EPSIS 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., 1960Sepsis: 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: 0-597-84623-5 1. Sepsis-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 sepsis. 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 SEPSIS ........................................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Sepsis............................................................................................. 5 E-Journals: PubMed Central ....................................................................................................... 62 The National Library of Medicine: PubMed ................................................................................ 71 CHAPTER 2. NUTRITION AND SEPSIS ............................................................................................ 115 Overview.................................................................................................................................... 115 Finding Nutrition Studies on Sepsis ......................................................................................... 115 Federal Resources on Nutrition ................................................................................................. 118 Additional Web Resources ......................................................................................................... 119 CHAPTER 3. DISSERTATIONS ON SEPSIS ........................................................................................ 121 Overview.................................................................................................................................... 121 Dissertations on Sepsis .............................................................................................................. 121 Keeping Current ........................................................................................................................ 121 CHAPTER 4. CLINICAL TRIALS AND SEPSIS ................................................................................... 123 Overview.................................................................................................................................... 123 Recent Trials on Sepsis .............................................................................................................. 123 Keeping Current on Clinical Trials ........................................................................................... 131 CHAPTER 5. PATENTS ON SEPSIS ................................................................................................... 133 Overview.................................................................................................................................... 133 Patents on Sepsis........................................................................................................................ 133 Patent Applications on Sepsis.................................................................................................... 154 Keeping Current ........................................................................................................................ 188 CHAPTER 6. BOOKS ON SEPSIS ...................................................................................................... 189 Overview.................................................................................................................................... 189 Book Summaries: Federal Agencies............................................................................................ 189 Book Summaries: Online Booksellers......................................................................................... 191 Chapters on Sepsis ..................................................................................................................... 195 CHAPTER 7. MULTIMEDIA ON SEPSIS ............................................................................................ 205 Overview.................................................................................................................................... 205 Audio Recordings....................................................................................................................... 205 CHAPTER 8. PERIODICALS AND NEWS ON SEPSIS ......................................................................... 207 Overview.................................................................................................................................... 207 News Services and Press Releases.............................................................................................. 207 Newsletter Articles .................................................................................................................... 211 Academic Periodicals covering Sepsis........................................................................................ 212 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 213 Overview.................................................................................................................................... 213 U.S. Pharmacopeia..................................................................................................................... 213 Commercial Databases ............................................................................................................... 214 Researching Orphan Drugs ....................................................................................................... 215 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 219 Overview.................................................................................................................................... 219 NIH Guidelines.......................................................................................................................... 219 NIH Databases........................................................................................................................... 221 Other Commercial Databases..................................................................................................... 223 APPENDIX B. PATIENT RESOURCES ............................................................................................... 225 Overview.................................................................................................................................... 225 Patient Guideline Sources.......................................................................................................... 225
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Finding Associations.................................................................................................................. 229 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 231 Overview.................................................................................................................................... 231 Preparation................................................................................................................................. 231 Finding a Local Medical Library................................................................................................ 231 Medical Libraries in the U.S. and Canada ................................................................................. 231 ONLINE GLOSSARIES................................................................................................................ 237 Online Dictionary Directories ................................................................................................... 242 SEPSIS DICTIONARY.................................................................................................................. 243 INDEX .............................................................................................................................................. 343
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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 sepsis is indexed in search engines, such as www.google.com or others, a nonsystematic 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 sepsis, 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 sepsis, 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 sepsis. 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 sepsis, 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 sepsis. 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 SEPSIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on sepsis.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and sepsis, 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 “sepsis” (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: •
Prevention and Treatment of Acute Renal Failure in Sepsis Source: JASN. Journal of the American Society of Nephrology. 14(3): 792-805 March 2003. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-6423. Website: www.jasn.org/. Summary: Acute renal failure (ARF) is a common complication of sepsis and has a poor prognosis. Mortality (death) was reported higher in patients with septic ARF (74.5 percent) than in those whose renal (kidney) failure did not result from sepsis (45.2 percent). This article discusses the use of drug therapy to interfere with each of the dysfunctional pathways to improve the course of septic ARF. These include inhibition of inflammatory mediators, improvement of renal hemodynamics (blood flow) by
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amplifying vasodilator mechanisms and blocking vasoconstrictor mechanisms, interruption of leukocyte infiltration, inhibition of the coagulation cascade, and administration of growth factors to accelerate renal recovery. The author also highlights the available supportive measures, including dialysis, that can be used for septic patients with ARF. The author notes that, unfortunately, treatment of ARF in sepsis is still only supportive; there have been no conclusive drug therapies available to treat the condition. 1 figure. 1 table. 136 references. •
Urosepsis: When to Suspect, How to Confirm, How to Manage Source: Journal of Critical Illness. 12(10): 616-618, 623-625. October 1997. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Greenwich, CT 06831-0010. (203) 661-0600. Summary: This article reminds physicians of the recommended care for patients with urosepsis (bacteremia that originates in the urinary tract). Urosepsis can be acquired in the hospital (nosocomial) or in the community. The mere presence of bacteriuria is not sufficient to diagnose urosepsis in patients who have symptoms of sepsis. Urosepsis develops only in specific clinical situations: when host defenses are impaired (as they are in patients who have diabetes mellitus or systemic lupus erythematosus) or when they are circumvented or bypassed by mechanical factors (such as obstruction or preexisting renal disease). To confirm the diagnosis of urosepsis, the same pathogen found in the urine must be found in the blood; in addition, the pathogen must be linked to a site of infection in the genitourinary tract or to urologic instrumentation or catheterization. The author stresses that knowing the source of urosepsis helps physicians to determine the most likely causative organisms and therefore the most appropriate antibiotic therapies. Nosocomial urosepsis usually results from either urologic manipulation or an indwelling Foley catheter in nonleukopenic, immunocompromised patients. Community-acquired urosepsis may complicate any type of urinary tract infection, but only in patients with preexisting renal disease, obstruction, or impaired host defenses. If urosepsis is related to obstruction, antibiotics can temporarily control the infection process, but they cannot eliminate it. Whenever possible, urologic or surgical correction of the obstruction should be performed. (AAM).
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Life-Threatening Retroperitoneal Sepsis After Hemorrhoid Injection Sclerotherapy: Report of a Case Source: Diseases of the Colon and Rectum. 42(3): 421-423. March 1999. Contact: Available from Williams and Wilkins. 352 West Camden Street, Baltimore, MD 21201-2436. Summary: This article reports a case of life threatening retroperitoneal sepsis after injection sclerotherapy for first degree hemorrhoids. A 50 year old man with symptomatic first degree hemorrhoids was seen in the outpatient department. An experienced surgical registrar injected three internal hemorrhoids with 3 to 5 mL of 5 percent oily phenol. Four days later, the patient was admitted as an emergency, complaining of tight central chest pain. For 6 hours he had experienced chills and pelvic pain radiating to his lower abdomen and the backs of his thighs. Anorectal instrumentation was not attempted, because the patient was reporting severe pelvic pain. Investigation revealed leukocytosis, raised creatinine kinase, and electrocardiographic changes suggestive of anteroseptal myocardial infarction. Streptokinase, cefotaxime, and metronidazole were administered. Later that day, his
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pelvic pain worsened. He remained pyrexial (having a fever), developed tachycardia (rapid heartbeat), and went into urinary retention. Computed tomography revealed extensive retroperitoneal fluid but no localized abscess. Blood culture isolated gram negative bacilli, but exploratory laparotomy found no colonic lesion. The fecal stream was diverted with an end sigmoid colostomy and the rectal stump was oversewn. Hyperbaric oxygen, antibiotics, and intensive inotropic and ventilatory support were continued in the postoperative period. The patient eventually made a good recovery. The authors note that life threatening sepsis after injection sclerotherapy for hemorrhoids has been reported only once previously. One table summarizes the cases of life threatening complications after rubber band ligation of hemorrhoids. 1 table. 9 references.
