. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal 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] 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] Retinosis: Non-inflammatory degeneration of the retina. [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] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] 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]
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Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rheumatology: A subspecialty of internal medicine concerned with the study of inflammatory or degenerative processes and metabolic derangement of connective tissue structures which pertain to a variety of musculoskeletal disorders, such as arthritis. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Ribonucleoside Diphosphate Reductase: An enzyme of the oxidoreductase class that catalyzes the formation of 2'-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. (From Dorland, 27th ed) EC 1.17.4.1. [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] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rotenone: A botanical insecticide that is an inhibitor of mitochondrial electron transport. [NIH]
Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Ruthenium: A hard, brittle, grayish-white rare earth metal with an atomic symbol Ru, atomic number 44, and atomic weight 101.07. It is used as a catalyst and hardener for platinum and palladium. [NIH] Rutin: 3-((6-O-(6-Deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranosyl)oxy)-2-(3,4dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one. Found in many plants, including buckwheat, tobacco, forsythia, hydrangea, pansies, etc. It has been used therapeutically to decrease capillary fragility. [NIH] Ryanodine: Insecticidal alkaloid isolated from Ryania speciosa; proposed as a myocardial depressant. [NIH] Salicylic: A tuberculosis drug. [NIH] Saline: A solution of salt and water. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] 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
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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] Sarcoplasmic Reticulum: A network of tubules and sacs in the cytoplasm of skeletal muscles that assist with muscle contraction and relaxation by releasing and storing calcium ions. [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] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sciatica: A condition characterized by pain radiating from the back into the buttock and posterior/lateral aspects of the leg. Sciatica may be a manifestation of sciatic neuropathy; radiculopathy (involving the L4, L5, S1 or S2 spinal nerve roots; often associated with intervertebral disk displacement); or lesions of the cauda equina. [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] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [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] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sedentary: 1. Sitting habitually; of inactive habits. 2. Pertaining to a sitting posture. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segmentation: The process by which muscles in the intestines move food and wastes through the body. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [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] Seminal fluid: Fluid from the prostate and other sex glands that helps transport sperm out of the man's body during orgasm. Seminal fluid contains sugar as an energy source for sperm. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Senna: Preparations of Cassia senna L. and C. angustifolia of the Leguminosae. They contain sennosides, which are anthraquinone type cathartics and are used in many different preparations as laxatives. [NIH] Sensibility: The ability to receive, feel and appreciate sensations and impressions; the quality of being sensitive; the extend to which a method gives results that are free from false negatives. [NIH] 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] 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
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broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Behavior: Sexual activities of humans. [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] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Sexually Transmitted Diseases: Diseases due to or propagated by sexual contact. [NIH] Sharpness: The apparent blurring of the border between two adjacent areas of a radiograph having different optical densities. [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]
Shock, Septic: Shock due to circulatory insufficiency caused most commonly by gramnegative bacteremia. It is less often the result of the persistent presence of other microorganisms in the blood (fungemia, viremia); in rare instances, it is caused by gram-positive organisms, but with different symptomatology. [NIH] Shock, Traumatic: Shock produced as a result of trauma. [NIH] Shunt: A surgically created diversion of fluid (e.g., blood or cerebrospinal fluid) from one area of the body to another area of the body. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Sigmoid: 1. Shaped like the letter S or the letter C. 2. The sigmoid colon. [EU] Sigmoid Colon: The lower part of the colon that empties into the rectum. [NIH] 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] Silicon: A trace element that constitutes about 27.6% of the earth's crust in the form of
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silicon dioxide. It does not occur free in nature. Silicon has the atomic symbol Si, atomic number 14, and atomic weight 28.09. [NIH] Silicon Dioxide: Silica. Transparent, tasteless crystals found in nature as agate, amethyst, chalcedony, cristobalite, flint, sand, quartz, and tridymite. The compound is insoluble in water or acids except hydrofluoric acid. [NIH] Sinusitis: An inflammatory process of the mucous membranes of the paranasal sinuses that occurs in three stages: acute, subacute, and chronic. Sinusitis results from any condition causing ostial obstruction or from pathophysiologic changes in the mucociliary transport mechanism. [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] Smoldering leukemia: Disease in which the bone marrow does not function normally. Also called preleukemia or myelodysplastic syndrome. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Social Isolation: The separation of individuals or groups resulting in the lack of or minimizing of social contact and/or communication. This separation may be accomplished by physical separation, by social barriers and by psychological mechanisms. In the latter, there may be interaction but no real communication. [NIH] Social Work: The use of community resources, individual case work, or group work to promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [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] 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]
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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] Spasmodic: Of the nature of a spasm. [EU] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] 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 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] Sperm Head: The anterior, usually ovoid, nucleus-containing part of spermatozoa. [NIH] Spermatozoa: Mature male germ cells that develop in the seminiferous tubules of the testes. Each consists of a head, a body, and a tail that provides propulsion. The head consists mainly of chromatin. [NIH] Spermatozoon: The mature male germ cell. [NIH] Sphincter: A ringlike band of muscle fibres that constricts a passage or closes a natural orifice; called also musculus sphincter. [EU] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] 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
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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] Spinal Stenosis: Narrowing of the spinal canal. [NIH] Spinous: Like a spine or thorn in shape; having spines. [NIH] Splanchnic Circulation: The circulation of blood through the vessels supplying the abdominal viscera. [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] Spondylitis: Inflammation of the vertebrae. [EU] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sprains and Strains: A collective term for muscle and ligament injuries without dislocation or fracture. A sprain is a joint injury in which some of the fibers of a supporting ligament are ruptured but the continuity of the ligament remains intact. A strain is an overstretching or overexertion of some part of the musculature. [NIH] Sputum: The material expelled from the respiratory passages by coughing or clearing the throat. [NIH] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [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]
Steady state: Dynamic equilibrium. [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] Stellate: Star shaped. [NIH] Stem Cell Factor: Hematopoietic growth factor and the ligand of the c-kit receptor CD117 (proto-oncogene protein C-kit). It is expressed during embryogenesis and provides a key signal in multiple aspects of mast-cell differentiation and function. [NIH]
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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] 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] Sterilization: The destroying of all forms of life, especially microorganisms, by heat, chemical, or other means. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, 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] Stomach Ulcer: An open sore in the lining of the stomach. Also called gastric ulcer. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptococcus: A genus of gram-positive, coccoid bacteria whose organisms occur in pairs or chains. No endospores are produced. Many species exist as commensals or parasites on man or animals with some being highly pathogenic. A few species are saprophytes and occur in the natural environment. [NIH] Streptozocin: An antibiotic that is produced by Stretomyces achromogenes. It is used as an antineoplastic agent and to induce diabetes in experimental animals. [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] Stroke Volume: The amount of blood pumped out of the heart per beat not to be confused with cardiac output (volume/time). [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure-activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects. [NIH] Stupor: Partial or nearly complete unconsciousness, manifested by the subject's responding