Federally Funded Research on Sepsis The U.S. Government supports a variety of research studies relating to sepsis. 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 sepsis. 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 sepsis. The following is typical of the type of information found when searching the CRISP database for sepsis: •
Project Title: ACUTE LUNG INJURY--ALCOHOLISM AND GLUTATHIONE DEPLETION Principal Investigator & Institution: Guidot, David M.; Associate Professor of Medicine; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: The Acute Respiratory Distress Syndrome (ARDS) is a common and severe form of lung injury with a mortality of approximately 50 percent. A prospective study of 351 critically ill patients recently identified that a history of chronic alcohol abuse increased the incidence and severity of ARDS regardless of the at-risk diagnosis. This observation distinguishes chronic alcohol abuse as the first reported co-morbid variable that significantly increases a patient's risk of developing ARDS and raises questions about the pathophysiology and specific treatment of acute lung injury. This project will test the hypothesis that chronic alcohol abuse decreases alveolar type II cell levels of glutathione, an important antioxidant, thereby impairing surfactant secretion and function and rendering the lung susceptible to injury. In ARDS the alveolar type II cells are severely damaged, and their ability to secrete glutathione and surfactant into the
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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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alveolar lining fluid are critical to patient survival. Because sepsis is the most common risk factor for ARDS, this project will focus on the sepsis syndrome in both patients and in an animal model. Preliminary studies presented in this proposal show that chronic alcohol ingestion in rats decreases type II cell glutathione levels and, in parallel, decreases type II cell surfactant secretion both in vitro and in vivo, and predisposes to endotoxin-mediated acute lung injury. In addition, we determined that otherwise healthy alcoholics have markedly decreased levels of glutathione in their lung lavage fluid compared to control subjects. The fundamental mechanisms by which chronic alcohol use affects alveolar epithelial function will be examined in a rat model of sepsis in vivo and in isolated type II cells in vitro. Parallel clinical studies in both healthy subjects and in critically ill patients with sepsis will examine the effects of chronic alcohol abuse on lung glutathione homeostasis and surfactant production both in isolated type II cells and in lung lavage fluid. We will thereby test the clinical relevance of the fundamental mechanisms elucidated in the animal model. Importantly, our preliminary studies indicate that glutathione replacement can decrease ethanolmediated lung injury in our animal model, and this project will ultimately focus on developing a glutathione replacement regimen that reduces the harmful effects of chronic alcohol ingestion on the lungs of patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACUTE LUNG INJURY-MECHANISMS AND THERAPY Principal Investigator & Institution: Crapo, James D.; Executive Vice President for Academic Af; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 01-MAY-1984; Project End 31-MAR-2005 Summary: PROPOSED PROGRAM (Adapted from Applicant's Abstract) The long-term objectives of this Program Project application are to evaluate basic mechanisms and develop new treatments for acute lung injury. High concentrations of oxygen and septic lung injury are the primary models that will be evaluated. The proposed program consists of four projects and three core units. Project 1 will evaluate the efficacy of small molecular weight catalytic antioxidants in the treatment of both hyperoxic and LPS + sepsis-initiated lung injury. This project will also develop new antioxidant mimetics and explore their relationships with the antioxidant properties of heme oxygenase (HO). Project 2 will test the hypothesis that activation of extrinsic coagulation and disordered fibrin turnover are central elements in hyperoxic and septic lung injury. The efficacy of specific blockade of the initiating steps of extrinsic coagulation in reducing inflammation and acute lung injury will be tested using two new anticoagulant drugs that block tissue factor (TF) function and do not cause bleeding. Project 3 will evaluate the regulation and function of the extracellular superoxide dismutase (EC-SOD) in acute lung injury and determine the impact of cleavage of the C-terminal "heparin binding" domain of this enzyme in determining its distribution and function. Project 4 will evaluate control of metabolic pathways and upregulation of lung cell glycolysis in modulating responses to acute injury. This project will test the hypothesis that adaptation to oxidant stress in the lung requires elevated expression of hexokinase (HK), a rate limiting step in glycolysis in the lung. The overall rationale for the Program Project is to use an interdisciplinary approach to define the cellular pathways and cellular adaptive responses involved in acute lung injury and to test new strategies for pharmacologic therapy that can be extended to the treatment of humans with ARDS and sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: AMELIORATION OF SEPSIS BY MACROPHAGE ACTIVATION Principal Investigator & Institution: Williams, David L.; Professor; Surgery; East Tennessee State University Box 70565 Johnson City, Tn 37601 Timing: Fiscal Year 2002; Project Start 01-APR-1996; Project End 31-JAN-2005 Summary: During the previous grant period our research focused on understanding the early intracellular signaling events which are involved in the initiation and propagation of sepsis syndrome. We found that suppressing pro-inflammatory intracellular signaling events during the early phase of sepsis strongly correlated with improved outcome. Specifically, we investigated the protective efficacy of glucan ligands in polymicrobial sepsis and determined that receptor recognition of glucan modulates intracellular signaling pathways such that the inflammatory response to sepsis is "blunted". We established that glucan pre- or post-treatment would blunt sepsis induced tissue NFkappaB and NF-IL6 activation as well as decrease pro-inflammatory cytokine gene transcription. Blunting early increases in transcription factor activity and cytokine gene expression strongly correlated with decreased morbidity and mortality. We determined that glucan treatment blunted LPS induced NFkappaB activity through decreased MEKK1, NIK and IKKalpha/beta kinase activity as well as decreased IkappaBalpha phosphorylation and degradation. We confirmed the existence of multiple glucan binding sites on macrophages, defined the molecular structure of a glucan and confirmed that a heptaose (7 glucose subunit) polymer was the minimum binding unit. Preliminary data suggest that Toll receptor (TLR) 2, and perhaps CR3, confers responsiveness to glucan. The hypothesis for this continuation proposal is that lucan ligands ameliorate septic sequelae in polymicrobial sepsis by modulating inflammatory responses via interactions with Toll-like receptors (TLR) and/or CR3 (CD11b/CD18) binding sites. There are four specific aims. 1. We will characterize the receptor mediated interaction of glucan ligands with TLR 1, 2 and 4, the type 3 complement receptor (CR3) and CD 14 using a surface plasmon resonance approach. 2. We will establish the role of TLR2 and TLR4 in the anti-sepsis effect of glucan by studying CLP sepsis in TLR2 and TLR4 knockout mice. 3. We will investigate the role of CR3 (CD11b/CD18) in the antisepsis effect of glucan by studying CLP sepsis in CR3 knockout mice. 4. During the last grant period we made great strides in understanding the basic chemistry of (1-3)-beta-Dglucans. Using this knowledge, we will synthesize chemically pure, highly uniform, water soluble (1-3)-beta-D-glucan ligands which have specific structural characteristics. We will prepare a library of small molecular weight (1-3)-beta-D-glucans which will be used to prepare larger polymers. The synthetic polymers will be evaluated in receptor binding studies, in vitro intracellular signaling studies and in vivo protection studies using the CLP model. The successful completion of these aims will advance our understanding of the cellular and molecular events associated with sepsis syndrome and may lead to the development of new therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: APOPTOSIS IN SEPSIS: REGULATION BY TNF & DELTA-PKC Principal Investigator & Institution: Kilpatrick, Laurie E.; Associate Member; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 10-JAN-2002; Project End 31-DEC-2006 Summary: Spontaneous apoptosis of neutrophils is attenuated during sepsis and inflammatory cytokines such as TNFalpha have been implicated. The pathophysiological mechanisms involved in TNFalpha-mediated attenuation of apoptosis are poorly understood but proposed to be mediated by the p60 TNF receptor
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(p60TNFR). In adherent neutrophils to engage beta2 integrins, TNFalpha triggers phosphorylation of the p60TNFR, activation of cell survival signaling pathways and inhibition of spontaneous apoptosis. Our studies implicate phosphatidylinositol 3kinase (PI 3-kinase) in TNFalpha triggered NFkappaB activation and that TNFalpha activation of PI 3-kinase requires beta2 integrins. The protein kinase C isotype delta (delta-PKC) phosphorylates p60TNFR on serine residue(s) in TNFalpha activated neutrophils. Rottlerin, a delta-PKC inhibitor, suppressed the inhibitory effect of TNFalpha on neutrophil apoptosis and activation of the transcription factor NFkappaB suggesting that delta-PKC may regulate TNFalpha anti-apoptotic signaling. Our model proposes a selective role for delta-PKC in regulating anti-apoptotic signaling triggered by TNFalpha binding to the p60TNFR. The goal of this study is to establish a role for delta-PKC in TNFalpha mediated anti-apoptotic signaling through the p60TNFR using antisense technology to selectively deplete delta-PKC from HL60 cells differentiated to a neutrophilic phenotype. We will: 1: Determine whether delta-PKC regulates TNFalpha mediated anti- apoptotic signaling. Determine the effect of delta-PKC deletion on TNFalpha-mediated suppression of spontaneous apoptosis and activation of the antiapoptotic NFkappaB and the MAP kinases ERK1/2. 2: Assess the role of PI 3-kinase in TNFalpha mediated suppression of spontaneous apoptosis, and determine if deltaPKC is required for TNFalpha mediated activation of PI 3-kinase. 3: Identify the deltaPKC phosphorylation site on the p60TNFR and establish if phosphorylation is in the a) death domain, b) juxtamembrane region, or c) a novel domain. 4: Assess the role of delta-PKC in regulating the assembly of TNFalpha anti-apoptotic signaling complexes and their association with the p60TNFR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BACTERIAL SURFACE PROTEINS: POTENTIAL TARGETS FOR SEPSIS Principal Investigator & Institution: Hellman, Judith; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: Bacterial cell wall components released into the bloodstream are believed to be important in eliciting the inflammatory response that causes Gram-negative Sepsis. The bacterial outer membrane contains lipopolysaccharide (LPS), outer membrane proteins (OMPs), and phospholipids. LPS has been studied extensively as an important mediator in sepsis; the importance of OMPs in sepsis has not been systematically evaluated. Our preliminary data indicate that complexes containing three conserved OMPs and LPS are released from bacteria into human serum and are also released into the circulation of septic rats. We have identified the three proteins and have found that at least one of the proteins has biological activity. The major goals of this project are to further characterize release of the three OMPs in sepsis, to assess their roles in the pathogenesis of sepsis, and to evaluate anti-OMP immunity as a means of treating sepsis. The first specific aim is to assess release of OMPs and OMP/LPS complexes in humans with Gram- negative sepsis and in two models of experimental Gram-negative sepsis in rats. The second specific aim is to evaluate individual OMPs, OMP/LPS complexes, and OMPs on the surface of intact bacteria for biological activity in vitro on isolated immune cells, an in vivo by studying lethality, induction of cytokines in blood and organs, and pulmonary neutrophil sequestration in LPS resistant and LPS responsive mice. The third specific aim is to evaluate protective effects of active immunity on toxicity of OMP containing preparations in mice and in the rat infection models of sepsis. The applicant's long-term career objective is to become an
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independent investigator studying basic mechanisms of Gram- negative infection and sepsis. The career development plan is designed to expand the candidate's research knowledge base through hands-on research and educational activities. These will include course work (laboratory and didactic), attendance at and participation in laboratory meetings and research seminars, and formal and informal interactions with the Advisory Committee members. The ultimate goal of the candidate is to apply the fundamental knowledge of mechanisms involved in sepsis to develop anti-sepsis strategies that target bacterial toxins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INFECTIONS
CAPSULAR
POLYSACCHARIDES
AND
ENTEROCOCCAL
Principal Investigator & Institution: Huebner, Johannes; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-SEP-1998; Project End 31-JUL-2002 Summary: (Adapted from applicant's abstract): The long-term goal of this study is to understand the molecular, biochemical, and immunologic factors that contribute to the pathogenesis of Enterococcus faecalis and E.faecium infections, with special emphasis on multiply antibiotic-resistant enterococci. Further understand of the interaction of these bacteria with the human host defense system will give new insights into how to prevent disease due to enterococcal infections. The molecular and biochemical studies will concentrate on isolating and characterizing likely capsular polysaccharides of enterococci which will culminate in deterring the monosaccharide components and linkages in these antigens. Electron microscopy using antibodies specific to isolated polysaccharides will determine if the materials are extracellular capsules. The immunologic studies will focus on whether the isolated antigens are targets for protective immune responses. In this study between three and five serologically distinct antigens will be purified and characterized chemically and immunologically. A mouse peritonitis/sepsis model and a neonatal mouse model will be used to evaluate the effectiveness of antibodies specific for the capsular polysaccharides in prevention of enterococcal infections. Active immunization with purified capsule and passive protection using capsule-specific antibodies will be tested in this models. By the end of these studies we expect to have a clear understanding of the occurrence, biochemistry and immunology of capsular polysaccharides of enterococci, a definition of their role in pathogenesis of enterococcal infections, and the potential to develop immunotherapies to prevent infection in patient at-risk for this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHARACTERIZATION OF IRON TRANSPORT IN GBS Principal Investigator & Institution: Clancy, Kathryn A.; Children's Hospital and Reg Medical Ctr Box 5371, 4800 Sand Point Way Ne, Ms 6D-1 Seattle, Wa 98105 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Group B streptococcus is the predominant etiological agent of neonatal bacteremia, sepsis and meningitis, and has been correlated with preterm membrane rupture and premature birth. While a limited number of GBS virulence determinants have been identified, the contribution of iron and iron acquisition to the pathogenesis of GBS infection is unknown. All pathogens require iron and a correlation between bacterial virulence and iron acquisition has been established. However, as the concentration of available iron in the human host (10 [-18]M) is well
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below that required by bacteria (10 [-8] M), successful pathogens express specific systems to acquire sufficient concentrations of intracellular iron. One such system involved in siderophore-mediated iron uptake, is the focus of this application. Siderophores are high-affinity iron chelators secreted from the bacterial cell to scavenge iron from host iron-binding proteins. Specialized uptake systems transport the siderophore-iron complex across the bacterial membrane. We have identified a putative siderophore-mediated iron transport system, the fhu operon, in GBS. The operon is comprised of four genes, fhuC, fhuD, fhuB, and fhuG, encoding a putative ATPhydrolysis protein, siderophore (ferrichrome)- iron receptor protein, and two permeases, respectively. In this application, the role of the fhu operon in iron acquisition by GBS will be examined. Basic information on the requirement of GBS for iron, the ability of GBS to utilize siderophores as an iron source, and whether the organism secretes siderophores to acquire iron will first be established. The biochemical characterization of an isogenic mutant strain deficient for fhu will examine the role of this operon in GBS siderophore-iron transport. In order to define the siderophore specificity of the fhu operon, the construction and biochemical characterization of isogenic mutant strains deficient for each gene is proposed. In addition, heterologous expression studies will provide further evidence for the role of the fhu-encoded proteins in siderophore-iron transport. These studies will provide a basic understanding of the molecular mechanism of iron acquisition in GBS and will allow us to design appropriate in vivo studies to determine the role of iron transport in GBS pathogenesis. The potential of identifying novel therapeutic targets to prevent or treat infections is also proposed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHARACTERIZATION OF THE LPS RECEPTOR FOR ACUTE PHASE Principal Investigator & Institution: Goyert, Sanna M.; Associate Professor; North Shore University Hospital 300 Community Dr Manhasset, Ny 11030 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: Sepsis due to Gram-negative infection remains a major cause of mortality. One of the earliest events occurring in a systemic infection is the acute phase response which has, as one of its major hallmarks, alteration of the concentration of plasma proteins (acute phase proteins, APP). APP are a set of functionally diverse proteins produced in the liver and defined in general as those proteins which show changes in plasma concentration (positive or negative) of 25 percent or more following the stimulus. APP are thought to increase host defenses as well as to control inflammation. There is a large body of evidence showing that cytokines (TNFalpha, IL-1 and IL-6) can induce the expression of APP. Since lipopolysaccharide (LPS, endotoxin), a component of the outer membrane of Gram-negative bacteria which is thought to be the major bacterial component of Gram-negative bacteria responsible for inducing the cascade of events leading to lethality in sepsis, stimulates both the production of TNFalpha, IL-1 and IL-6 as well as the production of APP, it has been reasonable to assume that the LPS induction of APP results from a secondary effect of cytokines secreted by macrophages when LPS stimulates them through the CD14-LPS receptor. To study the role of CD14 in the response to LPS, we have recently produced mice which lack the CD14-LPS receptor. These CD14-deficient mice produce little or no cytokines in response to very high concentrations of LPS; surprisingly however, they have a normal APP response. These observations indicate that mice have a non-CD14 receptor for LPS through which expression of APP is induced. Furthermore, as shown in Preliminary Studies, hepatocytes from CD14-deficient mice respond directly to LPS, indicating that this
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11
receptor is on hepatocytes. Accordingly, we propose to (1) study the binding characteristics of LPS and Lipid A to hepatocytes; determine whether their binding is specific and saturable; determine their binding constants (2) isolate and biochemically characterize the hepatocyte non-CD14 LPS receptor involved in the induction of the acute phase proteins using molecular methods of protein purification and gene cloning followed by functional verification and (2) determine the molecular mechanism(s) by which the LPS-APP receptor functions by comparing the genes induced via this receptor in hepatocytes to those induced by LPS via the CD14 receptor on monocytes/macrophages. These studies will not only clarify our understanding of the mechanisms involved in the induction of acute phase proteins by LPS, but will also increase our understanding of the pleiotropic effects of LPS and its various roles in sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--FORWARD GENETICS Principal Investigator & Institution: Beutler, Bruce; Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): While several of the genes that support the innate immune response have been identified through studies of natural mutations or gene knockouts, the great majority of these genes remain undiscovered. The Forward Genetics Core Laboratory will implement the goal of identifying most or perhaps all of the genes that subserve innate immunity. This goal will be achieved through the concerted production of novel mutations that impair innate immunity and through the mapping and isolation of those mutations that are created. Saturation mutagenesis will be accomplished in mice using N-ethyl-N-nitrosourea (ENU), a potent chemical agent that is known to produce chiefly A to G and A to T substitutions. Animals bearing mutations will be screened for phenotypic impairment of innate immune responses at the FI and F3 generations, to identify both dominant and recessive mutations of genes that are critical for innate immune responses. One screen to be employed relies upon a test of the ability to resolve infection of a type that is known to be contained entirely through innate immune mechanisms. In this acute model, a photometrically based assay of sepsis that depends upon extracorporeal detection of bacterial luminescence will be employed. Other screens measure the ability of host phagocytes to engulf and to kill microbes; the ability to respond to a battery of microbial inducers (PAMPs), and the ability to develop a state of tolerance to these inducers. Hence, a broad array of genes is tested, encompassing much of the functionality of the innate immune system. The Forward Genetics Core will interact particularly strongly with the Bioinformatics Core (which will pinpoint additional genes that appear to be involved in the innate immune response), the Molecular Biology Core, which will actively study mutations that are induced. Perhaps foremost, the Forward Genetics Core Laboratory will yield a rich harvest of mutants that will permit extensive genetic dissection of innate immune responses, and their failure in septic shock. These mutants will immediately be made available to the scientific community at large and simultaneously refined for positional cloning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORE--GENOMICS LABORATRORY Principal Investigator & Institution: Aderem, Alan A.; Professor & Head; Institute for Systems Biology 1441 N 34Th St Seattle, Wa 981038904
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Sepsis
Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The analysis of genetic information will be a central requirement for all of the projects described in this grant proposal. The Genomics Core will provide high-throughput facilities for DNA sequencing, mRNA expression analysis, and single-nucleotide polymorphism (SNP) detection at the Institute for Systems Biology (ISB). The sequencing core is a high-capacity, fully automated facility developed to manage sequence analysis from eDNA libraries, BAC libraries, or PCR products in a cost-effective manner. The in-house array production and analysis facility at the ISB will be used to quantitate mRNA expression of genes involved in sepsis. This facility is currently producing high-density arrays (up to 40,000 genes per array) as well as customized arrays with select sets of genes. The facility is automated to analyze multiple arrays from clinical samples, which will be necessary to correlate in vitro data with clinical data. SNP technology has been established to both discover new SNPs as well as provide high-throughput SNP detection from multiple patient samples. SNPs are discovered by a heteroduplex mismatch detection method that has been adapted for use with arrays in a high-throughput manner. Known SNPs are detected by hybridization of an allele-specific oligonucleotide probe to an array of PCR products amplified from patient's genomic DNA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--PROTEOMICS Principal Investigator & Institution: Aebersold, Ruedi H.; Professor and Co-Founder; Institute for Systems Biology 1441 N 34Th St Seattle, Wa 981038904 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): This core will facilitate studies in most of the collaborative projects and cores by providing expert and high throughput protein analysis for identification and quantification of proteins in complex samples. The core utilizes biochemical protein separation techniques and mass spectrometry as the primary technologies to achieve this goal, and members of this core facility are world leaders in this field. It is the aim of this core to establish a discovery science infrastructure for qualitative and quantitative proteomics at the Institute of Systems Biology. Through interactive collaborations with Glue Grant investigators this core will impact biomedical research in the regulation of the immune response during injury and sepsis. This core facility will permit participants in this grant proposal to 1) rapidly identify unknown proteins, 2) characterize specific post-translational modifications, 3) identify interacting proteins 4) localize protein:protein interaction sites, and 5) quantify the relative abundance of up to thousands of different proteins in complex specimens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DESIGN OF ATTENUATED TULAREMIA VACCINE Principal Investigator & Institution: Cross, Andrew M.; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: Its ease of transmission, history of having been weaponized and propensity to cause severe and fatal disease following inhalation, make Francisella tularensis (Ft) a Category A bioterrorism agent of concern. The only vaccine available for more than 40 years is efficacious, but its mode of attenuation is unknown and the FDA has not approved its general use. Development of new vaccines is limited by the paucity of information about the virulence determinants of Ft. This project will provide (1)
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measures to extend the disease-free interval until definitive therapy/vaccines are implemented; and (2) vaccines that induce humoral and cellular immunity to Ft. Project 1A will characterize mechanisms by which the unusual Ft LPS induces mediators responsible for the systemic inflammatory responses of tularemia, and determine if reagents already under clinical testing for sepsis are useful in the treatment of disseminated tularemia in a murine model. Upon stimulation, gamma-delta T cells rapidly produce inflammatory cytokines critical to both the initial innate immune response and organization of the adaptive responses. Activation of gamma-delta T cells is associated with convalescence from tularemia. Aminobisphosphonates drugs, widely used for bone disorders, stimulate gamma-delta T cells and might serve as initial therapy for individuals exposed to Ft (Project 1B). Project 2 will characterize the Ft capsule and develop a conjugate vaccine, using as carriers either the protective antigen of B. anthracis or proteins derived from plague or Ft. Adjuvants that also rapidly boost innate immunity (e.g. CpG) may accelerate a humoral response and provide early protection. Like the Vi vaccine for the intracellular pathogen, Salmonella Typhi, the Ft capsular conjugate vaccine is intended to prevent Ft from reaching its required intracellular niche. Durable immunity to Ft requires a cellular immune response. Based on our previous success in developing live attenuated strains of Salmonella, we will design an attenuated, easily administered Ft vaccine (Project 3A). Signature-tagged mutagenesis will define additional targets for attenuation and new virulence factors for further study (Project 3C). Activated T cells are sequestered in peripheral tissues. We will compare which immunization regimen optimally delivers primed effector/memory T cells to lung and liver, sites of Ft replication. These studies will provide public health officials short term and definitive treatment options in the event of a bioterror attack with Ft. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TECHNIQUES
DETECTING
NEONATAL
SEPSIS
USING
MOLECULAR
Principal Investigator & Institution: Jordan, Jeanne A.; Magee-Women's Health Corporation 204 Craft Ave Pittsburgh, Pa 152133180 Timing: Fiscal Year 2002; Project Start 16-AUG-2000; Project End 31-MAY-2004 Summary: (Adapted from the Investigator's Abstract): Approximately 150,000 to 500,000 infants greater than 34 weeks gestational age are admitted to NICUs annually who are at risk for systemic infection. These infants all receive systemic antibiotic therapy. However, the vast majority of these infants are not infected, but rather have symptoms that are secondary to other medical conditions. The current standard of care for evaluating neonatal sepsis is blood culturing, which lacks sensitivity and is not informative prior to at least 24 to 46 hours. As a result, there is prolonged use of antibiotic therapy in many newborns that could be shortened if a more rapid test to rule out sepsis was available. This application proposes to investigate two potential tests, a PCR-based amplification assay for detecting bacterial 16S ribosomal DNA and an ELISA-based assay for defensins, to determine their usefulness as early predictors of systemic neonatal infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEVELOPMENT EXPRESSION OF CHEMOKINES AND THEIR RECEPTORS Principal Investigator & Institution: Calhoun, Darlene A.; Pediatrics; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620
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Sepsis
Timing: Fiscal Year 2002; Project Start 13-AUG-2001; Project End 31-JUL-2003 Summary: (provided by applicant) Despite the development of newer and more effective antibiotic therapies, sepsis related mortality in neonates undergoing intensive care has remained constant for nearly two decades. The rate of infection among these neonates ranges from 25% to 50%, with bacterial infection remaining a major cause of death and long-term morbidity. The cost of caring for premature neonates, who are the most susceptible to infection, represents over 50% of the total dollars expended for neonatal intensive care unit (NICU) services. The unique susceptibility of the human neonate to serious and overwhelming bacterial infections relates in part to deficiencies of antibody, complement, and T lymphocytes. However, while deficiencies in these contribute to the neonate s susceptibility, neutrophil defects appear to be the major host defense abnormality. Functional defects in neonatal polymorphonuclear leukocyte adherence, aggregation, chemotaxis, phagocytosis, and intracellular killing have been described in both the term and preterm infant. Of these defects, neutrophil chemotaxis, as assessed by in vitro assays, is abnormal at birth. While term infants rapidly establish normal chemotactic function, the process of postnatal maturation begins two to three weeks after birth in the preterm infant and proceeds very slowly. Neutrophils follow a concentration gradient of chemotactic factors in their movement from the vascular compartment to the site of microbial invasion. Chemokines are chemotactic cytokines that largely control leukocyte migration. While considerable information has emerged in the past ten years related to the role of chemokines in the adult, very little information exists as to the physiologic significance of chemokines in the neonate. Candidate chemokine/chemokine receptors for influencing neutrophil chemotaxis include members of the CXC chemokines. We propose that understanding the gene regulation for the expression of specific chemokine receptors (CXCR) during development would enhance our understanding of chemotaxis in the neonate. We further propose that defining circulating concentrations of chemokines critical for neutrophil migration would be essential to understanding their role in both health and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEVELOPMENT OF NEW LIPID A BINDING AGENTS Principal Investigator & Institution: Savage, Paul B.; Associate Professor; Chemistry and Biochemistry; Brigham Young University A-261 Asb Provo, Ut 846021231 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAY-2003 Summary: Sepsis affects the lives of hundreds of thousands of people each in the U.S. Sepsis caused by Gram-negative bacteria results from adverse host immune response to the Lipid A (LA) portion of endotoxin. Compounds with high affinity for LA, including polymyxin B (PMB) and derivatives, are capable of detoxifying LA nd protection a host against sepsis. By binding LA, these compounds also sensitize Gram-negative bacteria to hydrophobic antibiotics. However, therapeutic use of PMB is limited due to its toxicity. The aim of this research is to develop small molecules capable of strong and selective associating with LA for use in treatment of sepsis and as means of fighting bacterial infection. Taking the interactions of PMB with LA as a model, this research focuses on the preparation of simple compounds, based on cholic acid scaffolding, capable of mimicking the LA-binding behavior of PMB but lacking the toxicity of the antibiotic. Simple cholic-acid based LA binders will present many advantages over reported LA binding molecules including: ease of preparation and derivatization, greater control over biological stability, and potential oral bioavailablity. Cholic acid derivatives were designed to mimic a conformation of PMB believed to be important in its association with LA. Preliminary experiments with cholic acid derivatives
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demonstrate their ability to sensitize Gram- negative bacteria to hydrophobic antibiotics, a behavior of LA binding agents. Optimization of LA-binding characteristics will be achieved by preparing libraries of compounds made up by amino acids linked to cholic acid scaffold. The libraries will be screened for LA binding using affinity chromatography. The affinity chromatography stationary phase will be made up of LA immobilized through hydrophobic interactions of C18- silica particles or polystyrene beads. The types of amino acids in effective LA binders will be determined via mass spectroscopy. New LA-binding agents will be tested for the ability to sensitize Gramnegative bacteria to hydrophobic antibiotics and/or inhibit the effects of LA on human monocytes (specifically interleukin 1b production). Association of PMB and the new LAbinders with LA and LA derivatives will be compared using microtitration calorimetry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIAPHRAGM MITOCHONDRIAL ALTERATIONS IN SEPSIS Principal Investigator & Institution: Callahan, Leigh A.; Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-JUL-2002 Summary: (Applicant's abstract): Recent work suggests that mitochondria dysfunction plays a central role in sepsis, a major cause of death and morbidity in the United States. The underlying mechanisms responsible for this mitochondria dysfunction are not known. The goal of the present proposal is to test the hypothesis that increased free radical generation in sepsis produces specific biochemical, structural and genetic changes that result in marked physiologic alterations in mitochondrial function. We postulate: (a) mitochondria dysfunction in sepsis results from physiologic derangements of Krebs cycle enzymes, Complex I-IV electron transport chain components, and sarcomericcreatine kinase, (b) these physiologic changes are due, in turn, to alterations in the content and composition of mitochondrial proteins, and (c) protein changes are due, in part, to free radical-mediated decrements in mitochondrial gene transcription, expression, and translation. These hypotheses will be tested in three groups of experiments, using a model of endotoxin-induced sepsis. The purpose of Objective 1 is to fully characterize the specific physiologic derangements in the mitochondria in sepsis; we will examine Krebs cycle enzyme activities, evaluate specific performance of complexes within the electron transport chain, assess sarcomeric mitochondrial creatine kinase activity, and perform a metabolic control analysis. Objective II will identify changes in the content and composition of mitochondrial protein constituents (i.e. electron transport chain protein subunits, Krebs cycle enzymes, creatine kinase) and compare the time course of these alterations with the development of physiologic abnormalities determined in Objective I. Objective III will evaluate transcription, expression, and translation of mitochondria and nuclear genes encoding for mitochondrial proteins found to be depleted in Objective II. In all studies, we will determine the role of free radical modulation of these sepsis-induced changes. Our preliminary data provide the first evidence of substantial sepsis-associated oxidative modification and depletion of mitochondria protein subunits in Complexes I, III and IV, significant alterations in NADH generation via Krebs cycle enzymes, major decreases in mitochondria creatine kinase activity, and key free radical-mediated changes in gene expression of mitochondrial proteins in sepsis. These data suggest that the proposed experiments should provide important information regarding the pathogenesis of mitochondrial dysfunction in sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Sepsis