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only to vigorous stimulation. Also, in psychiatry, a disorder marked by reduced responsiveness. [EU] Styrene: A colorless, toxic liquid with a strong aromatic odor. It is used to make rubbers, polymers and copolymers, and polystyrene plastics. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Substrate: A substance upon which an enzyme acts. [EU] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] 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] Sulfur Dioxide: A highly toxic, colorless, nonflammable gas. It is used as a pharmaceutical aid and antioxidant. It is also an environmental air pollutant. [NIH] Sulfur Oxides: Inorganic oxides of sulfur. [NIH] Sumatriptan: A serotonin agonist that acts selectively at 5HT1 receptors. It is used in the treatment of migraines. [NIH] Sunburn: An injury to the skin causing erythema, tenderness, and sometimes blistering and resulting from excessive exposure to the sun. The reaction is produced by the ultraviolet radiation in sunlight. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suprofen: An ibuprofen-type anti-inflammatory analgesic and antipyretic. It inhibits prostaglandin synthesis and has been proposed as an anti-arthritic. [NIH] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]
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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] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic discussion of symptoms. 2. The combined symptoms of a disease. [EU] 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] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synaptic Vesicles: Membrane-bound compartments which contain transmitter molecules. Synaptic vesicles are concentrated at presynaptic terminals. They actively sequester transmitter molecules from the cytoplasm. In at least some synapses, transmitter release occurs by fusion of these vesicles with the presynaptic membrane, followed by exocytosis of their contents. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synovial: Of pertaining to, or secreting synovia. [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.
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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] Systolic blood pressure: The maximum pressure in the artery produced as the heart contracts and blood begins to flow. [NIH] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. [NIH] Tamoxifen: A first generation selective estrogen receptor modulator (SERM). It acts as an agonist for bone tissue and cholesterol metabolism but is an estrogen antagonist in mammary and uterine. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] 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] 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] Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by
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the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Thoracic: Having to do with the chest. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombopoietin: A humoral factor that controls blood platelet production through stimulation of megakaryocyte populations. Bone marrow megakaryocytes increase in both size and number in response to exposure to thrombopoietin. [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] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyrotropin: A peptide hormone secreted by the anterior pituitary. It promotes the growth of the thyroid gland and stimulates the synthesis of thyroid hormones and the release of thyroxine by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Ticlopidine: Ticlopidine is an effective inhibitor of platelet aggregation. The drug has been found to significantly reduce infarction size in acute myocardial infarcts and is an effective antithrombotic agent in arteriovenous fistulas, aorto-coronary bypass grafts, ischemic heart disease, venous thrombosis, and arteriosclerosis. [NIH] Tidal Volume: The volume of air inspired or expired during each normal, quiet respiratory cycle. Common abbreviations are TV or V with subscript T. [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]
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Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Tooth Loss: The failure to retain teeth as a result of disease or injury. [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] Toremifene: A first generation selective estrogen receptor modulator (SERM). Like tamoxifen, it is an estrogen agonist for bone tissue and cholesterol metabolism but is antagonistic on mammary and uterine tissue. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Total Lung Capacity: The volume of air contained in the lungs at the end of a maximal inspiration. It is the equivalent to each of the following sums: vital capacity plus residual volume; inspiratory capacity plus functional residual capacity; tidal volume plus inspiratory reserve volume plus functional residual capacity; tidal volume plus inspiratory reserve volume plus expiratory reserve volume plus residual volume. [NIH] Toxaemia: 1. The condition resulting from the spread of bacterial products (toxins) by the bloodstream. 2. A condition resulting from metabolic disturbances, e.g. toxaemia of pregnancy. [EU] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Traction: The act of pulling. [NIH] Tractus: A part of some structure, usually that part along which something passes. [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
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initiation, stimulation, or termination of the genetic transcription process. [NIH] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] 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] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocate: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocating: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Trees: Woody, usually tall, perennial higher plants (Angiosperms, Gymnosperms, and some Pterophyta) having usually a main stem and numerous branches. [NIH] Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [NIH] Trichomoniasis: An infection with the protozoan parasite Trichomonas vaginalis. [NIH] Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [NIH] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU] Trigeminal: Cranial nerve V. It is sensory for the eyeball, the conjunctiva, the eyebrow, the skin of face and scalp, the teeth, the mucous membranes in the mouth and nose, and is motor to the muscles of mastication. [NIH] Trigeminal Ganglion: The semilunar-shaped ganglion containing the cells of origin of most of the sensory fibers of the trigeminal nerve. It is situated within the dural cleft on the cerebral surface of the petrous portion of the temporal bone and gives off the ophthalmic,
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maxillary, and part of the mandibular nerves. [NIH] Trigeminal Nerve: The 5th and largest cranial nerve. The trigeminal nerve is a mixed motor and sensory nerve. The larger sensory part forms the ophthalmic, mandibular, and maxillary nerves which carry afferents sensitive to external or internal stimuli from the skin, muscles, and joints of the face and mouth and from the teeth. Most of these fibers originate from cells of the trigeminal ganglion and project to the trigeminal nucleus of the brain stem. The smaller motor part arises from the brain stem trigeminal motor nucleus and innervates the muscles of mastication. [NIH] Trophic: Of or pertaining to nutrition. [EU] Tropoelastin: A salt-soluble precursor of elastin. Lysyl oxidase is instrumental in converting it to elastin in connective tissue. [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] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tuftsin: N(2)-((1-(N(2)-L-Threonyl)-L-lysyl)-L-prolyl)-L-arginine. A tetrapeptide produced in the spleen by enzymatic cleavage of a leukophilic gamma-globulin. It stimulates the phagocytic activity of blood polymorphonuclear leukocytes and neutrophils in particular. The peptide is located in the Fd fragment of the gamma-globulin molecule. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tunica Media: The middle coat of blood vessel walls, composed principally of thin, cylindrical, smooth muscle cells and elastic tissue. It accounts for the bulk of the wall of most arteries. The smooth muscle cells are arranged in circular layers around the vessel, and the thickness of the coat varies with the size of the vessel. [NIH] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Typhimurium: Microbial assay which measures his-his+ reversion by chemicals which cause base substitutions or frameshift mutations in the genome of this organism. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH]
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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] Ultrasound test: A test that bounces sound waves off tissues and internal organs and changes the echoes into pictures (sonograms). [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]
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 Retention: Inability to urinate. The etiology of this disorder includes obstructive, neurogenic, pharmacologic, and psychogenic causes. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]
Urinary Tract Physiology: Functions and activities of the urinary tract as a whole or of any of its parts. [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] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Uterine Contraction: Contraction of the uterine muscle. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in
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which a fetus develops. Also called the womb. [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] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vagotomy: The interruption or removal of any part of the vagus (10th cranial) nerve. Vagotomy may be performed for research or for therapeutic purposes. [NIH] Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Headaches: A group of disorders characterized by recurrent headaches associated with abnormal dilation and constriction of cerebral blood vessels. Representative disorders from this category include migraine, cluster headache, and paroxysmal hemicrania. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoactive Intestinal Peptide: A highly basic, single-chain polypeptide isolated from the intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular, gastrointestinal, and respiratory systems. It is also found in several parts of the central and peripheral nervous systems and is a neurotransmitter. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilatation: A state of increased calibre of the blood vessels. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasodilator Agents: Drugs used to cause dilation of the 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] Vasopressins: Octapeptide antidiuretic hormones released by the neurohypophysis of all vertebrates (chemical composition varies with species). They control water metabolism and balance by regulating lung, gill, kidney, etc., and water loss, and also contract smooth muscle. They may also be neurotransmitters. Also included are synthetic vasopressin derivatives. Vasopressins are used pharmacologically as renal agents, vasoconstrictor agents, and hemostatics. [NIH] Vasopressor: 1. Stimulating contraction of the muscular tissue of the capillaries and arteries. 2. An agent that stimulates contraction of the muscular tissue of the capillaries and arteries. [EU]
Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH]
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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 back for gas exchange. [NIH] Venous Pressure: The blood pressure in a vein. It is usually measured to assess the filling pressure to the ventricle. [NIH] Venous Thrombosis: The formation or presence of a thrombus within a vein. [NIH] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventilator: A breathing machine that is used to treat respiratory failure by promoting ventilation; also called a respirator. [NIH] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Function: The hemodynamic and electrophysiological action of the ventricles. [NIH]
Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Verapamil: A calcium channel blocker that is a class IV anti-arrhythmia agent. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villi: The tiny, fingerlike projections on the surface of the small intestine. Villi help absorb nutrients. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viremia: The presence of viruses in the blood. [NIH]
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Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Afferents: The sensory fibers innervating the viscera. [NIH] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Visual Acuity: Acuteness or clearness of vision, especially of form vision, which is dependent mainly on the sharpness of the retinal focus. [NIH] Vital Capacity: The volume of air that is exhaled by a maximal expiration following a maximal inspiration. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [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] Voltage-gated: It is opened by the altered charge distribution across the cell membrane. [NIH]
Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [NIH] Wakefulness: A state in which there is an enhanced potential for sensitivity and an efficient responsiveness to external stimuli. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH]
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Xanthine: An urinary calculus. [NIH] Xanthine Oxidase: An iron-molybdenum flavoprotein containing FAD that oxidizes hypoxanthine, some other purines and pterins, and aldehydes. Deficiency of the enzyme, an autosomal recessive trait, causes xanthinuria. EC 1.1.3.22. [NIH] 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] X-ray therapy: The use of high-energy radiation from x-rays 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. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
411
INDEX 1 1-Methyl-4-phenyl-1,2,3,6tetrahydropyridine, 138, 295 A Abdomen, 295, 308, 309, 349, 355, 370, 372, 393, 394, 398, 405 Abdominal, 164, 295, 296, 307, 337, 351, 359, 370, 372, 385, 393, 402 Abdominal Pain, 295, 337, 351, 372, 402 Ablation, 157, 295 Abrasion, 251, 295 Abscisic Acid, 65, 80, 295 Acatalasia, 295, 313 Acceptor, 295, 354, 369 Acetylcholine, 4, 10, 180, 196, 201, 215, 244, 295, 316, 332, 355, 366 Acetylcysteine, 34, 187, 295 Acid Rain, 212, 295 Acidosis, 175, 194, 197, 295 Acrosome, 52, 295 Acrosome Reaction, 52, 295 Acrylonitrile, 296, 387 Actin, 14, 209, 210, 296, 360, 362, 363 Acupuncture Points, 148, 150, 296 Acute renal, 145, 296 Adaptability, 296, 314 Adaptation, 22, 33, 46, 296, 375 Adduct, 68, 250, 251, 296 Adenine, 296, 382 Adenocarcinoma, 74, 296 Adenosine, 8, 10, 100, 134, 159, 196, 215, 237, 296, 305, 345, 374 Adenosine Triphosphate, 196, 237, 296, 305, 374 Adenovirus, 7, 9, 35, 73, 113, 201, 296, 322 Adenylate Cyclase, 215, 296 Adhesives, 211, 296 Adipocytes, 296, 320, 353 Adjustment, 296 Adjuvant, 215, 296, 299, 338 Adoptive Transfer, 19, 296 Adrenal Cortex, 35, 296, 298, 321, 322, 332, 378, 385 Adrenal Glands, 296, 385 Adrenal Medulla, 297, 313, 331, 367 Adrenergic, 22, 57, 94, 168, 197, 203, 230, 242, 297, 327, 331, 355, 373, 396 Adrenergic Agonists, 57, 297
Adverse Effect, 12, 29, 175, 207, 240, 250, 297, 390 Aerobic, 17, 297, 333, 360, 369 Aerobic Metabolism, 297, 369 Aerobic Respiration, 297, 369 Aerosol, 297, 367 Afferent, 54, 158, 297, 353, 374, 393 Affinity, 21, 44, 48, 297, 304, 354, 359, 379, 391 Affinity Chromatography, 21, 297 Afterload, 37, 297 Agarose, 297, 342 Age of Onset, 297, 310, 401 Agonist, 10, 21, 48, 246, 297, 307, 327, 365, 373, 395, 397, 399 Air Sacs, 297, 299 Airway, 27, 103, 109, 127, 138, 191, 201, 221, 255, 260, 264, 297, 310, 391 Albumin, 76, 204, 234, 297, 342, 375 Aldehydes, 42, 228, 298, 406 Aldose Reductase Inhibitor, 228, 298 Aldosterone, 35, 41, 51, 58, 254, 298, 352 Algorithms, 298, 308 Alimentary, 298, 351 Alkaline, 220, 295, 298, 299, 311, 370 Alkaloid, 298, 312, 318, 361, 365, 387 Allergen, 138, 298, 325 Allergic Rhinitis, 130, 283, 298, 311 Allogeneic, 298, 340 Allograft, 82, 298 Allopurinol, 198, 298 Allylamine, 298, 299 Alopecia, 298, 323 Alpha 1-Antitrypsin, 117, 298 Alpha 1-Antitrypsin Deficiency, 117, 298 Alpha Particles, 298, 382 Alpha-Defensins, 298, 324 Alternative medicine, 265, 299 Alum, 299, 318 Alveoli, 33, 193, 194, 299, 343, 404 Amebiasis, 299, 359 Ameliorated, 46, 191, 197, 211, 299 Ameliorating, 50, 59, 299 Amine, 238, 251, 299, 343 Amino Acid Sequence, 299, 301, 338 Amino Acid Substitution, 299, 342 Aminolevulinic Acid, 144, 299
412 Nitric Oxide
Ammonia, 168, 188, 192, 216, 217, 220, 299, 396, 402 Ammonium Sulfate, 220, 299 Amphetamines, 299, 318 Amputation, 23, 299 Amyloid, 66, 119, 122, 299 Anaerobic, 17, 72, 73, 173, 197, 300 Anaesthesia, 93, 248, 300, 347 Anaesthetic, 248, 300 Anal, 115, 203, 242, 247, 300, 334, 355 Anal Fissure, 247, 300 Analgesic, 155, 300, 318, 332, 335, 345, 352, 361, 367, 368, 395 Analog, 12, 138, 300, 335, 346, 351, 379 Analogous, 300, 376, 400 Analytes, 202, 203, 300 Anaphylatoxins, 300, 319 Anastomosis, 9, 300 Anatomical, 35, 300, 305, 320, 326, 346, 371, 388 Androgens, 19, 296, 300, 321 Anemia, 16, 110, 126, 173, 235, 279, 282, 300, 334, 336, 341, 357 Anesthesia, 10, 112, 194, 297, 300, 329, 330 Anesthetics, 300, 331 Aneurysm, 300, 403 Angina, 94, 164, 198, 300, 301, 351, 365, 366, 371 Angina Pectoris, 94, 300, 351 Anginal, 198, 301, 366 Angiogenesis, 36, 61, 66, 84, 232, 251, 301, 357 Angioplasty, 124, 190, 301, 363 Angiotensinogen, 301, 385 Animal model, 28, 51, 54, 222, 261, 301 Anions, 62, 156, 298, 301, 350, 395 Annealing, 225, 301 Anode, 301 Anorectal, 247, 301 Anorexia, 299, 301, 337, 402 Antagonism, 301, 326 Anthracycline, 207, 301 Anthraquinones, 301, 313 Antiallergic, 301, 321 Antiarrhythmic, 301, 354 Antibacterial, 32, 47, 86, 239, 301, 392 Antibiotic, 301, 310, 332, 336, 360, 376, 392, 394 Antibodies, 32, 195, 301, 340, 343, 346, 356, 361, 375, 383 Anticoagulant, 301, 380 Antidepressant, 302, 335
Antifungal, 302, 323 Antigen, 6, 70, 74, 79, 88, 153, 183, 297, 301, 302, 319, 343, 345, 346, 347, 348, 352, 358 Antigen-Antibody Complex, 302, 319 Antihypertensive, 215, 302, 343, 365, 366 Anti-infective, 302, 336, 344 Anti-Infective Agents, 302, 336 Anti-Inflammatory Agents, 302, 304, 321 Antimicrobial, 32, 302, 324 Antineoplastic, 114, 206, 302, 321, 322, 323, 335, 338, 344, 360, 365, 370, 394 Antineoplastic Agents, 206, 302, 365 Antiproliferative, 30, 31, 302 Antipyretic, 302, 335, 352, 395 Antithrombotic, 302, 379, 398 Antiviral, 47, 110, 136, 168, 295, 302, 332, 349 Anuria, 302, 352 Anus, 203, 242, 300, 301, 302, 309, 384 Anxiety, 243, 302 Aorta, 47, 58, 62, 134, 138, 148, 157, 163, 302, 312, 385, 404 Apheresis, 235, 302 Apnea, 302 Apolipoproteins, 302, 354 Aponeurosis, 303, 337 Aqueous, 28, 82, 83, 144, 153, 162, 200, 238, 303, 306, 323, 329, 344, 353, 354 Arachidonate 12-Lipoxygenase, 303, 355 Arachidonate 15-Lipoxygenase, 303, 355 Arachidonate Lipoxygenases, 303, 355 Arachidonic Acid, 92, 143, 207, 240, 254, 303, 328, 346, 354, 379 Arginase, 6, 65, 72, 95, 103, 303 Aromatic, 198, 202, 228, 303, 359, 373, 395 Arrhythmia, 301, 303, 404 Arterial, 9, 21, 33, 42, 128, 173, 176, 187, 254, 298, 303, 304, 310, 315, 316, 320, 344, 345, 350, 366, 380, 397 Arteriolar, 25, 303, 310, 334, 385 Arterioles, 12, 25, 29, 39, 53, 303, 309, 312, 359, 363, 403 Arteriosclerosis, 92, 106, 107, 114, 143, 303, 345, 398 Arteriosus, 303, 382 Arteriovenous, 304, 315, 359, 398 Arteriovenous Fistula, 304, 398 Arthropathy, 227, 304 Articular, 169, 180, 181, 227, 304, 368 Artificial Eye, 304, 380 Artificial Limbs, 304
Index 413
Artificial Organs, 250, 304 Ascites, 253, 304 Ascitic Fluid, 254, 304 Ascorbic Acid, 124, 158, 203, 304, 344 Aseptic, 304, 368, 394 Aspartate, 79, 154, 304 Asphyxia, 216, 304, 367 Aspirate, 63, 304 Aspiration, 194, 304 Aspirin, 70, 99, 109, 157, 304 Assay, 10, 37, 171, 245, 304, 401 Astigmatism, 5, 304, 384 Astrocytes, 7, 66, 69, 87, 157, 212, 229, 304 Asymptomatic, 113, 227, 295, 299, 304, 370 Ataxia, 278, 279, 304, 343, 397 Atherogenic, 210, 305 Atmospheric Pressure, 305, 344 ATP, 46, 69, 109, 134, 169, 196, 296, 305, 327, 338, 339, 350, 356, 374, 380, 381, 399 Atrial, 66, 197, 254, 305, 320, 400 Atrioventricular, 305, 321 Atrium, 305, 312, 321, 400, 404 Atrophy, 278, 305, 364 Attenuated, 44, 57, 73, 76, 77, 305 Attenuation, 196, 215, 305 Autodigestion, 305, 370 Autoimmune disease, 28, 239, 305, 362 Autologous, 112, 305 Autonomic, 4, 93, 135, 215, 295, 305, 367, 372, 391, 393, 396 Autonomic Nervous System, 215, 305, 372, 391, 396 Autosuggestion, 305, 345 Axillary, 305, 310 Axillary Artery, 305, 310 Axons, 305, 325, 364, 368, 372, 386, 393 B Back Pain, 227, 305 Bacteremia, 305, 390 Bacterial Infections, 195, 237, 306, 315, 340, 385 Bacterial Physiology, 296, 306 Bacterial Translocation, 161, 306 Bactericidal, 71, 306, 332 Bacteriophage, 306, 375, 400 Bacteriostatic, 306, 332 Bacterium, 32, 306 Basal Ganglia, 52, 305, 306, 310, 337 Basal Ganglia Diseases, 305, 306 Base, 17, 181, 296, 306, 324, 325, 327, 332, 336, 338, 352, 353, 397, 401, 402 Basement Membrane, 306, 333
Basilar Artery, 9, 306 Basophil, 306, 343 Benign, 98, 247, 306, 310, 335, 337, 341, 364, 383 Benzene, 243, 306 Beta Rays, 306, 329 Beta-Defensins, 307, 324 Beta-pleated, 300, 307 Beta-Thromboglobulin, 307, 349 Bethanechol, 247, 307 Bile, 39, 62, 120, 307, 337, 342, 343, 351, 355, 378, 394 Bile Acids, 62, 307, 394 Bile Acids and Salts, 307 Bile Ducts, 307, 337, 378 Bile Pigments, 307, 351 Biliary, 62, 307, 370 Biliary Tract, 307, 370 Bilirubin, 298, 307, 337, 344 Binding Sites, 48, 59, 91, 168, 217, 307 Bioassay, 214, 307 Bioavailability, 21, 23, 24, 40, 49, 64, 76, 117, 141, 201, 307 Bioavailable, 23, 307 Biochemical Phenomena, 307, 308 Biochemical reactions, 307, 397 Biological Phenomena, 210, 308 Biological response modifier, 308, 348 Biological therapy, 308, 340 Biological Transport, 308, 326 Biopsy, 15, 308, 371 Biopterin, 11, 47, 308 Biosynthesis, 35, 42, 61, 62, 83, 303, 308, 323, 389 Biotechnology, 39, 64, 90, 144, 265, 275, 277, 278, 279, 308 Biotin, 149, 308 Biphasic, 161, 308 Bivalent, 61, 308, 359 Bladder, 4, 116, 119, 137, 160, 169, 308, 323, 347, 362, 364, 372, 380, 402 Bloating, 308, 351 Blood Cell Count, 308, 341 Blood Coagulation, 182, 308, 311, 398 Blood Coagulation Factors, 308 Blood Glucose, 308, 341, 348 Blood Platelet Disorders, 182, 308 Blood Platelets, 308, 358, 376, 389 Blood Substitutes, 16, 309 Blot, 6, 21, 309, 346 Blotting, Western, 309, 346 Body Fluids, 191, 309, 311, 328, 391
414 Nitric Oxide