Project Title: EFFECTS OF VASOACTIVE DRUGS ON PERFUSION IN SEPTIC SHOCK Principal Investigator & Institution: Murray, Patrick T.; Anesthesia and Critical Care; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): This Mentored Patient-Oriented Research Career Development Award application requests support (or a proposal which includes mentorship by an experienced investigator, multidisciplinary support from the Chairs and faculty of several Departments. formal training in an NIH-funded Clinical Research Training Program. and a research project dissecting the regional and systemic effects of traditional and novel vasoactive drugs in critically ill patients with septic shock. Sepsis. the systemic inflammatory response to infection. may lead to refractorv hypotension (septic shock) and multiple organ system failure (MOSF). Despite increased cardiac output and oxygen delivery, death often ensues from refractory hypotension or subsequent MOSF. Standard indicators of adequate tissue perfusion which are used to titrate therapy in hypovolemic or cardiogenic shock are unreliable in hyperdynamic septic shock. Rational septic shock therapy would preferably be guided by targeted interventions tc? optimize end-organ perfusion and function, and reverse detectable tissue hypoperfusion. The primary end-organ index of adequate perfusion used in current clinical practice is renal perfusion and function. The effects of vasoactive drug therapy on renal perfusion and function are reliably quantifiable with sophisticated existing technology. This application seeks to determine the regional circulatory effects of restoring vascular contractility with standard exogenous catecholamines and the novel use of exogenous vasopressin, alone or in combination, in septic humans, focusing on renal perfusion and function. We will also examine the systemic and regional effects of targeted vasodilator therapy with fenoldopam (a novel dopaminergic agonist) in septic humans, alone or in combination with the aforementioned vasoconstrictors. Specifically, we will address the hypotheses that: 1) Addition of inotropic support (badrenoceptor stimulation) to intravenous fluids alone, or in combination with pure vasopressor therapy (a-adrenoceptor stimulation), improves renal perfusion and function in patients with sepsis or septic shock. 2) Titration of vasopressor therapy to a mean arterial pressure above the lower renal autoregulation threshold improves renal perfusion in patients with vasopressor-dependent septic shock. 3) Vasopressin therapy restores septic vascular contractility, augments vasopressor-responsiveness, reverses hypotension. and improves systemic and renal perfusion in human subjects receiving standard therapy for sepsis or septic shock. 4) Septic renal vasoconstriction is reversed, and renal perfusion and function improved, by selective renal vasodilator therapy. The overall aim of these experiments is to develop rational pharmacologic regimens and strategies for hemodynamic support in septic shock. focusing on prevention and management of septic acute renal failure, as a surrogate endpoint to optimize systemic perfusion in hyperdynamic states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PKCDELTA
ENDOTHELIAL
BARRIER
FUNCTION
MODULATION
BY
Principal Investigator & Institution: Harrington, Elizabeth O.; Assistant Professor; Medicine; Brown University Box 1929 Providence, Ri 02912 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005
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Summary: Increased microvascular permeability causes pulmonary edema in acute lung injury, adult respiratory distress syndrome (ARDS), and multisystem organ failure. Disruption of endothelial cell-cell contacts is a possible cause of increased microvascular permeability. Identification of intracellular mechanisms which regulate changes in vascular permeability may lead to therapeutic strategies for controlling tissue damage due to sepsis or other causes of acute lung injury. Our preliminary results indicate that overexpression of protein kinase Cdelta (PKCDELTA) protects against thrombininduced increases in endothelial monolayer permeability. The hypothesis of this proposal is that PKCDelta blunts changes in endothelial monolayer permeability by modulating the organization of cytoskeleton junctional complexes. Endothelial cells (EC) normally form a tightly adherent monolayer. During an inflammatory or thrombogenic response endothelial monolayer permeability increases with the formation of interendothelial cell gaps as a result of both EC contraction and disruption of endothelial cell-cell interactions. EC contraction occurs by intracellular calcium mobilization, Rho GTPase activation, myosin light chain phosphorylation, actin microfilament reorganization, and focal adhesion complex (FA) formation. Disruption of endothelial cell-cell junctions occurs concomitantly with the redistribution of the adherens junction (AJ) protein complexes at the points of intercellular gap formation. The intracellular mechanisms by which edemagenic agents promote EC contraction and FA formation and the disassembly of the AJ complexes are not completely understood. A number of inflammatory and thrombogenic agents activate PKC, increasing monolayer endothelial permeability. The overall objective of this proposal is to determine the mechanism by which PKCDELTA modulates endothelial barrier function. Using microvascular EC which stably overexpress PKCDELTA and vector control, we will determine: I) whether diminished endothelial barrier function is due to the stabilization and association of AJ or FA with PKCDELTA; II) whether delta PKCDELTA blunts endothelial barrier function by modulating EC retraction at the level of actin stress fiber formation and/or function; and III) whether PKCDELTA reduces endothelial barrier function by altering MAPK signaltransduction pathway. The elucidation of the molecular mechanisms by which PKCDELTA decreases endothelial monolayer permeability may lead to the development of therapeutic agents which are protective against endothelial barrier dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENDOTHELIN CONVERTING ENZYME IN SEPSIS: CARDIAC FUNCTION Principal Investigator & Institution: Sharma, Avadhesh C.; Pharmaceutical Sciences; North Dakota State University Fargo, Nd 581055756 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): The long-term objective of our group is to characterize an interactive role of vasoactive substances in sepsis-induced myocardial dysfunction and related cardiovascular pathologies. Chronic peritoneal sepsis in our rat model produces myocardial dysfunction in an isolated heart preparation and cardiomyocytes. Induction of sepsis also increases susceptibility of the isolated hearts to a calcium paradox-mediated myocardial injury. In vivo, we have demonstrated that induction of sepsis results in disproportionate alterations in the circulating levels of Endothelin-1 (ET-1) and nitric oxide byproducts (nitrite and nitrate, NOx). Recently we observed that inhibition of metalloprotease (endothelin-converting enzyme [ECE], which converts proET-1 to ET-1) at the time of induction of endotoxemia decreased the expression of myocardial inducible nitric oxide synthase (iNOS) and downregulated the
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Sepsis
expression of p38 mitogen-activated protein kinase (MAPK) twenty-four hours later. Therefore, our immediate objective in the present proposal is to test the hypothesis that sepsis-induced alteration in the biosynthesis of myocardial ET-1 (regulated by ECE-1) via MAPK-dependent or -independent mechanism(s) would affect NOS proteins and cardiac function. The following two specific aims are designed to address this hypothesis. Specific Aim 1: To determine if ECE-1 inhibition at the time of induction of sepsis would affect sepsis-induced myocardial dysfunction (decrease in the rates of left ventricular contraction and relaxation, i.e., + dP/dt and -dP/ dt respectively) and the expression of p38MAPK and iNOS proteins at 12 and 24 h post sepsis (Year 1-2). Specific Aim 2: To determine if ECE-1 inhibition at the time of induction of sepsis via p38MAPK-dependent or -independent mechanism would affect myocardial function in an isolated heart preparation at 24 h post sepsis (Year 2-3). The specific aims were designed to assess if ECE-1 inhibition during sepsis would suppress sepsis-induced myocardial dysfunction characterized by downregulation of p38 MAPK and depressed expression of iNOS proteins. The novel aspect of the specific aims is that the results will provide evidence for a causal relationship between ET-1 biosynthesis and the expression of p38MAPK and iNOS proteins in the myocardium. An increased understanding of the underlying mechanisms during these two stages (12 and 24 h post sepsis) of sepsis will help design therapeutic interventions for early and late stages of sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ETHANOL PROMOTES LUNG ENDOTHELIAL:NEUTROPHIL INTERACTIONS Principal Investigator & Institution: Brown, Lou Ann S.; 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): Investigators in this Center Application have identified chronic alcohol abuse as a co-morbid variable that significantly increases the incidence and severity of the Acute Respiratory Distress Syndrome (ARDS). The overall theme of this Center application postulates that chronic ethanol ingestion enhances the risk of alveolar flooding in response to inflammatory mediators and activated neutrophils. This suggests a "two-hit" model wherein chronic ethanol ingestion constitutes the first hit but does not generate pulmonary dysfunction. However, the first hit does predispose the lung to an enhanced response to the inflammatory mediators and activated neutrophils produced during sepsis. We postulate that one mechanism by which chronic ethanol ingestion predisposes the lung to endothelial barrier dysfunction involves ethanol-induced decreases in the availability of the antioxidant glutathione (GSH), particularly the mitochondrial pool in pulmonary microvascular endothelial cells (MVEC). When GSH availability decreases, the reactive oxygen species (ROS) generated during normal respiration and ethanol detoxification becomes amplified. With chronic exposure to ROS, the MVEC is altered and the basal expression of adhesion molecules are upregulated. During sepsis, the adhesion of the activated neutrophils and the microenvironment is potentiated. The ethanol-induced GSH depletion then amplifies the ROS produced resulting in mitochondrial dysfunction and decreased ATP generation. With limited ATP availability, the MVEC are more susceptible to cytotoxinand neutrophil-induced apoptosis and necrosis. When MVEC death is enhanced, barrier dysfunction and neutrophil migration is potentiated. Furthermore, we propose that GSH precursors will attenuate this enhanced endothelial:neutrophil interaction and result in decreased sepsis-induced acute lung injury. Using a rat model of chronic ethanol ingestion, three Specific Aims will explore this hypothesis to determine: 1) if