Body Mass Index, 117, 309, 369 Bolus, 247, 309 Bolus infusion, 309 Bone Development, 32, 309 Bone Marrow, 306, 309, 332, 340, 346, 356, 358, 362, 378, 391, 394 Bone Marrow Cells, 309, 358 Bone Resorption, 170, 228, 309, 335 Bone scan, 309, 388 Boron, 309, 322 Boronic Acids, 243, 309 Bowel, 62, 203, 242, 300, 309, 326, 330, 347, 349, 353, 372, 394, 402 Bowel Movement, 309, 326, 394 Brachial, 150, 172, 309, 310 Brachial Artery, 150, 310 Brachytherapy, 310, 349, 351, 383, 406 Bradykinin, 23, 51, 115, 196, 226, 310, 351, 366, 375 Brain Ischemia, 310, 315 Brain Neoplasms, 310, 343, 397 Brain Stem, 10, 310, 315, 401 Branch, 291, 310, 329, 356, 357, 371, 382, 385, 392, 396, 397 Breakdown, 228, 310, 314, 326, 337, 368, 369 Broad-spectrum, 43, 310 Bronchi, 310, 311, 331, 351 Bronchial, 27, 33, 105, 125, 127, 213, 307, 310, 343, 380 Bronchial Provocation Tests, 127, 310 Bronchial Spasm, 307, 310 Bronchioles, 299, 310 Bronchiseptica, 310, 373 Bronchitis, 310, 317 Bronchoconstriction, 206, 222, 310 Bronchodilatation, 194, 310 Bronchodilator, 310, 351 Bronchopulmonary, 33, 55, 194, 310 Bronchopulmonary Dysplasia, 55, 194, 310 Bronchoscopy, 27, 311 Bronchus, 310, 311 Brucellosis, 113, 311 Buccal, 311, 356 Budesonide, 97, 311 Bypass, 3, 311, 363, 398 C Cadaver, 246, 311 Calcitonin Gene-Related Peptide, 31, 97, 103, 226, 311
Calcium channel blocker, 230, 247, 311, 366, 404 Calcium Channel Blockers, 247, 311, 366 Calcium Signaling, 7, 13, 84, 311 Calmodulin, 20, 59, 61, 67, 168, 311 Calpain, 14, 311 Cannula, 312, 370 Capillary, 13, 24, 33, 35, 199, 310, 312, 338, 387, 404 Capillary Permeability, 310, 312 Capsaicin, 158, 312 Capsules, 312, 335, 338 Carbohydrate, 312, 321, 339, 367, 377 Carbon Dioxide, 8, 38, 173, 194, 199, 241, 309, 312, 324, 337, 344, 374, 385, 404 Carbon Monoxide Poisoning, 154, 312 Carboxypeptidases, 115, 170, 312 Carcinogen, 296, 312, 359 Carcinogenesis, 168, 223, 249, 312 Carcinogenic, 238, 306, 312, 347, 366, 367, 379, 394 Carcinoma, 100, 111, 125, 146, 158, 312, 323 Cardiac Output, 22, 34, 197, 312, 341, 394 Cardiology, 97, 101, 117, 120, 124, 187, 257, 283, 312 Cardiomyopathy, 97, 101, 312 Cardiopulmonary, 3, 50, 93, 171, 176, 312 Cardiopulmonary Bypass, 93, 176, 312 Cardiotonic, 312, 326, 327, 373 Cardiovascular disease, 11, 15, 28, 32, 40, 42, 54, 61, 79, 215, 229, 230, 233, 254, 261, 313 Cardiovascular System, 29, 40, 65, 122, 257, 261, 313 Carotene, 313, 386 Carotid Arteries, 116, 201, 229, 313 Carrier Proteins, 313, 375 Case report, 313, 317 Case series, 313, 317 Caspase, 11, 41, 42, 73, 75, 155, 313 Cassia, 161, 313, 389 Catabolism, 198, 313 Catalase, 42, 65, 198, 204, 295, 313 Cataracts, 266, 313 Catecholamine, 313, 327, 373 Catfish, 256, 313 Catheterization, 174, 301, 313, 350, 363 Catheters, 250, 251, 313, 336, 346, 349 Cathode, 301, 307, 314, 329 Cations, 232, 314, 350 Cauda Equina, 314, 388
Index 415
Caudal, 314, 326, 345, 377 Causal, 34, 46, 314 Cause of Death, 15, 23, 25, 61, 314 Cell Adhesion, 80, 147, 314, 348 Cell Communication, 180, 244, 314 Cell Cycle, 31, 49, 52, 81, 314, 317, 322, 381 Cell Death, 7, 24, 40, 46, 52, 67, 76, 138, 148, 149, 156, 205, 208, 239, 303, 314, 364 Cell Differentiation, 30, 56, 79, 314, 390, 393 Cell Division, 208, 278, 306, 314, 340, 358, 359, 361, 375, 379, 389 Cell membrane, 211, 308, 311, 313, 314, 325, 333, 337, 350, 374, 376, 377, 405 Cell proliferation, 30, 31, 36, 61, 86, 138, 185, 208, 210, 233, 303, 314, 390 Cell Respiration, 88, 297, 314, 360, 369, 385 Cell Survival, 88, 314, 340 Cell Transplantation, 112, 314 Cellobiose, 314 Cellular metabolism, 46, 205, 235, 314 Cellulose, 21, 314, 375 Central Nervous System Infections, 315, 341, 343 Centrifugation, 315, 341 Ceramide, 78, 315 Cerebellar, 16, 65, 69, 135, 305, 315, 384, 400 Cerebellum, 310, 315, 377, 384 Cerebral Aqueduct, 315, 371, 398 Cerebral Arteries, 70, 147, 168, 306, 315 Cerebral hemispheres, 306, 310, 315, 397 Cerebral Infarction, 315, 344 Cerebral Palsy, 8, 315, 392 Cerebrospinal, 43, 84, 108, 315, 343, 390 Cerebrospinal fluid, 43, 108, 315, 343, 390 Cerebrovascular, 12, 29, 32, 230, 306, 311, 313, 315, 366, 397 Cerebrovascular Circulation, 12, 315 Cerebrovascular Disorders, 29, 315, 397 Cerebrum, 315, 397, 401 Cervical, 91, 129, 316, 355, 364 Cervical Ripening, 91, 129, 316 Cervix, 316 Character, 300, 316, 324 Chemical Warfare, 316, 324 Chemical Warfare Agents, 316, 324 Chemoprevention, 109, 223, 249, 316 Chemotactic Factors, 316, 319 Chemotherapy, 207, 316 Chest Pain, 172, 316 Chiropractic, 245, 316
Chlorine, 224, 255, 316 Cholelithiasis, 63, 316 Cholesterol, 62, 134, 172, 186, 201, 307, 316, 317, 321, 328, 337, 344, 354, 355, 394, 397, 399 Cholesterol Esters, 316, 354 Choline, 215, 316 Cholinergic, 10, 247, 316, 365 Choroid, 43, 55, 316, 320, 386 Chromatin, 303, 316, 392 Chromosomal, 316, 317, 375, 386 Chromosome, 317, 340, 354, 389, 400, 402 Chronic Disease, 40, 195, 205, 317 Chronic lymphocytic leukemia, 124, 317 Chronic Obstructive Pulmonary Disease, 121, 283, 317 Chronic renal, 135, 136, 317, 376, 402 Chylomicrons, 317, 354 Ciliary, 303, 317, 362 Circadian, 85, 317 CIS, 86, 317, 386 Cisplatin, 99, 317 Citrus, 304, 317 C-kit receptor, 317, 393 Clamp, 12, 41, 317 Claudication, 164, 227, 317 Clinical Medicine, 102, 317, 378 Clinical study, 41, 317 Clinical trial, 5, 33, 55, 56, 63, 171, 177, 275, 317, 320, 362, 381, 383 Cloning, 68, 308, 317 Coagulation, 249, 308, 317, 342, 375, 398 Coal, 306, 318 Coca, 215, 318 Cocaine, 11, 318 Cochlea, 143, 318 Codeine, 204, 242, 318, 368 Coenzyme, 206, 304, 318 Cofactor, 47, 61, 318, 365, 380, 398 Colchicine, 318, 401 Colitis, 117, 318, 351 Collagen, 30, 44, 181, 186, 296, 306, 318, 333, 335, 338, 357, 375, 379 Collapse, 11, 310, 318, 341, 391 Colloidal, 298, 318 Colloids, 203, 318, 329 Colorectal, 158, 318 Colostomy, 204, 242, 318 Combinatorial, 66, 318 Complement, 18, 47, 300, 319, 348, 357, 375
416 Nitric Oxide
Complementary and alternative medicine, 141, 165, 319 Complementary medicine, 141, 319 Computational Biology, 275, 277, 319 Computed tomography, 173, 319, 388 Computerized axial tomography, 319, 388 Computerized tomography, 319 Conception, 320, 334, 394 Cone, 320, 352 Confidence Intervals, 213, 320 Congestion, 320, 324, 332 Congestive heart failure, 70, 111, 254, 320, 355 Conjugated, 98, 307, 320, 323, 342, 363 Conjunctiva, 320, 400 Connective Tissue, 33, 228, 304, 309, 318, 320, 335, 337, 338, 356, 372, 386, 387, 396, 401 Connective Tissue Cells, 320 Consciousness, 300, 320, 324, 325, 327, 386 Constipation, 204, 242, 247, 320, 351, 372 Constriction, 25, 205, 221, 320, 351, 403 Constriction, Pathologic, 320, 403 Consumption, 34, 40, 67, 74, 84, 173, 192, 194, 320, 325, 337, 370 Contamination, 234, 320, 342 Contractility, 4, 11, 320 Contraindications, ii, 320 Contralateral, 320, 359, 368, 384 Controlled study, 129, 320 Conus, 320, 382 Convulsions, 320, 328, 378 Coordination, 17, 63, 315, 320, 362 Cor, 5, 15, 320, 321 Cor pulmonale, 15, 321 Cornea, 304, 321, 388, 394 Corneal Transplantation, 5, 321 Corneum, 248, 321, 331 Coronary Arteriosclerosis, 171, 321, 362 Coronary Circulation, 301, 321, 366 Coronary heart disease, 231, 313, 321 Coronary Thrombosis, 321, 359, 362, 363 Corpus, 4, 94, 321, 371, 378, 397 Corpus Luteum, 321, 378 Cortex, 6, 16, 35, 58, 98, 100, 146, 305, 315, 321, 331, 332, 335, 384 Cortical, 112, 321, 389, 397 Corticosteroid, 56, 321, 378 Cortisol, 58, 298, 322 Cortisone, 322, 378 Cranial, 12, 315, 322, 341, 350, 357, 367, 368, 370, 372, 400, 401, 403
Craniocerebral Trauma, 306, 322, 341, 343, 397 Creatinine, 4, 5, 90, 322, 352, 402 Critical Care, 37, 50, 91, 94, 96, 99, 110, 113, 120, 129, 130, 283, 322 Crossing-over, 322, 384 Cross-Linking Reagents, 204, 322 Croton Oil, 322, 373 Cryptosporidiosis, 39, 322 Curative, 322, 365, 397 Curcumin, 144, 322 Cutaneous, 22, 104, 130, 150, 168, 282, 322, 353, 356, 374 Cyanide, 207, 322 Cyanosis, 322, 342 Cyclin, 31, 81, 322 Cyclin A, 31, 322 Cyclophosphamide, 68, 153, 322 Cyclosporins, 189, 323 Cyproterone, 323, 335 Cyst, 304, 323 Cystathionine beta-Synthase, 323, 344 Cysteine, 14, 34, 46, 57, 85, 88, 201, 203, 234, 295, 311, 312, 323, 324, 339, 395 Cystine, 323 Cystitis, 153, 194, 195, 226, 323 Cytochrome, 11, 17, 27, 35, 42, 53, 68, 71, 79, 113, 126, 128, 138, 203, 323, 385 Cytochrome b, 323, 385 Cytokine, 19, 24, 26, 67, 68, 73, 78, 82, 129, 136, 158, 323, 349 Cytoplasm, 6, 182, 303, 311, 314, 323, 331, 340, 359, 363, 387, 388, 396 Cytoskeletal Proteins, 14, 311, 323 Cytoskeleton, 15, 323, 348, 360 Cytostatic, 68, 189, 323 Cytotoxic, 6, 16, 24, 34, 49, 59, 68, 75, 169, 185, 201, 312, 324, 383, 390 Cytotoxicity, 89, 119, 147, 160, 168, 180, 189, 200, 238, 244, 298, 317, 324, 353 Cytotoxins, 181, 324 D Databases, Bibliographic, 275, 324 De novo, 247, 324 Deamination, 214, 324, 402 Decarboxylation, 324, 343 Decidua, 324, 360, 374 Decongestant, 324, 373 Decontamination, 234, 324 Defense Mechanisms, 49, 51, 324, 348 Defensins, 18, 298, 307, 324 Deferoxamine, 198, 324
Index 417
Defibrillation, 59, 324 Degenerative, 181, 186, 201, 227, 320, 324, 342, 356, 368, 386, 387 Deletion, 67, 303, 324 Delirium, 324, 341 Delusions, 325, 381 Dementia, 41, 243, 325 Dendrites, 325, 365 Density, 20, 33, 48, 61, 186, 188, 309, 315, 325, 328, 354, 367, 376, 379, 392 Dentate Gyrus, 325, 343 Depolarization, 325, 390 Deprivation, 7, 44, 325 Dermal, 151, 245, 325 Desensitization, 48, 70, 84, 325 Detoxification, 23, 27, 325 Deuterium, 325, 344 Developed Countries, 325, 336 Diabetes Mellitus, 23, 120, 239, 254, 261, 325, 339, 341 Diabetic Foot, 255, 325 Diabetic Retinopathy, 261, 325, 374 Diagnostic procedure, 179, 266, 325 Diarrhea, 39, 299, 322, 325, 351 Diarrhoea, 325, 337 Diastole, 325 Diastolic, 215, 325, 326, 345 Diastolic blood pressure, 215, 326 Diencephalon, 315, 326, 345, 397 Dietitian, 172, 326 Diffusion, 35, 43, 49, 69, 86, 105, 190, 255, 256, 308, 312, 326, 347, 350 Digestion, 298, 307, 309, 326, 328, 349, 355, 394, 403 Digestive system, 177, 326 Digestive tract, 326, 391, 393 Digitalis, 326, 369 Dihydrotestosterone, 19, 326, 384 Dihydroxy, 298, 326, 379, 387 Dilatation, 29, 128, 300, 301, 326, 378, 403 Dilatation, Pathologic, 326, 403 Dilate, 172, 326 Dilated cardiomyopathy, 243, 326 Dilation, 12, 53, 310, 326, 343, 403 Dilator, 4, 326, 366 Diltiazem, 247, 326 Dimerization, 27, 66, 225, 326 Dimethyl, 25, 326, 351, 355, 365, 366 Diploid, 326, 375 Dipyridamole, 211, 326 Disaccharides, 197, 326 Disease Progression, 6, 129, 326
Disinfectant, 326, 332 Disposition, 61, 327 Dissociation, 297, 327, 350 Distal, 49, 247, 327, 329, 352, 381 Diuretic, 162, 327, 351, 392 DNA Polymerase beta, 112, 327 DNA Topoisomerase, 327, 338 Dobutamine, 66, 327 Dominance, 112, 327 Dopamine, 4, 203, 242, 318, 327, 373 Dorsal, 327, 377, 392, 393 Dorsum, 327, 337 Dose-dependent, 161, 327 Drive, ii, vi, 39, 133, 188, 227, 232, 251, 327, 350, 354 Drug Delivery Systems, 190, 327 Drug Interactions, 270, 327 Drug Tolerance, 328, 399 Duct, 120, 312, 313, 328, 370, 387 Duodenum, 307, 328, 394 Dura mater, 328, 358, 370 Dyes, 203, 300, 328, 336, 366, 373 Dynamometer, 172, 328 Dyslipidemia, 231, 254, 328 Dyspepsia, 207, 328 Dysplasia, 33, 279, 328 Dystrophy, 278, 328 E Eclampsia, 328, 378 Ecosystem, 295, 328 Edema, 33, 181, 259, 325, 328, 350, 363, 366, 378, 402 Effector, 25, 69, 215, 295, 319, 328, 353, 365, 373 Effector cell, 328, 353, 365 Efficacy, 70, 91, 328, 355 Eicosanoids, 98, 328 Elastin, 21, 33, 186, 318, 328, 333, 401 Elective, 328 Electric shock, 324, 328 Electroacupuncture, 150, 329 Electrocardiogram, 172, 173, 329 Electrochemistry, 47, 329 Electrocoagulation, 318, 329 Electrode, 192, 301, 314, 329 Electrolysis, 301, 314, 329 Electrolyte, 298, 321, 324, 329, 353, 360, 377, 391, 402 Electrons, 44, 60, 192, 302, 306, 314, 329, 350, 369, 382, 383 Electrophysiological, 329, 404 Elementary Particles, 329, 365, 381
418 Nitric Oxide
Embolism, 194, 329, 349, 382 Embolus, 329, 347, 349 Embryo, 48, 309, 314, 329, 338, 347, 369, 376 Embryogenesis, 329, 393 Emesis, 243, 329 Emphysema, 298, 317, 329 Emulsions, 309, 329 Encapsulated, 203, 329 Encephalitis, 329, 330 Encephalomyelitis, 84, 330 Encephalopathy, 97, 330 Endarterectomy, 301, 330 Endemic, 113, 330, 357, 393 Endometrial, 18, 330 Endometriosis, 128, 330 Endometrium, 18, 102, 324, 330, 358, 360 Endothelium, Lymphatic, 330 Endothelium, Vascular, 330 Endotoxemia, 175, 330 Endotoxin, 24, 52, 63, 68, 70, 196, 211, 222, 330, 366, 401 End-stage renal, 317, 330, 376 Energy balance, 330, 353 Enteric Nervous System, 67, 169, 330 Enteritis, 39, 330 Enterocolitis, 330 Enterocytes, 39, 331 Entorhinal Cortex, 138, 331, 343 Environmental Exposure, 331, 367 Environmental Health, 105, 118, 144, 274, 276, 331 Enzymatic, 53, 61, 71, 185, 189, 205, 311, 313, 319, 331, 335, 343, 386, 401 Enzyme Inhibitors, 331, 375 Eosinophil, 99, 331 Eosinophilic, 331 Epicondylitis, 264, 331 Epidemic, 254, 261, 331, 393 Epidemiological, 24, 40, 54, 331 Epidermal, 331, 352, 358 Epidermis, 321, 331, 352, 378 Epidermoid carcinoma, 331, 393 Epinephrine, 176, 297, 327, 331, 351, 367, 401 Epithelial Cells, 27, 43, 68, 69, 70, 100, 104, 126, 201, 307, 331, 342 Epithelium, 43, 191, 208, 306, 330, 331, 337 Epoprostenol, 331, 346 Erectile, 4, 37, 128, 164, 196, 331, 332, 371 Erection, 4, 37, 331, 332, 378 Erythema, 181, 332, 395
Erythrocytes, 76, 300, 308, 309, 311, 332, 384 Erythromycin, 122, 332 Erythropoietin, 79, 332 Esophageal, 122, 332 Esophagus, 326, 332, 373, 384, 394 Essential Tremor, 278, 332 Estradiol, 26, 58, 147, 332 Estrogen, 13, 18, 19, 20, 26, 48, 58, 85, 217, 218, 323, 332, 389, 397, 399 Estrogen receptor, 26, 218, 332 Ethanol, 40, 157, 332 Ethidium, 332, 379 Etodolac, 236, 332 Eukaryotic Cells, 72, 323, 332, 347, 368, 402 Evacuation, 320, 332, 353 Evoke, 332, 394 Excipients, 332, 336, 373 Excitation, 12, 120, 188, 299, 333 Excitotoxicity, 201, 333 Excrete, 302, 333, 352 Exercise Test, 172, 333 Exercise Tolerance, 92, 174, 333 Exhaustion, 301, 333, 357 Exocytosis, 333, 343, 396 Exogenous, 11, 31, 35, 36, 39, 50, 66, 76, 89, 129, 139, 218, 222, 333, 338, 380, 401 Exotoxin, 89, 333 Expiration, 193, 333, 336, 348, 385, 405 Expiratory, 33, 102, 213, 333, 336, 399 External-beam radiation, 333, 351, 383, 406 Extracellular Matrix, 30, 320, 333, 335, 336, 348, 357, 368 Extracellular Matrix Proteins, 333, 336, 357 Extracellular Space, 333, 360 Extracorporeal, 103, 127, 333, 342 Extracorporeal Circulation, 103, 127, 333 Extrapyramidal, 327, 333 Extravasation, 60, 128, 333 Eye Infections, 296, 334 F Facial, 228, 334, 391 Family Planning, 275, 334 Fascioliasis, 123, 334 Fat, 194, 296, 303, 307, 309, 313, 315, 320, 321, 329, 334, 353, 354, 362, 367, 369, 377, 386, 395 Fatigue, 282, 334, 341 Fatty acids, 41, 96, 298, 328, 334, 354, 379
Index 419
Fecal Incontinence, 203, 242, 334, 347 Feces, 203, 242, 320, 334, 394 Felodipine, 247, 334 Femoral, 20, 174, 312, 334, 377 Femoral Artery, 312, 334 Femoral Vein, 20, 334, 377 Femur, 334 Ferritin, 102, 334 Fertilizers, 224, 334, 366 Fetal Hemoglobin, 65, 72, 334 Fetus, 8, 11, 58, 130, 309, 332, 334, 374, 378, 403 Fibrillation, 324, 334 Fibrin, 136, 308, 334, 335, 372, 375, 398 Fibrinogen, 334, 375, 398 Fibrinolytic, 51, 335 Fibroblast Growth Factor, 43, 108, 158, 335 Fibroblasts, 34, 81, 116, 151, 229, 320, 335, 349 Fibronectin, 234, 335 Fibrosis, 5, 30, 70, 126, 279, 298, 335, 388 Filler, 241, 335 Filtration, 33, 335, 352 Finasteride, 19, 335 Fissure, 247, 325, 335 Flatus, 334, 335, 337 Flavoring Agents, 335, 336, 373 Fluorescence, 15, 27, 42, 54, 168, 255, 256, 332, 335 Fluorouracil, 326, 335 Fluoxetine, 93, 335 Flurbiprofen, 236, 335 Flushing, 196, 335 Flutamide, 19, 335 Foam Cells, 186, 335 Focal Adhesions, 53, 335 Folate, 114, 336 Fold, 48, 335, 336, 359 Folic Acid, 336 Food Additives, 211, 336 Food Coloring Agents, 336 Food Preservatives, 336 Foot Ulcer, 325, 336 Foramen, 336, 342, 372 Forearm, 23, 94, 99, 115, 172, 309, 336 Fractionation, 14, 299, 336 Frameshift, 336, 401 Frameshift Mutation, 336, 401 Friction, 251, 336 Fructose, 336, 339 Functional Residual Capacity, 336, 399 Fungemia, 336, 390
Fungi, 302, 323, 334, 336, 337, 359, 360, 406 Fungicide, 337, 357 G Gallate, 138, 142, 337 Gallbladder, 98, 295, 307, 326, 337 Gallstones, 63, 307, 316, 337 Gamma Rays, 337, 383 Ganglia, 32, 52, 295, 306, 330, 337, 364, 372, 393, 396 Ganglion, 267, 337, 368, 386, 400 Gap Junctions, 337, 396 Gas exchange, 13, 33, 175, 193, 194, 218, 337, 343, 385, 386, 404 Gasoline, 306, 337 Gastric, 150, 157, 237, 267, 305, 337, 343, 394 Gastric Acid, 237, 337 Gastric Mucosa, 157, 267, 337 Gastrin, 337, 343 Gastroenteritis, 5, 337 Gastrointestinal tract, 62, 123, 306, 332, 337, 354, 389, 394 Gelatin, 338, 339, 398 Gene Expression, 11, 18, 24, 31, 48, 70, 73, 80, 89, 108, 136, 221, 266, 279, 338 Gene Targeting, 25, 338 Genetic Code, 338, 367 Genetics, 45, 327, 338 Genistein, 144, 338 Genital, 338, 402 Genitourinary, 195, 338, 402 Genotype, 92, 107, 108, 338, 373 Germ Layers, 309, 338 Gestation, 8, 130, 338, 372, 374, 378 Giardiasis, 338, 359 Ginkgo biloba, 165, 215, 338 Ginseng, 108, 165, 338 Gland, 35, 296, 297, 322, 338, 356, 370, 374, 380, 388, 389, 394, 398 Glioma, 146, 153, 338 Glomerular, 19, 338, 352, 366, 385 Glomerular Filtration Rate, 338, 352, 366 Glomerulus, 338, 352, 364 Glottis, 338, 373 Glucocorticoid, 151, 228, 266, 311, 339, 360, 378 Glucose, 19, 46, 114, 228, 231, 261, 262, 278, 298, 304, 308, 314, 325, 339, 341, 348, 374, 388, 392 Glucose Intolerance, 231, 325, 339 Glucose tolerance, 339 Glucose Tolerance Test, 339
420 Nitric Oxide
Glutamate, 7, 16, 40, 61, 83, 108, 124, 162, 333, 339 Glutamate-Cysteine Ligase, 124, 339 Glutamic Acid, 336, 339, 342, 379 Glutathione Peroxidase, 23, 205, 339 Glycine, 299, 307, 339, 389 Glycols, 339, 344 Glycolysis, 234, 339 Glycoprotein, 298, 332, 334, 335, 339, 362, 398, 401 Glycoside, 162, 326, 339, 369, 387 Goblet Cells, 331, 339 Gonad, 339 Gonadal, 19, 339, 394 Governing Board, 340, 377 Graft, 31, 189, 239, 323, 340, 343, 346, 362, 363 Graft Rejection, 239, 323, 340, 346 Graft Survival, 189, 340 Grafting, 204, 242, 340, 346 Graft-versus-host disease, 340, 362 Gram-negative, 24, 77, 306, 310, 330, 340, 386, 390 Gram-Negative Bacteria, 24, 77, 340, 386 Gram-positive, 340, 390, 394 Granule, 135, 325, 340, 387 Granulocytes, 306, 340, 354, 362, 390, 405 Granulomatous Disease, Chronic, 340, 385 Growth factors, 36, 43, 56, 182, 186, 228, 229, 340 Guanosine Triphosphate, 211, 340 Guanylate Cyclase, 33, 65, 67, 72, 85, 91, 94, 180, 187, 189, 197, 211, 244, 340, 366 H Haematemesis, 329, 340 Hair follicles, 340, 405 Half-Life, 27, 186, 340, 346 Haploid, 340, 375 Haptens, 297, 340 Headache, 108, 121, 128, 129, 196, 256, 341, 343, 403 Headache Disorders, 341 Heart attack, 172, 204, 313, 341 Heart Catheterization, 174, 341 Heart failure, 229, 264, 321, 341 Heat Stroke, 23, 341 Hematocrit, 39, 308, 341 Hematopoiesis, 208, 209, 341 Hematopoietic Stem Cells, 208, 209, 341 Hematopoietic tissue, 208, 209, 309, 341 Hemicrania, 341, 403 Hemocytes, 138, 341
Hemodialysis, 341, 352, 353 Hemodynamics, 26, 50, 94, 175, 255, 264, 341, 352 Hemoglobin A, 235, 341, 377 Hemoglobin E, 174, 342 Hemoglobin H, 334, 342 Hemoglobin M, 174, 322, 342 Hemoglobinuria, 278, 342 Hemoperfusion, 97, 342 Hemorrhage, 52, 182, 309, 322, 329, 341, 342, 363, 394, 405 Hemostasis, 182, 342, 348, 389 Hepatic, 62, 86, 123, 139, 149, 253, 298, 324, 339, 342, 355 Hepatitis, 85, 110, 123, 173, 234, 342, 371 Hepatitis A, 234, 342 Hepatocytes, 189, 342 Hepatorenal Syndrome, 254, 342 Hepatovirus, 342 Hereditary, 298, 342, 364, 386 Heredity, 338, 342 Herniated, 226, 342 Hesperidin, 151, 342 Heterodimers, 342, 348 Heterogeneity, 297, 342 Heterotrophic, 158, 336, 342 Heterozygotes, 327, 342 Hippocampus, 142, 325, 343, 395 Histamine, 60, 128, 157, 181, 197, 226, 300, 310, 343, 355 Histamine Release, 60, 300, 343 Histidine, 343 Homeostasis, 7, 43, 57, 62, 64, 145, 201, 239, 254, 343, 391 Homologous, 48, 81, 308, 322, 338, 342, 343, 381, 389, 396, 400 Homozygotes, 327, 343 Hormonal, 19, 305, 321, 343 Host, 18, 32, 49, 72, 86, 184, 186, 196, 306, 324, 340, 343, 346, 354, 386, 405 Humoral, 12, 37, 244, 340, 343, 398 Humour, 343 Hyaline membrane disease, 194, 343 Hybridomas, 343, 349 Hydra, 343, 351 Hydralazine, 229, 230, 343 Hydrocephalus, 43, 343, 350, 351 Hydrofluoric Acid, 344, 391 Hydrogen Cyanide, 241, 344 Hydrogen Peroxide, 49, 122, 203, 228, 313, 339, 344, 354, 395
Index 421
Hydrolysis, 191, 200, 238, 303, 314, 317, 344, 350, 373, 376, 381, 401 Hydrophilic, 251, 344 Hydrophobic, 56, 188, 189, 344, 354 Hydroxides, 344 Hydroxyl Radical, 59, 137, 197, 255, 344 Hydroxylysine, 318, 344 Hydroxyproline, 318, 344 Hydroxyurea, 65, 72, 111, 344 Hyperbaric, 153, 344 Hyperbaric oxygen, 153, 344 Hyperbilirubinemia, 344, 351 Hypercapnia, 39, 344 Hypercholesterolemia, 42, 62, 63, 64, 328, 344 Hyperglycemia, 22, 23, 228, 344 Hyperhomocysteinemia, 21, 24, 323, 344 Hyperlipidemia, 328, 345 Hyperplasia, 201, 246, 335, 345 Hypersensitivity, 298, 325, 331, 345, 354, 387 Hyperthermia, 22, 259, 345 Hypertriglyceridemia, 328, 345 Hypertrophy, 19, 321, 345, 400 Hyperuricemia, 54, 345 Hypotension, 11, 25, 58, 73, 196, 210, 232, 244, 267, 307, 320, 345 Hypotensive, 58, 190, 345, 352 Hypothalamus, 66, 143, 148, 305, 310, 326, 345, 374, 397 Hypothyroidism, 129, 345 Hypoxanthine, 345, 406 Hypoxemia, 8, 175, 345 I Iatrogenic, 23, 345 Ibuprofen, 345, 352, 395 Id, 140, 163, 278, 283, 284, 290, 292, 345 Idiopathic, 44, 51, 112, 194, 345 Iliac Vein, 334, 346 Iloprost, 12, 110, 346 Imidazole, 17, 189, 222, 308, 343, 346 Immune response, 18, 77, 184, 296, 299, 302, 305, 321, 322, 340, 346, 357, 395, 405 Immune system, 16, 181, 196, 201, 210, 308, 328, 346, 354, 356, 362, 363, 373, 403, 405 Immunity, 19, 74, 77, 78, 100, 104, 118, 121, 124, 184, 189, 324, 346, 349, 367 Immunization, 296, 346 Immunoblotting, 19, 38, 346 Immunodeficiency, 74, 80, 84, 278, 346 Immunogenic, 60, 204, 346
Immunoglobulins, 235, 346, 375 Immunohistochemistry, 6, 19, 37, 58, 346 Immunologic, 76, 296, 316, 346, 383 Immunology, 96, 97, 114, 119, 125, 126, 127, 153, 156, 158, 184, 260, 296, 297, 346 Immunosuppressive, 189, 322, 323, 339, 346, 397 Immunosuppressive therapy, 346 Immunotherapy, 55, 296, 308, 325, 346 Impairment, 24, 29, 62, 124, 187, 253, 304, 315, 324, 334, 346, 359, 381 Implant radiation, 346, 349, 351, 383, 406 Implantation, 18, 48, 102, 119, 176, 188, 320, 346 Impotence, 4, 190, 332, 346 In situ, 6, 9, 36, 245, 347 In Situ Hybridization, 6, 347 In vitro, 6, 9, 10, 12, 14, 18, 19, 20, 28, 35, 38, 43, 48, 49, 51, 53, 57, 60, 69, 74, 78, 88, 94, 100, 134, 136, 137, 149, 162, 181, 182, 210, 211, 221, 235, 347, 397 Incision, 347, 350 Incontinence, 203, 242, 343, 347 Incubation, 36, 347, 373 Incubation period, 347, 373 Indicative, 213, 219, 255, 347, 371, 403 Infarction, 28, 30, 186, 230, 310, 315, 347, 385, 398 Infiltration, 117, 201, 210, 347 Inflammatory bowel disease, 95, 223, 243, 248, 249, 347 Infusion, 3, 58, 66, 91, 173, 222, 347, 363, 400 Ingestion, 13, 163, 265, 339, 347, 376 Inhalation, 66, 119, 173, 176, 187, 194, 206, 219, 221, 222, 225, 297, 310, 347, 376 Initiation, 3, 16, 48, 61, 63, 175, 347, 400 Initiator, 347, 349 Inlay, 348, 386 Inorganic, 195, 198, 202, 241, 309, 317, 344, 348, 362, 366, 395 Inositol, 150, 348, 388 Inotropic, 327, 334, 348 Insight, 9, 32, 33, 38, 40, 54, 64, 348 Inspiratory Capacity, 348, 399 Inspiratory Reserve Volume, 348, 399 Insulator, 224, 348, 362 Insulin, 4, 15, 51, 106, 114, 119, 126, 146, 154, 170, 231, 232, 254, 261, 339, 348, 401 Insulin-dependent diabetes mellitus, 348 Insulin-like, 126, 348 Integrins, 53, 336, 348