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chronic ethanol ingestion potentiates inflammatory mediator-induced oxidative stress in MVEC, 2) if ethanol-induced chronic ROS up regulates MVEC adhesion factor expression and neutrophil transmigration during sepsis and 3) if intervention with GSH precursors will attenuate ethanol potentiation of adhesion factor expression and neutrophil transmigration during sepsis. This proposal will improve our understanding of the relationship between alcohol and lung injury and potentially identify strategies for ARDS prevention and treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTIONAL AND METABOLIC PROPERTIES OF TOXIC NEUTROPHILS Principal Investigator & Institution: Mccall, Charles E.; Professor; Internal Medicine; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Sepsis is the major cause of morbidity and mortality in critical care units in the USA. During sepsis, expression of pro-inflammatory genes is repressed when blood leukocytes are stimulated ex vivo with bacterial endotoxin. Endotoxin tolerance may reflect a state of immunosuppression that contributes to the high mortality rate observed in sepsis. The objective of this proposal is to define the molecular basis of endotoxin tolerance, using three models: blood leukocytes of patients with sepsis, blood monocytes, and THP-1 pro-monocytic cells. We will test the hypothesis that a labile factor(s) mediate the tolerant phenotype by repressing the transcription of proinflammatory genes such as IL-1beta and PGHS-2. Aim 1 using a biochemical approach and an in vitro transcription assay to identify, characterize, and purify the transcription repressor(s). An alternative genetic approach seeks to identify the transcription repressor in endotoxin tolerant THP-1 cells using differential display RT-PCR. Aim 2 investigates the intracellular signaling pathways utilized by endotoxin to modulate proinflammatory gene expression. Constitutively active or dominant-negative mutants of kinase mediators are employed in co-transfection assays to test the impact of various kinase activities on IL-1beta transcription. Immunologic approaches are used to identify activated/inactivated kinases in the normal and tolerant phenotypes. Aim 3 proposes to translate our understanding of the in vitro endotoxin tolerant THP-1 cell model to the in vivo tolerant phenotype of septic patients. A genetic approach, using differential display RT-PCR, and a biochemical approach, using the purified repressor, will compare the two phenotypes. Immunological techniques also will be applied to the septic patient model to identify kinases that regulate endotoxin responses and they be activated/inactivated in the tolerant phenotype. These investigations will increase our understanding of the mechanisms that regulate pro- inflammatory gene expression and contribute to improving the management of patients with sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DISCOVERY
GBS:
EPIDEMIOLOGIC
CHARACTERIZATION
FOR
GENE
Principal Investigator & Institution: Foxman, Betsy; Professor; Epidemiology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Group B Streptococcus (GBS) is a major cause of neonatal sepsis and meningitis. First emerging as a pathogen in newborn nurseries in the 1970s, it is now a pathogen of concern in nursing homes, intensive care units and
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Sepsis
outpatient settings. Little is known about GBS virulence factors. The overall goals of this application are 1) to use genetic fingerprinting techniques to better describe the molecular epidemiology of GBS of several epidemiologically defined collections; and 2) to identify new genes associated with GBS disease. By combining epidemiologic information with molecular genetics, we can maximize our ability to detect GBS virulence-related genes associated with invasive disease, extra-intestinal colonization, transmission and antibiotic resistance. This strategy also gives us insight as to the relative importance of the identified genes and their potential mechanism. A better understanding of the molecular epidemiology and the identification of new GBS virulence genes will facilitate the discovery of new therapies and prevention strategies for GBS disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC AND INFLAMMATORY MARKERS OF SEPSIS Principal Investigator & Institution: Angus, Derek C.; Professor; Critical Care Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (Verbatim from the Applicant's Abstract): Sepsis, a diffuse inflammatory response to infection, occurs in over 450,000 cases per year in the US and frequently progresses to organ dysfunction and death. Although experimental studies using cells and animals have greatly improved our understanding of the pathophysiology of sepsis, there remains a remarkable paucity of biochemical and genetic data regarding the natural history of this important public health problem. In particular, there is a need for better markers of sepsis and outcome and a more rigorous evaluation of the complex relationships among the many genetic, inflammatory, and clinical factors that appear to influence the development and outcome of sepsis. Because pneumonia is the most common cause of sepsis, patients with this infection represent an excellent clinical model for studying sepsis in a relatively homogeneous population. We propose to study a large cohort of patients (n=2,703) with community-acquired pneumonia (CAP). Our study will be "piggy-backed" onto a multicenter trial of alternative hospital quality improvement initiatives that is already funded and slated to begin enrolling patient's early in 2001. In addition to collecting detailed clinical data, we will carry out careful genetic analyses, focusing on allelic variations in the coding or noncoding regions of genes whose products are important in the expression and/or regulation of the inflammatory response. We will also obtain measurements over time of the plasma concentrations or cell surface expression of several key inflammatory molecules. We will determine the influence of specific polymorphisms on the development, course and outcome of pneumonia and sepsis. We will test whether genetic predisposition to an exuberant inflammatory response protects against infection yet also increases risk for adverse systemic effects and outcome. We will compare genetic data from patients with results obtained from a cohort of healthy controls (n=300). We will test several existing hypotheses regarding the association of circulating inflammatory molecules with outcome. We will use time-varying regression analyses and probabilistic networks to explore in new detail relationships among genetic polymorphisms and the inflammatory response in sepsis. Finally, we will construct and evaluate two sets of clinical decision tools: i.) clinical risk prediction rules that incorporate genetic and inflammatory response variables with existing clinical factors, and; ii.) a state-transition simulation model of the course of sepsis that allows time-dependent estimates of the effects of alternative treatment decisions. This study will generate: new and valuable information regarding existing lines of inquiry and laboratory investigation; new
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hypotheses arising from the use of time-dependent modeling; and new clinical decision tools that have immediate and practical value for designing clinical trials and improving patient care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC MUTATIONS THAT PREDOPOSE TO INFECTIOUS DISEASE Principal Investigator & Institution: Butler, Bruce; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: The innate immune response is dependent upon a discrete collection of proteins that mediate the detection of microbial invaders and their elimination. Only a handful of these proteins are known at present, and among them, the Toll-like receptors and associated signaling proteins play a prominent role as sensors. The program of which this Bridging proposal is a part will permit the identification of many critical genes involved in the innate immune response. We propose to examine each of these genes in turn, starting with the Toll-like receptors and moving to new genes as they are discovered. Our ultimate goal is to determine whether mutations at these loci contribute to susceptibility to sepsis in humans, or influence the outcome of sepsis once it is established. The approach taken is one in which modem techniques for mutation detection will be used to assay genetic load within the coding region at each locus, in disease populations and in ethnically matched control populations. In particular, we will emphasize the use of advanced methods for mutation detection, coupled with highthroughput sequencing to achieve this end. In accordance with the emerging principle that most complex human diseases may be ascribed to low-frequency codominant mutations affecting multiple loci, it is expected that mutations will be over-represented in specific loci within a disease population, given that those loci encode genes that are important in fighting infection. Preliminary work has supported this principle as it applies to the TLR4 locus in meningococcal disease: there is a significant excess ofmissense mutations at this locus in the disease population, compared with controls. We intend to generalize the principle, seeking to establish the importance of rare mutations at multiple loci in the pathogenesis of diverse infections. This proposal will entail extensive interactions between the Forward Genetics Core, the Genomics Core, and the Sequencing Core. Mutational data bearing on the involvement of specific genes in sepsis will quickly be disseminated to the scientific community at large through a webbased information system. Ultimately, these studies may foretell susceptibility to infection, and explain the strong heritability of infectious diseases in molecular terms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GLU6PASE AND 6P2K/FBASE GENE REGULATION IN SEPSIS Principal Investigator & Institution: Maitra, Subir R.; Emergency Medicine; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Sepsis is that critical condition of the patient which, if uncorrected, leads to death. The initial hyperglycemia seen in sepsis is followed by hypoglycemia with concomitant hyperlacticacidemia. Glucose-6-phosphatase (Glu-6-Pase) is a key enzyme in the homeostatic regulation of blood glucose concentration, which catalyses the final step in gluconeogenesis and glycogenolysis. Another important enzyme for regulation of gluconeogenesis is 6-phosphofructo-2-kinase/fructose-2,6bisphosphatase