422 Nitric Oxide
Intensive Care, 11, 25, 173, 190, 212, 259, 348 Intensive Care Units, 11, 25, 348 Interferon, 67, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79, 87, 89, 111, 145, 223, 348, 349 Interferon-alpha, 348 Interleukin-1, 67, 69, 74, 89, 124, 154, 239, 349 Interleukin-12, 67, 69, 74, 124, 349 Interleukin-2, 349 Interleukin-4, 67, 226, 349 Interleukin-6, 136, 226, 349 Interleukin-8, 63, 69, 100, 136, 226, 349 Intermittent, 127, 164, 195, 205, 349 Internal Medicine, 9, 24, 39, 59, 349, 387 Internal radiation, 349, 351, 383, 406 Interstitial, 20, 54, 194, 195, 197, 226, 310, 333, 349, 351, 364, 385, 406 Intervertebral, 227, 342, 349, 355, 383, 388 Intervertebral Disk Displacement, 349, 355, 383, 388 Intestinal, 19, 23, 62, 197, 217, 298, 306, 313, 322, 330, 331, 339, 349, 357, 370, 403 Intestine, 307, 309, 330, 349, 353, 372 Intoxication, 324, 349, 405 Intracranial Embolism, 315, 349 Intracranial Embolism and Thrombosis, 315, 349 Intracranial Hemorrhages, 343, 350, 397 Intracranial Hypertension, 341, 343, 350 Intrathecal, 162, 350 Intravascular, 51, 74, 341, 350 Intravenous, 22, 91, 150, 173, 336, 347, 350 Intrinsic, 83, 297, 306, 350 Intubation, 313, 350 Invasive, 50, 69, 100, 213, 218, 346, 350, 357 Invertebrates, 341, 350 Involuntary, 306, 332, 334, 350, 363, 384, 391, 392 Ion Channels, 52, 211, 304, 350, 365, 396 Ion Exchange, 315, 350, 351 Ion Transport, 43, 350, 360 Ionization, 350, 351 Ionizing, 298, 331, 350, 383 Ions, 41, 207, 248, 306, 311, 327, 329, 344, 350, 361, 377, 381, 388 Iontophoresis, 264, 350 Irradiation, 221, 351, 406 Irritable Bowel Syndrome, 127, 351 Ischemic stroke, 204, 351 Isoenzyme, 9, 351
Isoproterenol, 94, 351 Isosorbide, 129, 229, 230, 351 Isosorbide Dinitrate, 230, 351 Isozymes, 53, 59, 225, 351 Isradipine, 247, 351 J Jaundice, 254, 342, 344, 351 Jellyfish, 226, 351 Joint, 45, 118, 121, 135, 180, 181, 258, 266, 282, 304, 351, 368, 393, 396 K Kallidin, 226, 310, 351 Kallikrein-Kinin System, 51, 352 Kallikreins, 351, 352 Kb, 274, 352 Keratin, 352 Keratinocytes, 214, 349, 352 Keratoconus, 5, 352 Keto, 193, 229, 352 Ketoprofen, 236, 352 Kidney Cortex, 352, 359 Kidney Disease, 19, 129, 177, 195, 254, 261, 274, 279, 352 Kidney Failure, 20, 330, 352 Kidney Failure, Acute, 352 Kidney Failure, Chronic, 352 Kidney stone, 353, 402 Kidney Transplantation, 246, 353 Killer Cells, 353 Kinetic, 27, 49, 182, 350, 353 L Labile, 186, 244, 319, 353 Labyrinth, 318, 353, 404 Lactation, 353, 370 Large Intestine, 326, 349, 353, 384, 391 Laryngeal, 118, 353 Larynx, 338, 353 Latency, 157, 353 Lavage, 33, 353 Laxative, 353, 392 Lectin, 89, 353, 358 Left ventricular assist device, 119, 176, 353 Leishmaniasis, 73, 130, 353 Lens, 144, 313, 353 Leptin, 41, 85, 353 Lesion, 82, 184, 186, 336, 353, 355, 402 Lethal, 50, 197, 306, 322, 353 Lethargy, 343, 345, 354 Leucocyte, 331, 354 Leukapheresis, 302, 354 Leukemia, 124, 278, 334, 354, 378
Index 423
Leukocytes, 9, 49, 63, 123, 183, 211, 308, 309, 316, 340, 348, 354, 401 Leukotrienes, 197, 303, 328, 354 Libido, 300, 354 Library Services, 290, 354 Lidoflazine, 247, 354 Life cycle, 308, 337, 354 Ligament, 354, 380, 393 Ligands, 17, 348, 354 Ligation, 17, 20, 88, 354 Linkages, 341, 354 Linoleic Acids, 98, 354 Lipid Peroxidation, 129, 137, 168, 228, 354, 369 Lipophilic, 167, 248, 354 Lipoprotein, 186, 328, 340, 354, 355 Liposome, 201, 354 Lipoxygenase, 67, 154, 156, 206, 303, 354 Lisinopril, 47, 355 Liver Circulation, 254, 355 Liver Cirrhosis, 175, 342, 355 Liver scan, 355, 388 Liver Transplantation, 64, 254, 355 Localization, 7, 14, 18, 27, 48, 61, 116, 346, 355 Localized, 12, 28, 35, 185, 190, 196, 310, 329, 347, 355, 364, 375, 402 Locomotion, 355, 375 Longitudinal study, 130, 355 Long-Term Potentiation, 59, 65, 87, 355 Loperamide, 204, 242, 355 Lordosis, 355, 372 Low Back Pain, 227, 355 Low-density lipoprotein, 42, 62, 186, 210, 328, 354, 355 Luciferase, 32, 356 Lumbar, 227, 305, 314, 349, 355, 356 Luminol, 203, 356 Lung Transplantation, 91, 113, 130, 175, 356 Lupus, 135, 173, 214, 282, 356, 397 Luteal Phase, 356, 360 Lymph, 33, 305, 306, 316, 330, 343, 356 Lymph node, 305, 306, 316, 356 Lymphatic, 330, 347, 356, 376, 391, 393 Lymphatic system, 356, 391, 393 Lymphocyte, 302, 353, 356, 357, 358 Lymphocytic, 117, 356 Lymphoid, 209, 301, 354, 356 Lymphokine, 119, 356 Lymphokine-activated killer cells, 119, 356
Lymphoma, 278, 356 Lysine, 342, 344, 356, 401 M Macula, 54, 256, 356 Macula Lutea, 356 Macular Degeneration, 243, 356 Magnetic Resonance Imaging, 21, 173, 204, 227, 357, 388 Major Histocompatibility Complex, 266, 349, 357 Malabsorption, 278, 357 Malaise, 311, 357 Malaria, 67, 72, 80, 107, 113, 117, 121, 124, 234, 357 Malaria, Falciparum, 357 Malaria, Vivax, 357 Malignant, 98, 138, 156, 214, 220, 221, 278, 296, 302, 310, 357, 364, 383 Malnutrition, 298, 305, 357, 362 Mammary, 357, 397, 399 Mandibular Nerve, 357, 401 Maneb, 51, 357 Manic, 357, 381 Manic-depressive psychosis, 357, 381 Manifest, 115, 357 Mastication, 357, 400, 401 Matrix metalloproteinase, 21, 151, 357 Maxillary, 358, 370, 401 Mechanical ventilation, 33, 173, 311, 358 Medial, 10, 303, 358, 368 Mediate, 6, 11, 26, 31, 36, 61, 84, 158, 327, 353, 358 Medicament, 221, 358 MEDLINE, 275, 277, 279, 358 Medullary, 135, 358 Megakaryocytes, 181, 182, 309, 358, 398 Meiosis, 308, 358, 396, 402 Melanin, 358, 373, 401 Melanocytes, 358 Melanoma, 55, 99, 264, 278, 358 Membrane Glycoproteins, 358 Membrane Proteins, 358, 381 Memory, 212, 216, 301, 324, 325, 355, 358 Meninges, 315, 322, 328, 358 Meningitis, 60, 358 Menstrual Cycle, 356, 358, 378 Menstruation, 18, 324, 356, 358 Mental Disorders, 178, 358, 381 Mental Health, iv, 5, 178, 274, 276, 359, 382 Mental Retardation, 8, 280, 359 Mesencephalic, 52, 359, 384
424 Nitric Oxide
Mesenteric, 47, 58, 134, 306, 359 Mesentery, 39, 359, 372 Metabolite, 326, 359, 378, 383 Metalloporphyrins, 27, 359 Metallothionein, 41, 75, 85, 359 Metaphase, 308, 359, 402 Metastasis, 221, 357, 359 Metastasize, 55, 359, 388 Metastatic, 228, 310, 359, 388 Methionine, 326, 359, 395 Metronidazole, 70, 74, 359 MI, 28, 30, 51, 72, 77, 123, 159, 202, 249, 293, 359 Microbe, 359, 399 Microbiology, 184, 260, 296, 359 Microcirculation, 9, 12, 39, 54, 105, 255, 259, 355, 359, 375 Microdialysis, 10, 15, 16, 23, 245, 360 Microfilaments, 335, 360 Microorganism, 318, 360, 371, 405 Micro-organism, 328, 360, 390 Microscopy, 7, 12, 14, 16, 27, 41, 259, 306, 360 Microspheres, 8, 360 Microtubules, 360, 370 Mifepristone, 102, 360 Migration, 39, 66, 74, 186, 360 Mineralocorticoids, 296, 321, 360 Mitochondria, 6, 11, 24, 41, 73, 98, 101, 256, 360, 363, 368 Mitochondrial Swelling, 360, 364 Mitogen-Activated Protein Kinase Kinases, 360 Mitogen-Activated Protein Kinases, 11, 360 Mitomycin, 115, 360 Mitosis, 303, 361 Mitotic, 49, 361, 404 Mobilization, 311, 361 Modeling, 20, 34, 38, 119, 168, 256, 361 Modification, 12, 57, 112, 150, 162, 210, 261, 361 Modulator, 4, 26, 259, 361 Molecular Structure, 361, 400 Monitor, 23, 26, 92, 95, 148, 162, 203, 322, 361, 367 Monoclonal, 343, 346, 351, 361, 383, 406 Monoclonal antibodies, 346, 361 Monocyte, 67, 72, 89, 102, 174, 210, 361 Mononuclear, 17, 67, 77, 80, 121, 124, 183, 184, 361, 401
Monophosphate, 80, 127, 187, 189, 196, 211, 361 Morphine, 71, 162, 203, 204, 242, 243, 318, 361, 363, 368 Morphogenesis, 30, 361 Morphological, 104, 134, 182, 329, 358, 361 Motility, 52, 63, 85, 92, 143, 170, 204, 214, 242, 267, 361, 389 Motor Neurons, 6, 43, 361 Mucinous, 337, 361 Mucins, 331, 339, 361, 387 Mucociliary, 106, 122, 362, 391 Mucocutaneous, 353, 362 Mucolytic, 295, 362 Mucosa, 117, 306, 330, 331, 337, 356, 362, 363, 403 Mucus, 361, 362, 402 Multicenter study, 91, 96, 362 Multiple Organ Failure, 24, 362 Multiple sclerosis, 41, 84, 223, 232, 243, 248, 249, 362 Muscle Contraction, 300, 362, 388 Muscle Fibers, 362 Muscular Atrophy, 278, 362 Muscular Dystrophies, 328, 362 Mutagenic, 265, 362, 366 Mycophenolate mofetil, 135, 362 Mydriatic, 326, 362, 373 Myelin, 362 Myelodysplastic syndrome, 104, 362, 391 Myeloid Cells, 209, 362 Myocardial infarction, 23, 24, 28, 30, 40, 107, 186, 197, 198, 230, 307, 321, 327, 359, 362, 363 Myocardial Ischemia, 229, 300, 362 Myocardial Reperfusion, 363, 385 Myocardial Reperfusion Injury, 363, 385 Myocarditis, 214, 363 Myocardium, 28, 30, 102, 116, 205, 300, 359, 362, 363 Myofibrils, 311, 363 Myoglobin, 235, 363, 377 Myotonic Dystrophy, 278, 363 N Naive, 363 Narcosis, 363 Narcotic, 174, 361, 363, 367 Nasal Cavity, 213, 363, 370 Nasal Septum, 363 Natural killer cells, 349, 363 Nausea, 337, 363, 402 NCI, 1, 177, 273, 317, 364
Index 425
Neck Pain, 226, 364 Necrosis, 65, 67, 69, 70, 78, 87, 89, 97, 129, 145, 151, 152, 158, 170, 174, 181, 226, 239, 303, 315, 347, 359, 362, 363, 364, 385, 401 Need, 3, 8, 24, 176, 195, 223, 227, 247, 249, 253, 260, 266, 267, 285, 297, 317, 357, 364, 399 Neonatal, 12, 39, 98, 103, 118, 222, 263, 283, 364 Neoplasia, 278, 364 Neoplasm, 364, 401 Neoplastic, 343, 356, 364 Nephritis, 135, 364 Nephron, 338, 352, 364 Nephropathy, 19, 254, 261, 352, 364 Nephrosis, 342, 364 Nerve Fibers, 226, 364, 392 Nervous System, 4, 7, 60, 169, 180, 201, 216, 244, 258, 278, 295, 297, 299, 305, 306, 310, 315, 318, 337, 339, 354, 355, 358, 361, 362, 364, 365, 368, 372, 377, 389, 396 Neural, 37, 189, 225, 297, 300, 311, 343, 364 Neuroblastoma, 98, 122, 129, 364 Neurodegenerative Diseases, 41, 52, 243, 306, 364 Neurogenic, 31, 60, 136, 227, 364, 402 Neurogenic Inflammation, 31, 60, 364 Neurologic, 210, 343, 364 Neuromuscular, 139, 295, 364, 365, 376, 402 Neuromuscular Junction, 295, 365 Neuropathy, 243, 254, 298, 365, 371, 388 Neuropeptide, 31, 128, 311, 365 Neurotoxic, 40, 61, 295, 365 Neurotoxicity, 41, 51, 259, 365 Neurotoxins, 122, 365 Neurotransmitters, 4, 169, 215, 361, 365, 391, 403 Neutrons, 298, 351, 365, 382, 383 Neutrophil, 95, 120, 162, 174, 190, 298, 365 New Guinea, 124, 365 Niacin, 365, 401 Nicardipine, 247, 365 Nickel, 136, 365 Nicotine, 29, 100, 365 Nifedipine, 70, 247, 365 Nimodipine, 247, 366 Nisoldipine, 247, 366 Nitrates, 58, 172, 366 Nitrendipine, 247, 366