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(6PF2K/FBPase), which is responsible for the production and hydrolysis of fructose-2,6bisphosphate (Fru-2,6- P2), a modulator of glycolytic to gluconeogenic flux. We have demonstrated that gene expression of Glu-6-Pase and 6PF2K/FBPase are reciprocally modulated during hyperglycemic phase of hemorrhagic shock. In this proposal, we are focusing on the regulation of expression of these two genes as models of hormonal counter-regulation during sepsis. In addition to studying the hormonal regulation of these genes in sepsis, we also propose to determine the hormonal response elements of these genes by promoter analysis. Sepsis will be induced in fasted, anesthetized rats by cecal ligation and puncture (CLP) method and will be observed for 0.5 h, 3 h, and 20 h periods. Control rats will undergo sham operation and will be observed for the same time. The liver and kidney from control and CLP rats will be freeze-clamped in liquid nitrogen and stored at -70 degrees C for future assay of glucose-6- phosphate, fructose-6phosphate, glucose-6-phosphate dehydrogenase activity, Glu-6-Pase and 6PF2K/FBPase enzyme activity and gene expression. Blood samples will be collected at the same time periods to assay glucose, corticosterone, insulin and glucagon concentration in the plasma. Relatively selective pharmacologic antagonists of hormones and cytokines will be administered prior to CLP to observe their effects on Glu-6-Pase and 6PF2K/FBPase gene expression. Hepatocytes will be isolated from control and CLP rats and will be incubated with agonists to observe their effects on Glu-6-Pase and 6PF2K/FBPase gene expression. Freshly prepared, primary cultures of hepatocytes will be transfected and then incubated with hormones and hormonal response element will be confirmed by DNA footprinting. The results of this study are essential to understand the molecular basis of deranged metabolism in sepsis. Understanding the mechanism might be useful for developing appropriate therapeutic intervention during sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY AND SEPSIS Principal Investigator & Institution: Spolarics, Zoltan; Associate Professor; Cell Biology & Molec Medicine; Univ of Med/Dent Nj Newark Newark, Nj 07103 Timing: Fiscal Year 2002; Project Start 01-FEB-1997; Project End 31-JAN-2005 Summary: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human genetic polymorphism. A clinically significant variant is the type A deficiency present in 10-12% of African Americans. G6PD is a major supporter of cellular redox status. Our clinical investigations on young African American trauma patients revealed that after severe trauma, the type A- G6PD deficiency predisposes to the development of bacteremic sepsis, an augmented inflammatory response and worsens anemia. The defect also alters the trauma-induced monocyte responses. We will investigate the impact of the defect on the sepsis-associated multiple organ dysfunction/failure and mortality after major trauma. We will test if a compromised RBC function and an altered activation status of the reticolo-endothelial/monoculear phagocyte system contribute to the adverse clinical effects of the deficiency. The study use G6PD deficient and nondeficient human endothelial cells (HUVEC), monocytes and neutrophils and an animal model. Hypotheses: 1: After severe trauma, the sepsis-associated mortality is greater in G6PD deficient patients than non-deficient patients. The adverse clinical course of G6PD deficient patients is associated with a diminished production of antiinflammatory cytokines by monocytes, increased hemolysis, and decreased RBC deformability. The prospective cohort study will compare the clinical parameters in G6PD deficient and nondeficient patients after major trauma (ISS>13) and the time dependent changes in cytokine patterns representative of the proinflammatory/anti-
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inflammatory balance in leukocytes. Alterations in RBC deformability, lipid peroxidation, nitrosylated protein, nitroso-thiol and glutathione content will also be followed. 2: After oxidative stress, G6PD deficient endothelial cells and monocytes display an augmented pro-inflammatory response compared to non-deficient cells. Activation of redox-dependent transcription factors ( NFkB,AP1,SP1) and redox status (GSH/GSSG) and the accompanying changes in cytokine production will be determined after ischemia- reoxygenation or chemically-induced oxidative stress in deficient and non-deficient HUVEC and monocytes. 3. G6PD deficiency diminishes the antioxidant capacity of endothelial cells more severely than the antioxidant capacity of phagocytes which results in an enhanced phagocyte-mediated endothelial dysfunction. Phagocytemediated endothelial cell apoptosis/injury will be measured in co-cultures using deficient or non-deficient cells. Using specific inhibitors of G6PD in an animal model will test endothelial cell dysfunction. The studies will elucidate if the adverse clinical effects of G6PD deficiency are manifested in elevated mortality and worsening organ dysfunction after injuries. The study will reveal important and novel information on the potential mechanisms, including RBC dysfunction, monocyte activation, and the role of redox regulated gene expression that is responsible for the adverse clinical effects of G6PD deficiency in trauma patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THERAPEUTICS
GRAM-NEGATIVE
SEPSIS:
PHARMACOPHORE-BASED
Principal Investigator & Institution: David, Sunil A.; Molecular Biosciences; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Gram-negative sepsis, a common and serious sequel of systemic bacterial infections is the leading cause of mortality, accounting for some 200,000 fatalities annually in the US alone. The pathogenesis of Gram-negative septic shock is due to the host response to endotoxins, or lipopolysaccharides (LPS), present on the surface of gram-negative bacteria. There are, to date, no FDA-approved therapeutic options targeting the endotoxin itself to prevent or treat this disease. We have shown that relatively simple, and synthetically easily accessible molecules of the lipopolyamine class specifically bind to LPS and neutralize its toxicity both in vitro and in animal models of septic shock. The affinity of the lipopolyamines toward LPS, however, is relatively weak (2-10 (M). In this proposal, our goal is to identify highaffinity LPS binders with nonlipopolyamine scaffolds as novel leads for the therapy of Gram-negative sepsis. A focused library of ~6000 compounds, each possessing the primary pharmacophore for LPS binding will be screened using a well-established fluorescence displacement method implemented in HTS formats. Binding, however, does not necessarily manifest in neutralization of LPS toxicity. For neutralization, an additional, appropriately positioned long-chain aliphatic group is essential. Highaffinity binders ("hits") identified in HTS will be alkylated appropriately to generate LPS-neutralizing compounds (sequestrants). In in vitro assays, the potency of lead compounds in inhibiting the release of LPS-mediated proinflammatory cytokines such as tumor necrosis factor will be characterized. In a select subset of promising leads identified in the screens described above, we will verify that the mechanism of action of inhibition of LPS toxicity is via its sequestration by showing that relevant upstream cellsignaling events are blocked. The protective effects of particularly promising molecules will then be examined in two well-established murine models of gram-negative sepsis. We will systematically evaluate the toxicity of the test-compounds in a carefully chosen
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panel of in vitro assays. Molecular modeling techniques will be applied in an effort to correlate experimentally observed binding affinities of the test compounds with features of molecular interaction such as binding geometry, H-bonds, electrostatic, hydrophobic, and van der Waals contributions to the free energy of binding. Based on the data from the primary screen, in silico modeling, and biological assays, we will synthesize a series of analogues around promising leads using a combination of focused virtual library screening and classical medicinal chemistry approaches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HEME OXYGENASE-1 AND SEPSIS USING TRANSGENIC MICE Principal Investigator & Institution: Choi, Augustine M.; Professor; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-MAY-2003 Summary: (Adapted from the applicant's abstract): Heme oxygenase (HO) catalyzes the first and rate-limiting step in the oxidative degradation of heme to bilirubin. While HO2 is constitutively expressed, HO-1 is highly induced by heme, metal ions, cytokines, and agents causing oxidative stress such as LPS during gram negative sepsis. The PI's laboratory has shown that HO-1 induction may play a role in protection against oxidative stress in an in vivo model of septic shock and MOSF. In this proposal the investigators propose to utilize HO-1 transgenic and knockout mice to test their hypothesis that HO-1 plays a critical role in providing protection against oxidative stress. Specifically, they propose to 1) generate and identify transgenic mice overexpressing HO-1 selectively in the endothelial and vascular smooth muscle cells in the vascular wall, 2) determine the physiological, biochemical and cellular responses of HO-1 overexpressing transgenic mice in a murine model of septic shock and MOSF, 3) apply HO-1 knockout mice to this sepsis model, and 4) determine the mechanism(s) by which HO-1 induction protects against oxidative stress. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IL-6 AND HEPATIC DYSFUNCTION IN SEPSIS Principal Investigator & Institution: Deutschman, Clifford S.; Professor; Anesthesia; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: ( Applicant's abstract.) Sepsis and the related Systemic Inflammatory Response Syndrome (SIRS) and Multiple Organ Dysfunction Syndrome (MODS) are important causes of death and disability in surgical or injured patients, although the exact cause of death is often obscure. These disorders are complex, involve a number of molecular mediators and effect most organs. Little is understood, however, about the manner in which organ dysfunction develops in these diseases. One important organ that is damaged in sepsis/SIRS/MODS is the lever. Intra-abdominal fecal contamination causes SIRS/MODS-like abnormalities in the liver of rodents. In this study we will examine one proposed mechanism that we believe contributes to the development of liver dysfunction in sepsis /SIRS/MODS. We have shown that intra-abdominal fecal contamination causes an early down regulation of transcription in this organ. This change affects many genes, including some encoding molecules that 1) transfer bile acids out of liver cells and into the biliary system and 2) allow liver cells to burn fat. We propose that the inflammatory cytokine IL-6 mediates some aspects of decreased gene expression, leading to liver cells that cannot excrete bile salts or burn fat. A build-up of bile salts and fat in liver cells "poisons" them so that they die. When enough liver cells
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die, liver dysfunction develops. The role played by IL-6 in this proposed mechanism of hepatic dysfunction will be studied in the setting of normal IL-6 levels, IL-6 absence, IL6 excess and IL-6 repletion after depletion. Several specific measures will be studied. These include 1) transcription of the bile acid transporters Ntcp and Mrp2 and the ratelimiting enzyme in fat oxidation, CPTII, to be determined using transcription elongation analysis, 2) activation of two hepatic nuclear proteins, C/EBPalpha and HNF-1alpha, that modulate transcription of Ntcp, Mrp2 and CPTII and 3) the development of cholestasis (bile trapping in cells) and steatosis (fat trapping in cells) as indicated by microscopic examination of fixed liver sections. In addition, we will mimic IL-6 levels in sepsis in normal mice by 1) administering intravenous IL-6 and 2) injecting a virus that is taken up by the liver and produces high intrahepatic levels of IL-6. We will then study transcription, transcription factor activation, cholestasis and steatosis. These studies should provide key information on the role played by an important inflammatory mediator, IL-6, in the complex series of events that results in the hepatic dysfunction of SIRS/MODS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNITY TO PNEUMOCOCCAL SURFACE PROTEIN A AND C Principal Investigator & Institution: Briles, David E.; Professor; Microbiology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-AUG-1984; Project End 31-OCT-2002 Summary: (Adapted from the applicant's abstract): The proposal is aimed at continuing Dr. Briles' research efforts in the study of pneumococcal surface antigens. The application focuses on the first cell-associated protein described, PspA, as well as a second newly discovered protein, PspC. These two proteins may serve as vaccines themselves or as protein carriers for capsular polysaccharide-protein conjugates. PspA is present on all pneumococcal strains and can elicit protective immunity against sepsis and nasopharyngeal carriage in mice. PspC is related to PspA, but larger in size, and shows virtual identity with PspA in its C-terminal half. The proposed studies will determine whether PspC is a virulence factor and whether it can elicit protection. The relative roles of PspA and PspC in virulence and carriage in nonimmune animals will be examined. In addition, the relative roles of immunity against PspA and PspC in carriage, sepsis, and spread of pneumococci from the nasopharynx will be explored. The ability of human antibody to these molecules to protect mice from infection will be evaluated. Cross-reactive regions between the PspA and PspC proteins will be identified as well as the regions of each molecule most useful as a vaccine. Immunity to PspA and PspC will be evaluated to determine whether it involves opsonization, blocks virulence functions, or acts by other mechanisms. The data obtained will assist with the development of correlates of protective immunity for PspA and PspC that can be applied to vaccine development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMMUNOLOGICAL ASPECTS OF HEMORRHAGE Principal Investigator & Institution: Chaudry, Irshad H.; Professor, Professor, Vice Chairman & Di; Surgery; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 31-MAR-2003 Summary: Our recent studies indicate that proestrus female mice [with cycle- increased levels of estrogen and prolactin (PRL)] have improved immune responses after trauma-