Nitric acid, 224, 366 Nitric-Oxide Synthase, 123, 366 Nitrogen Dioxide, 169, 183, 199, 200, 205, 219, 224, 237, 256, 366 Nitrogen Oxides, 17, 49, 183, 219, 295, 366 Nitroglycerin, 3, 93, 121, 148, 172, 185, 191, 198, 212, 351, 366 Nitroprusside, 190, 202, 366 Nitrosamines, 238, 366, 367 Nitrosation, 71, 85, 367 Nitrous Oxide, 17, 169, 188, 205, 367 Norepinephrine, 176, 215, 297, 327, 367 Normotensive, 41, 51, 367 Nuclear, 21, 24, 35, 66, 76, 92, 109, 121, 141, 143, 218, 306, 329, 332, 337, 364, 367, 386 Nuclei, 6, 10, 112, 150, 298, 329, 357, 361, 365, 367, 368, 381 Nucleic acid, 5, 200, 201, 246, 322, 332, 338, 345, 347, 366, 367, 382 Nutritive Value, 336, 367 O Obstetrics, 26, 45, 107, 128, 129, 367 Ocular, 55, 139, 211, 367 Oculomotor, 359, 367 Odour, 303, 367, 402 Oliguria, 352, 367 Omega-3 fatty acid, 154, 367 Oncogene, 31, 111, 121, 278, 367, 393 Oncogenic, 348, 367, 381 Oncology, 111, 113, 137, 148, 153, 156, 249, 367 Opacity, 313, 325, 367 Ophthalmic, 236, 367, 377, 400, 401 Opium, 361, 368 Opsin, 368, 386 Optic Chiasm, 345, 368 Optic Disk, 320, 325, 356, 368 Optic Nerve, 134, 368, 370, 386, 388 Optic nerve head, 134, 368 Organ Culture, 57, 368 Organ Transplantation, 323, 368 Organelles, 43, 315, 323, 358, 368, 375 Osmolarity, 245, 368 Osmoles, 368 Osmosis, 368 Osmotic, 122, 229, 298, 351, 360, 368 Osseointegration, 309, 368 Osteoarthritis, 181, 195, 207, 240, 243, 332, 352, 368 Osteoblasts, 129, 228, 368 Osteoclasts, 228, 369
426 Nitric Oxide
Osteogenesis, 309, 369 Osteolytic, 228, 369 Osteoporosis, 228, 369 Ouabain, 51, 369 Outpatient, 174, 369 Ovary, 321, 332, 339, 369, 376 Overexpress, 7, 369 Overweight, 41, 139, 369 Ovulation, 243, 356, 369 Ovum, 295, 321, 324, 338, 354, 369, 378, 405 Oxidants, 34, 40, 42, 46, 49, 64, 228, 369 Oxidation-Reduction, 369 Oxidative metabolism, 128, 297, 354, 369 Oxidative Stress, 5, 19, 24, 34, 41, 43, 46, 61, 117, 145, 146, 185, 205, 229, 243, 261, 369 Oxides, 183, 224, 241, 304, 366, 370, 395 Oxygen Consumption, 119, 333, 370, 385 Oxygenase, 47, 59, 99, 109, 136, 147, 151, 170, 370 Oxygenation, 55, 118, 187, 193, 222, 260, 345, 370 Oxygenator, 312, 370 Oxytocin, 4, 370 P Pachymeningitis, 358, 370 Paclitaxel, 76, 370 Palate, 213, 370 Palladium, 370, 387 Palliative, 323, 370, 397 Pancreas, 295, 308, 326, 348, 370, 401 Pancreatic, 81, 278, 370 Pancreatic cancer, 278, 370 Pancreatitis, 124, 370 Paneth Cells, 298, 331, 370 Paracentesis, 254, 370 Paralysis, 359, 370, 392 Paranasal Sinuses, 370, 391 Parasite, 18, 65, 67, 75, 78, 83, 370, 400 Paratuberculosis, 70, 184, 371 Parenchyma, 55, 371 Parietal, 237, 371, 372 Parietal Lobe, 371 Paroxysmal, 278, 300, 341, 371, 373, 403, 405 Particle, 354, 371, 392, 400 Parturition, 367, 371 Patch, 12, 41, 230, 320, 371, 400 Pathogen, 76, 183, 184, 210, 234, 347, 371
Pathogenesis, 5, 27, 29, 30, 33, 34, 49, 55, 60, 62, 64, 153, 184, 223, 247, 248, 249, 253, 256, 257, 371 Pathologic, 31, 221, 295, 303, 308, 321, 344, 345, 371, 385 Pathologic Processes, 303, 371 Pathologies, 225, 232, 371 Pathophysiology, 9, 20, 24, 25, 37, 42, 50, 58, 60, 196, 208, 254, 257, 258, 259, 260, 261, 371 Patient Education, 282, 288, 290, 293, 371 Pelvic, 330, 371, 380 Penile Erection, 4, 37, 201, 232, 371 Penis, 36, 371, 378 Perception, 127, 212, 320, 371, 388 Percutaneous, 190, 371, 373 Perfusion, 8, 37, 173, 194, 197, 205, 245, 345, 371, 399 Perhexiline, 94, 247, 264, 371 Periaqueductal Gray, 142, 371 Pericardium, 372, 396 Perinatal, 8, 11, 117, 131, 216, 372 Periodontal disease, 32, 228, 335, 372 Perioperative, 254, 372 Peripheral blood, 60, 124, 183, 184, 348, 372, 378 Peripheral Nerves, 4, 372, 393 Peripheral Nervous System, 128, 257, 364, 372, 395, 403 Peripheral Vascular Disease, 15, 254, 372 Peristalsis, 62, 201, 372 Peritoneal, 74, 75, 76, 83, 123, 158, 162, 304, 372 Peritoneal Cavity, 304, 372 Peritoneum, 359, 372 Peritonitis, 89, 164, 254, 372 Perivascular, 88, 160, 311, 372 Perspiration, 216, 372 Pertussis, 75, 77, 372, 405 PH, 50, 66, 67, 75, 77, 81, 82, 199, 373 Phagocyte, 49, 83, 369, 373 Pharmaceutic Aids, 336, 373 Pharmaceutical Preparations, 216, 248, 315, 332, 338, 373 Pharmacologic, 14, 30, 36, 37, 39, 45, 51, 64, 215, 300, 322, 340, 373, 399, 402 Pharmacotherapy, 11, 242, 258, 373 Pharynx, 363, 373 Phenotype, 6, 30, 44, 220, 221, 373 Phenyl, 52, 373 Phenylalanine, 373, 401 Phenylephrine, 58, 149, 373
Index 427
Phonophoresis, 351, 373 Phorbol, 229, 373, 380 Phorbol Esters, 229, 373, 380 Phosphodiesterase, 196, 373 Phospholipases, 53, 373, 390 Phospholipids, 334, 348, 354, 374, 380 Phosphorus, 311, 374 Phosphorylase, 311, 374 Phosphorylate, 23, 360, 374 Phosphorylated, 318, 360, 374 Phosphorylation, 6, 41, 111, 121, 123, 125, 360, 374, 380 Photocoagulation, 318, 374 Photodynamic therapy, 55, 374 Photosensitivity, 282, 374 Photosensitizer, 234, 374 Phototransduction, 374, 388 Physical Examination, 172, 173, 374 Pigment, 307, 358, 363, 374 Pilot study, 18, 136, 175, 374 Pituitary Gland, 321, 335, 374 Placenta, 332, 374, 378, 382 Plaque, 301, 305, 375 Plasma cells, 301, 375 Plasma protein, 234, 298, 330, 375, 381 Plasmapheresis, 302, 375 Plasmid, 201, 375, 403 Plasmin, 375 Plasminogen, 51, 234, 375 Plasminogen Activators, 375 Plasticity, 61, 84, 201, 258, 375 Plastids, 368, 375 Platelet Activation, 375, 390 Platelet Aggregation, 59, 61, 190, 201, 210, 233, 249, 250, 264, 300, 331, 346, 366, 375, 376, 398 Platelet Count, 308, 375 Platelet Factor 4, 349, 376 Plateletpheresis, 302, 376 Platelets, 181, 182, 186, 190, 196, 211, 234, 303, 307, 311, 366, 375, 376, 398 Platinum, 317, 370, 376, 387 Plexus, 43, 376 Pneumonectomy, 36, 376 Poisoning, 324, 337, 349, 363, 376 Pollen, 376, 382 Polyarthritis, 266, 376 Polycystic, 129, 195, 279, 376 Polyethylene, 251, 376 Polymerase, 112, 376 Polymers, 160, 188, 189, 376, 380, 395
Polymorphism, 42, 51, 93, 94, 113, 115, 124, 128, 264, 376 Polymyxin, 97, 376 Polypeptide, 23, 197, 201, 299, 312, 318, 334, 363, 375, 376, 403, 406 Polysaccharide, 142, 297, 302, 314, 377 Polyunsaturated fat, 154, 377, 398 Polyvinyl Alcohol, 251, 377 Pons, 306, 310, 377, 386 Pontine, 10, 377 Popliteal, 334, 377 Popliteal Vein, 334, 377 Porphyrins, 359, 377 Posterior, 148, 227, 300, 303, 305, 306, 315, 316, 327, 364, 370, 377, 388 Postmenopausal, 369, 377 Postnatal, 33, 48, 56, 377, 394 Postoperative, 254, 332, 336, 362, 377 Postsynaptic, 61, 65, 377, 390, 396 Post-translational, 11, 47, 377 Potassium, 13, 29, 41, 298, 360, 377 Potassium Channels, 29, 41, 377 Potentiate, 52, 116, 377 Potentiating, 121, 377 Potentiation, 94, 355, 377, 390 Practice Guidelines, 276, 283, 377 Prednisolone, 378 Prednisone, 266, 378 Preeclampsia, 107, 378 Pre-Eclampsia, 147, 307, 378 Preleukemia, 362, 378, 391 Prenatal, 11, 194, 329, 378 Presynaptic, 378, 396 Prevalence, 15, 19, 227, 230, 254, 378 Priapism, 4, 174, 378 Prickle, 352, 378 Primary Biliary Cirrhosis, 107, 120, 378 Probe, 28, 34, 360, 378 Prodrug, 378, 383 Progesterone, 18, 360, 378, 394 Progression, 6, 19, 34, 61, 221, 264, 301, 322, 378 Progressive, 30, 34, 314, 317, 325, 328, 340, 352, 362, 363, 364, 368, 375, 378, 385, 401 Projection, 324, 367, 368, 378, 384 Proline, 318, 344, 379 Promoter, 32, 51, 86, 110, 113, 379 Prone, 57, 90, 135, 379 Prophase, 308, 379, 396, 402 Prophylaxis, 136, 254, 379 Propidium, 42, 379 Proportional, 172, 199, 379
428 Nitric Oxide
Prospective study, 355, 379 Prostaglandin, 83, 87, 129, 135, 138, 159, 203, 207, 226, 239, 240, 242, 331, 379, 395, 398 Prostaglandins A, 181, 379 Prostaglandins D, 379 Prostaglandins E, 136, 379 Prostaglandins F, 360, 379, 380 Prostate, 278, 352, 380, 389 Prostheses and Implants, 304, 380 Protease, 33, 34, 298, 380 Protective Agents, 311, 380 Protein Binding, 380, 399 Protein C, 57, 108, 201, 235, 298, 299, 302, 306, 334, 352, 354, 380, 402 Protein Kinase C, 360, 380 Protein Kinases, 34, 360, 380 Protein S, 74, 279, 308, 332, 338, 380, 387 Protein-Serine-Threonine Kinases, 360, 380 Protein-Tyrosine Kinase, 338, 380 Proteinuria, 378, 381 Proteolytic, 298, 319, 334, 352, 375, 381 Prothrombin, 234, 381, 398 Protocol, 174, 381 Proton Pump, 206, 237, 381 Proton Pump Inhibitors, 206, 237, 381 Protons, 298, 344, 350, 381, 382 Proto-Oncogene Proteins, 370, 381 Proto-Oncogene Proteins c-mos, 370, 381 Proto-Oncogenes, 31, 381 Protozoa, 353, 360, 381 Proximal, 327, 352, 363, 378, 381 Psychiatric, 226, 358, 381 Psychiatry, 111, 381, 395, 404 Psychosis, 243, 381 Puberty, 19, 382 Public Health, 254, 261, 276, 382 Public Policy, 275, 382 Publishing, 64, 382 Puerperium, 367, 382 Pulmonary Artery, 34, 38, 46, 173, 194, 309, 382, 404 Pulmonary Circulation, 33, 38, 44, 382 Pulmonary Edema, 136, 194, 265, 316, 352, 382 Pulmonary Embolism, 114, 194, 283, 382 Pulmonary Ventilation, 173, 382, 386 Pulposus, 227, 349, 382 Pulse, 215, 361, 382 Pupil, 321, 326, 362, 382 Purines, 256, 382, 389, 406
Pyrogenic, 89, 197, 382 Q Quercetin, 124, 158, 382 Quiescent, 229, 382 R Race, 360, 382 Radiation therapy, 55, 333, 336, 344, 349, 351, 383, 406 Radiculopathy, 383, 388 Radioactive, 309, 324, 340, 344, 346, 349, 350, 351, 355, 361, 367, 383, 388, 406 Radioimmunotherapy, 383 Radiolabeled, 309, 351, 383, 406 Radiological, 136, 371, 383 Radiotherapy, 113, 310, 351, 383, 406 Rage, 372, 383 Ramipril, 22, 383 Random Allocation, 383 Randomization, 41, 383 Randomized, 3, 91, 96, 120, 129, 328, 383 Reactive Oxygen Species, 14, 24, 41, 53, 67, 95, 135, 144, 187, 193, 205, 383 Reagent, 195, 199, 203, 316, 356, 383 Reality Testing, 381, 384 Receptors, Serotonin, 384, 389 Recombinant, 9, 18, 70, 201, 384, 403 Recombination, 16, 81, 169, 338, 384 Reconstitution, 18, 384 Rectal, 127, 384 Rectum, 301, 302, 309, 318, 326, 335, 337, 347, 353, 380, 384, 390 Recurrence, 237, 316, 357, 384 Red blood cells, 80, 235, 332, 370, 384, 388 Red Nucleus, 305, 384 Reductase, 17, 25, 34, 60, 65, 68, 72, 77, 205, 228, 298, 335, 384, 397 Refer, 1, 250, 311, 319, 337, 338, 355, 356, 363, 365, 381, 383, 384 Reflex, 22, 122, 372, 384 Reflux, 195, 384 Refraction, 384, 392 Refractory, 25, 96, 254, 329, 384 Regeneration, 36, 158, 228, 335, 384 Regimen, 74, 328, 373, 384 Relaxant, 4, 17, 235, 384 Reliability, 188, 192, 384 Remission, 357, 384 Renal Artery, 58, 385 Renal Circulation, 254, 385 Renal failure, 254, 324, 342, 385 Renin, 19, 22, 41, 51, 54, 89, 230, 254, 301, 352, 385
Index 429
Renin-Angiotensin System, 19, 22, 254, 385 Reperfusion Injury, 59, 91, 139, 141, 175, 197, 198, 204, 205, 210, 211, 243, 245, 385 Resection, 203, 242, 385 Residual Volume, 336, 385, 399 Resorption, 343, 369, 385 Respiration, 46, 74, 79, 98, 194, 205, 302, 312, 361, 385, 386 Respirator, 358, 385, 404 Respiratory Burst, 49, 385 Respiratory distress syndrome, 66, 112, 113, 187, 194, 243, 311, 385 Respiratory failure, 33, 98, 206, 263, 385, 404 Respiratory Physiology, 99, 102, 125, 126, 385, 404 Respiratory System, 297, 362, 386, 403 Restitution, 39, 386 Restoration, 39, 205, 363, 384, 385, 386, 405 Resuscitation, 245, 386 Reticular, 10, 386 Reticular Formation, 10, 386 Retina, 170, 304, 316, 320, 325, 353, 356, 368, 374, 386, 387 Retinae, 356, 386 Retinal, 137, 320, 325, 368, 374, 386, 405 Retinal Ganglion Cells, 368, 386 Retinoblastoma, 31, 49, 278, 386 Retinol, 386 Retinopathy, 94, 254, 298, 325, 386 Retinosis, 206, 386 Retrovirus, 74, 386 Reversion, 386, 401 Rhamnose, 369, 386 Rheumatism, 4, 345, 386, 387 Rheumatoid, 4, 5, 112, 181, 194, 207, 214, 223, 232, 240, 243, 248, 249, 266, 332, 352, 369, 387 Rheumatoid arthritis, 5, 112, 181, 194, 207, 214, 223, 232, 240, 243, 248, 249, 266, 332, 352, 387 Rheumatology, 5, 94, 117, 387 Rhinitis, 114, 283, 310, 387 Ribonucleoside Diphosphate Reductase, 344, 387 Ribose, 112, 228, 296, 387 Ribosome, 387, 400 Rigidity, 375, 387 Risk factor, 15, 24, 29, 51, 54, 63, 107, 117, 215, 254, 261, 344, 379, 387 Rod, 306, 317, 330, 387
Rotenone, 159, 387 Rubber, 172, 296, 387 Ruthenium, 92, 191, 387 Rutin, 382, 387 Ryanodine, 13, 387 S Salicylic, 77, 387 Saline, 3, 118, 172, 387 Saliva, 83, 191, 387 Salivary, 122, 124, 158, 192, 326, 370, 387 Salivary glands, 326, 387 Saphenous, 116, 387 Saphenous Vein, 116, 387 Saponins, 159, 387, 394 Sarcoplasmic Reticulum, 80, 388 Scans, 173, 226, 388 Schizoid, 388, 405 Schizophrenia, 388, 405 Schizotypal Personality Disorder, 388, 405 Sciatica, 227, 388 Sclera, 316, 320, 388 Sclerosis, 6, 43, 94, 108, 126, 223, 248, 249, 278, 303, 362, 388 Screening, 41, 225, 234, 317, 388 Sebaceous, 388, 405 Second Messenger Systems, 23, 365, 388 Secondary tumor, 359, 388 Secretory, 237, 298, 389, 396 Sedative, 318, 389 Sedentary, 15, 389 Segmental, 228, 389, 392 Segmentation, 389 Segregation, 384, 389 Seizures, 86, 324, 371, 389 Selective estrogen receptor modulator, 389, 397, 399 Semen, 380, 389 Seminal fluid, 379, 389 Senile, 369, 389 Senna, 313, 389 Sensibility, 300, 389 Sensor, 109, 203, 205, 389 Sepsis, 24, 25, 28, 64, 74, 89, 91, 94, 176, 187, 194, 195, 259, 260, 306, 336, 389 Septic, 11, 16, 25, 60, 91, 93, 96, 97, 120, 210, 214, 232, 239, 243, 267, 283, 304, 389 Serine, 312, 323, 352, 360, 380, 381, 389, 401 Serotonin, 4, 226, 335, 373, 384, 389, 395, 401 Serous, 304, 330, 390 Sex Behavior, 108, 355, 390
430 Nitric Oxide
Sex Characteristics, 300, 382, 390, 397 Sex Determination, 279, 390 Sexually Transmitted Diseases, 217, 390 Sharpness, 390, 405 Shock, Septic, 244, 390 Shock, Traumatic, 243, 390 Shunt, 80, 173, 193, 390 Side effect, 55, 196, 207, 212, 240, 245, 266, 269, 297, 308, 323, 345, 390, 399 Sigmoid, 100, 390 Sigmoid Colon, 100, 390 Signal Transduction, 6, 10, 34, 37, 69, 348, 390 Signs and Symptoms, 195, 227, 384, 390, 402 Silicon, 187, 188, 192, 203, 224, 225, 251, 390, 391 Silicon Dioxide, 188, 192, 391 Sinusitis, 122, 391 Skeletal, 9, 15, 58, 85, 227, 229, 300, 317, 351, 362, 363, 388, 391, 392 Skeleton, 296, 334, 351, 379, 391 Skull, 322, 391, 397 Sleep apnea, 123, 391 Small intestine, 18, 307, 317, 328, 330, 338, 343, 349, 391, 401, 404 Smoldering leukemia, 362, 391 Sneezing, 373, 391 Social Isolation, 203, 242, 388, 391 Social Work, 174, 391 Sodium, 22, 41, 80, 190, 198, 220, 298, 331, 352, 360, 366, 374, 391, 396 Solid tumor, 221, 301, 391 Solitary Nucleus, 305, 391 Solvent, 306, 332, 368, 392 Somatic, 329, 343, 358, 361, 372, 392 Sorbitol, 229, 298, 392 Sound wave, 392, 402 Soybean Oil, 377, 392 Spasm, 247, 359, 392 Spasmodic, 310, 373, 392 Spastic, 351, 392 Spasticity, 267, 392 Specialist, 285, 326, 392 Specificity, 49, 60, 225, 297, 303, 378, 392, 399 Spectrum, 130, 168, 322, 392 Sperm, 52, 295, 300, 317, 376, 389, 392, 401 Sperm Head, 295, 392 Spermatozoa, 295, 389, 392 Spermatozoon, 295, 392
Sphincter, 104, 115, 203, 204, 242, 247, 353, 392 Spinal Nerve Roots, 383, 388, 392 Spinal Nerves, 372, 393 Spinal Stenosis, 227, 393 Spinous, 331, 352, 393 Splanchnic Circulation, 254, 393 Spleen, 73, 77, 306, 356, 393, 401 Spondylitis, 117, 332, 393 Sporadic, 6, 44, 364, 386, 393 Sprains and Strains, 355, 393 Sputum, 99, 126, 393 Squamous, 101, 331, 393 Squamous cell carcinoma, 101, 331, 393 Squamous cells, 393 Stabilization, 15, 393 Staging, 388, 393 Steady state, 46, 213, 393 Steel, 317, 393 Stellate, 16, 393 Stem Cell Factor, 19, 317, 393 Stem Cells, 182, 208, 209, 332, 340, 394 Stent, 190, 394 Sterility, 102, 128, 323, 394 Sterilization, 235, 394 Steroid, 33, 58, 127, 160, 217, 259, 264, 266, 307, 322, 388, 394 Stimulant, 327, 343, 351, 394 Stimulus, 52, 53, 147, 320, 327, 328, 329, 333, 349, 350, 353, 364, 384, 394, 398 Stomach Ulcer, 267, 394 Stool, 204, 242, 247, 347, 351, 353, 394 Strand, 83, 376, 394 Streptococcus, 72, 83, 89, 394 Streptozocin, 19, 394 Stroke Volume, 312, 394 Stroma, 5, 371, 394 Stromal, 309, 330, 394 Structure-Activity Relationship, 20, 394 Stupor, 354, 363, 394 Styrene, 387, 395 Subacute, 190, 347, 391, 395 Subarachnoid, 52, 341, 350, 395 Subclinical, 347, 389, 395 Subcutaneous, 296, 328, 395 Subiculum, 343, 395 Subspecies, 392, 395 Substance P, 60, 332, 359, 384, 389, 395 Suction, 335, 395 Sulfur, 69, 169, 219, 295, 333, 359, 395 Sulfur Dioxide, 169, 219, 395 Sulfur Oxides, 295, 395
Index 431
Sumatriptan, 32, 395 Sunburn, 214, 395 Superoxide Dismutase, 22, 40, 43, 62, 119, 198, 204, 395 Supplementation, 9, 40, 41, 50, 145, 146, 147, 155, 157, 161, 162, 262, 395 Suppression, 63, 75, 84, 126, 127, 138, 161, 210, 239, 321, 395 Suprofen, 236, 395 Surfactant, 33, 56, 130, 136, 395 Sweat, 372, 396 Sympathetic Nervous System, 22, 254, 305, 396 Sympathomimetic, 327, 331, 351, 367, 396 Symphysis, 380, 396 Symptomatic, 92, 370, 396 Symptomatology, 197, 390, 396 Synapses, 16, 139, 355, 365, 396 Synapsis, 396 Synaptic, 7, 16, 61, 82, 201, 355, 365, 390, 396 Synaptic Transmission, 7, 365, 396 Synaptic Vesicles, 396 Synergistic, 161, 214, 396 Synovial, 181, 396 Systemic lupus erythematosus, 282, 396 Systolic, 173, 215, 345, 397 Systolic blood pressure, 215, 397 T Tachycardia, 305, 327, 397 Tacrolimus, 189, 397 Tamoxifen, 389, 397, 399 Telangiectasia, 279, 397 Telencephalon, 306, 397 Temporal, 87, 100, 341, 343, 356, 397, 400 Teratogenic, 326, 397 Testis, 332, 397 Testosterone, 19, 335, 384, 397 Thalamic, 305, 397 Thalamic Diseases, 305, 397 Therapeutics, 114, 146, 147, 150, 171, 173, 175, 176, 248, 270, 397 Thermal, 167, 199, 225, 327, 365, 397 Thigh, 334, 397 Thioredoxin, 34, 397 Third Ventricle, 345, 397 Thoracic, 103, 109, 116, 121, 127, 134, 157, 213, 305, 398 Thorax, 99, 103, 120, 295, 356, 398 Threonine, 123, 360, 380, 381, 389, 398 Threshold, 173, 345, 398
Thrombin, 206, 234, 334, 375, 376, 380, 381, 398 Thrombocytes, 376, 398 Thrombolytic, 375, 398 Thrombomodulin, 123, 380, 398 Thrombopoietin, 182, 398 Thromboxanes, 303, 328, 398 Thrombus, 9, 250, 321, 347, 351, 362, 363, 375, 398, 404 Thyroid, 345, 398, 401 Thyrotropin, 345, 398 Thyroxine, 298, 373, 398 Ticlopidine, 136, 398 Tidal Volume, 348, 398, 399 Tin, 226, 376, 398 Tissue Distribution, 64, 399 Tolerance, 37, 71, 148, 198, 215, 243, 296, 339, 399 Tomography, 399 Tonus, 372, 399 Tooth Loss, 32, 399 Tooth Preparation, 296, 399 Topical, 247, 248, 264, 332, 344, 399 Toremifene, 101, 399 Torsion, 347, 399 Total Lung Capacity, 219, 399 Toxaemia, 378, 399 Toxicology, 35, 105, 118, 136, 138, 145, 146, 149, 154, 158, 276, 399 Toxins, 302, 329, 342, 347, 361, 383, 399, 404 Trace element, 309, 365, 390, 398, 399 Traction, 317, 399 Tractus, 136, 399 Transcriptase, 386, 399 Transcription Factors, 24, 34, 399 Transdermal, 230, 247, 248, 400 Transduction, 6, 34, 311, 390, 400 Transfection, 18, 308, 400 Transfusion, 173, 174, 235, 400 Translation, 64, 332, 400 Translational, 56, 89, 400 Translocate, 160, 400 Translocating, 306, 400 Translocation, 11, 84, 306, 332, 400 Transmitter, 66, 295, 304, 327, 350, 358, 367, 396, 400 Transplantation, 36, 109, 195, 233, 245, 246, 317, 346, 357, 400 Trauma, 134, 243, 246, 324, 364, 370, 390, 400 Trees, 387, 400
432 Nitric Oxide
Tremor, 359, 400 Trichomoniasis, 359, 400 Tricuspid Atresia, 321, 400 Tricyclic, 189, 244, 248, 249, 400 Trigeminal, 31, 111, 357, 400, 401 Trigeminal Ganglion, 111, 400, 401 Trigeminal Nerve, 400, 401 Trophic, 43, 401 Tropoelastin, 33, 401 Trypsin, 298, 401 Tryptophan, 201, 318, 389, 401 Tuberculosis, 65, 70, 73, 85, 87, 153, 184, 264, 320, 356, 387, 401 Tuberous Sclerosis, 279, 401 Tubulin, 75, 360, 401 Tuftsin, 88, 401 Tumour, 97, 137, 337, 401 Tunica Media, 229, 401 Type 2 diabetes, 15, 93, 94, 122, 401 Typhimurium, 71, 73, 86, 104, 401 Tyrosine, 6, 44, 53, 84, 100, 142, 158, 170, 327, 380, 401 U Ubiquitin, 27, 78, 137, 402 Ulcer, 237, 247, 394, 402 Ulceration, 207, 240, 402 Ulcerative colitis, 214, 243, 347, 402 Ultrasound test, 172, 402 Unconscious, 219, 300, 324, 345, 402 Univalent, 344, 369, 402 Uraemia, 370, 402 Urea, 216, 303, 352, 396, 402 Uremia, 352, 385, 402 Ureters, 353, 385, 402 Urethra, 371, 380, 402 Uric, 54, 64, 93, 203, 298, 345, 382, 402 Urinary, 4, 5, 84, 91, 93, 120, 129, 150, 195, 307, 323, 338, 343, 347, 367, 402, 406 Urinary Retention, 307, 402 Urinary tract, 91, 120, 195, 402 Urinary tract infection, 195, 402 Urinary Tract Physiology, 91, 402 Urine, 3, 5, 76, 191, 195, 302, 308, 322, 327, 342, 347, 352, 353, 367, 381, 402 Urogenital, 195, 338, 402 Uterine Contraction, 370, 402 Uterus, 18, 160, 316, 321, 324, 330, 358, 378, 402, 403 V Vaccine, 74, 296, 299, 381, 403 Vacuoles, 368, 403 Vagina, 316, 358, 403
Vagotomy, 136, 403 Valves, 195, 403 Vascular, 4, 9, 10, 12, 15, 17, 20, 21, 23, 24, 25, 26, 29, 31, 33, 35, 36, 37, 40, 42, 44, 45, 47, 50, 51, 53, 54, 56, 57, 58, 61, 64, 67, 68, 69, 72, 80, 83, 84, 86, 92, 94, 96, 102, 106, 107, 114, 115, 119, 126, 128, 130, 134, 135, 141, 143, 147, 148, 149, 153, 154, 158, 160, 180, 182, 185, 186, 187, 190, 191, 196, 201, 206, 210, 212, 217, 221, 229, 230, 231, 232, 233, 235, 242, 243, 244, 245, 246, 250, 251, 254, 261, 298, 311, 315, 316, 325, 330, 331, 334, 341, 344, 347, 351, 352, 355, 359, 364, 366, 374, 375, 398, 403 Vascular endothelial growth factor, 33, 84, 126, 130, 153, 158, 246, 403 Vascular Headaches, 31, 403 Vascular Resistance, 25, 33, 44, 94, 334, 403 Vasculitis, 315, 370, 403 Vasoactive, 20, 23, 25, 54, 60, 130, 168, 175, 181, 197, 221, 226, 403 Vasoactive Intestinal Peptide, 168, 226, 403 Vasoconstriction, 15, 44, 57, 194, 196, 206, 210, 221, 327, 331, 403 Vasodilatation, 15, 60, 113, 189, 193, 212, 245, 352, 403 Vasodilation, 15, 16, 22, 23, 25, 26, 53, 102, 117, 128, 130, 168, 187, 196, 201, 210, 231, 235, 254, 261, 346, 403 Vasodilator Agents, 197, 403 Vasomotor, 9, 53, 82, 124, 403 Vasopressins, 352, 403 Vasopressor, 25, 403 Vector, 201, 400, 403 Vein, 31, 100, 107, 118, 172, 173, 300, 304, 334, 346, 350, 367, 377, 387, 404 Venoms, 324, 365, 404 Venous, 9, 24, 174, 176, 304, 307, 308, 315, 350, 366, 375, 380, 398, 400, 404 Venous blood, 174, 308, 315, 375, 404 Venous Pressure, 176, 404 Venous Thrombosis, 24, 307, 398, 404 Ventilation, 175, 187, 404 Ventilator, 358, 385, 404 Ventral, 136, 345, 367, 377, 392, 393, 404 Ventricle, 305, 321, 343, 382, 397, 400, 404 Ventricular, 28, 59, 176, 198, 320, 344, 363, 400, 404 Ventricular Function, 59, 198, 404
Index 433
Venules, 39, 309, 312, 330, 359, 404 Verapamil, 247, 404 Vertebrae, 227, 349, 392, 393, 404 Vertebral, 227, 306, 404 Vestibule, 318, 404 Veterinary Medicine, 39, 136, 275, 404 Villi, 344, 404 Vinblastine, 401, 404 Vincristine, 401, 404 Viral, 69, 78, 123, 193, 237, 295, 329, 367, 381, 386, 400, 404 Viremia, 390, 404 Virulence, 305, 399, 405 Virus, 72, 73, 74, 80, 84, 85, 93, 110, 173, 201, 215, 234, 306, 315, 349, 375, 400, 404, 405 Viscera, 359, 392, 393, 405 Visceral, 130, 305, 353, 372, 405 Visceral Afferents, 305, 405 Viscosity, 211, 295, 405 Visual Acuity, 5, 405 Vital Capacity, 399, 405 Vitamin A, 348, 386, 405 Vitreous Hemorrhage, 325, 405
Voltage-gated, 41, 405 Vulgaris, 152, 153, 405 W Wakefulness, 10, 324, 405 Weight Gain, 266, 405 White blood cell, 61, 191, 301, 306, 317, 354, 356, 361, 362, 363, 365, 375, 405 Whooping Cough, 373, 405 Withdrawal, 37, 44, 58, 131, 221, 243, 324, 405 Womb, 403, 405 Wound Healing, 185, 206, 218, 240, 335, 348, 357, 405 X Xanthine, 64, 82, 100, 168, 298, 406 Xanthine Oxidase, 64, 168, 298, 406 Xenograft, 301, 406 X-ray, 173, 181, 314, 319, 335, 337, 351, 367, 383, 388, 406 X-ray therapy, 351, 406 Y Yeasts, 337, 373, 406 Z Zymogen, 380, 406
Nitric oxide
434
435
Nitric oxide
436