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Sepsis
hemorrhage as opposed to markedly depressed responses in males. Moreover, the survival rate of proestrus females following sepsis after trauma-hemorrhage was significantly higher than age-matched males. In contrast to young proestrus mice, aged females (defined by lowered estradiol levels) show marked immunosuppression after trauma. Our hypothesis, therefore, is that it is the high estradiol or a high estradiol: androgen ratio which directly (receptor- mediated) or indirectly (receptor-independent) enhance immune functions in proestrus females, and the loss of these estrogenic effects may contribute to the failure to maintain immune responses in aged females after trauma-hemorrhage. Studies are proposed to determine the mechanism of regulation of estradiol and estrone by hypothalamic/pituitary factors adrenals and aromatase activity and determine how differences in estradiol levels or the estradiol: androgen ratio due to the estrus cycle, ovariectomy (OVX, in middle aged mice to reduce estrogen), and age affect immune responses after trauma. Sex steroids (SS) receptor- mediated and receptor-independent gene activation mechanisms will be studied in T-cells and macrophages (Mphi). Since activation of AF-1 and AF-2 regions of estrogen receptor (ER) is critical for agonist and antagonist effects, activation of the ER agonist regions by estrogens in T-lymphocytes will be evaluated by transfection studies. Moreover, since SS non-ligand response also involve [Ca2+]i mobilization, T cells and Mphi will be examined for Ca2+ signal transduction and the expression and translocation of PKC isoforms. The release of TH1 and TH2 cytokines and IL-6 and the effects of PRL on their release in proestrus, OVX, aged, ER-, and PRL-knockout mice will also be evaluated. Additionally, the effect of SS on PRL and TH1 and TH2 cytokine-induced JAK-STAT expressions will be evaluated. Analysis of bone marrow for lymphoblastoid/myeloblastoid cell composition, and the effect of SS on the population of these cells will be determined. We will evaluate if administration of beta-estradiol, Raloxifene or PRL in vivo after trauma-hemorrhage improves the depressed immune responses in estrogen deficient mice. If a single dose is ineffective, multiple doses of these drugs with or without gonadotropin releasing hormone (GnRH) or flutamide (androgen receptor antagonist) will be administered to determine whether synergistic beneficial effects on immune responses are produced and whether the susceptibility to sepsis after trauma is decreased. Detailed mechanistic studies of T cell and Mphi functions using molecular biological techniques to determine why low estradiol fails to maintain immune functions in aged females after trauma and the use of estradiol, Raloxifene, PRL, GnRH or flutamide to restore immune functions should yield novel information and provide an innovative approach for improving the immune responses and reducing mortality from sepsis following trauma-hemorrhage in postmenopausal as well as in surgically OVX patients with low estrogen activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMPROVED LIVER FUNCTION AND REGENERATION WITH A20 Principal Investigator & Institution: Ferran, Christiane; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Necrosis and apoptosis of hepatocytes are critical pathologic features associated with liver injury. Hepatocyte apoptosis is a feature of viral hepatitis, ischemic liver injury, sepsis, cholestasis, and a result of exposure to hepatotoxic substances such as ethanol, acetaminophen and cytostatic drugs. Massive hepatocyte apoptosis and necrosis result in fulminant hepatic failure (FHF). Only 14% of patients diagnosed with FHF recover with medical therapy. Orthotopic liver transplantation (OLT) has dramatically improved the fate of these patients (49%
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undergo OLT), yet 37% die while awaiting OLT. This gloomy picture is balanced by the unique capacity of the liver to regenerate. Hepatocyte replication leads to a full recovery of liver function and mass 1-2 weeks following surgical, viral or chemical hepatic loss. We propose that protecting hepatocytes from apoptosis and promoting their proliferation are two strategies that could beneficially impact FHF. Our preliminary data demonstrate that A20 promotes hepatocyte proliferation and is anti-apoptotic. A20 is part of the physiologic response of hepatocytes to injury. A20 is upregulated in hepatocytes by pro-inflammatory stimuli including TNF and LPS and functions to protect from TNF mediated apoptosis. Gene transfer of A20 to mice livers protects from lethality in the galactosamine and LPS (D-gal/LPS) model of toxic FHF. Adenovirus mediated expression of A20 in livers of BALB/c mice yields an 89% survival rate following administration of D-gal/LPS as compared to 15-20% in control mice. Mice expressing A20 maintain normal liver function as assessed by prothrombin time while controls suffer from a severe bleeding diathesis. Expression of A20 in the liver protects from lethality associated with a subtotal (87%) liver resection (LR). In this model, resection of 87% of the liver mass results in 100% lethality. In contrast, >60% of mice expressing A20 survive the 87% LR and demonstrate increased regenerative capacity as assessed by the number of PCNA (proliferating cell nuclear antigen) positive nuclei in the liver. These results qualify A20 as a critical gene involved in accelerating liver regeneration and promoting hepatocyte survival and function, even when facing extreme metabolic demands. These encouraging results prompted the submission of this proposal. Our specific aims are i) to dissect, in vitro, the molecular basis of the (1) antiapoptotic and (2) pro-proliferative function of A20 in hepatocytes and ii) to confirm that liver directed gene therapy using A20 will beneficially impact upon toxic, FAS-mediated and surgical experimental models of FHF. From a basic science standpoint, the in vitro work proposed will address the effect of A20 upon transcription factors and expression of genes involved in apoptosis, activation and proliferation of hepatocytes. This should unveil many unknowns in our understanding of hepatocyte biology and could lead to the discovery of novel therapeutic targets. From a therapeutic standpoint, validation of the beneficial effect of A20 in the murine in vivo models of FHF should set the basis for extending this approach to models of FHF in non human primates and potentially to clinical applications. The generation of novel safer and tissue specific viral vectors for gene transfer and the development of non-viral means of protein delivery to cells will facilitate clinical translation of A20 based therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INVESTIGATION OF XRCC5 MUTANT MICE Principal Investigator & Institution: Hasty, Edward P.; Molecular Medicine; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 07-JUL-1997; Project End 31-MAR-2006 Summary: Genomic instability is a major cause of cancer and believed to be a major contributor to aging. The gene Xrcc5, that codes for the protein, Ku80 is important for maintaining genomic stability by repairing double-strand breaks (DSBs) in DNA and by capping chromosomal ends. Mice deleted for Ku80 are immunodeficient due to defective repair of DSBs that occur during Variable (Diversity) Joining recombination and cells derived from ku80-mutant mice are hypersensitive to ionizing radiation and reactive oxygen species. In addition, these cells exhibit cytogenetic aberrations including telomeric fusions. ku80-mutant mice exhibit an early onset of age-related changes in a variety of tissues that are also observed in control mice; thus, Ku80 may be important for the normal aging process. These changes include growth plate closure, osteopenia, skin
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Sepsis
and follicular atrophy, degenerative processes in the liver and shortened life span. Early mortality was at least partly due to early onset of the age - specific diseases, sepsis and cancer. Even though onset of cancer is early for ku80-mutant mice, the total incidence is low. Interestingly, deletion of the tumor suppressor protein, p53, greatly increased the risk of lymphoma suggesting that Ku80 is also a tumor suppressor. The biological role of Ku80 in maintaining genomic stability will be determined during aging and oncogenesis and completion of this proposal will significantly impact our understanding of Ku80's role during these events. l: Determine the contribution genomic instability, induced by either oxidative damage or telomere dysfunction, has on the ku80-mutant phenotype. The onset and spectra of genetic mutations will be compared between ku80-mutant and control mice. To determine the impact of oxidative damage, DNA lesions will be measured in ku80- mutant mice after exposure to ionizing radiation and by overexpressing proteins that eliminate oxygen radicals, catalase and Cu/Zn-superoxide dismutase. To investigate the impact of telomere maintenance, ku80-/- mTR-/- mice will be investigated. 2: Determine the impact general genomic instability has on oncogenesis in ku80-mutant mice that are deleted for p53 in nonlymphoid tissue. The role of the tumor suppression protein, p53, will be analyzed for its impact on oncogenesis in ku80-mutant mice with specific attention given to mammary tissue in a defined mouse model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LIVER/LUNG INTERACTIONS DURING GRAM NEGATIVE ENDOTOXEMIA Principal Investigator & Institution: Matuschak, George M.; Professor; Internal Medicine; St. Louis University St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 01-DEC-1989; Project End 31-JUL-2003 Summary: (Adapted from the applicant's abstract): During gram-negative bacteremic sepsis, a liver-lung axis of inflammation predisposes to critical organ injury due to an imbalanced expression of inflammatory vs. anti- inflammatory gene products. Such postbacteremic organ dysfunction is thought to be augmented by secondary ischemichypoxic stress owing to reduction-oxidation (redox)-sensitive transcription factors and subsequent amplification of inflammatory responses mediated by expression of key cytokine and noncytokine genes. The objective of the proposed research is to test the hypothesis that postbacteremic O2 limitation within the liver and the lungs differentially modulates the activation of a defined group of redox-sensitive transcription factors, thereby altering cytokine expression in a directionally- opposite and organ-specific manner. Experiments are designed to determine the effects of secondary reductions in the hepatic vs. pulmonary O2 supply in modulating postbacteremic transactivation of nuclear factor-kB (NF-kB), activator protein (AP)-1, NFIL-6, and the cyclic AMP response element binding protein (CREB). The biologic significance of these changes will be assessed by examining the concomitant expression of inflammatory cytokines (TNF-alpha, IL-1alpha, IL-1beta), anti-inflammatory cytokines (IL-6, IL-10), prostaglandin (PG) H synthase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in these organ systems in relation to redox status during ex situ organ perfusion. Experiments are also designed to define postbacteremic protein:DNA interactions during hypoxic stress and reoxygenation by assessing the activation of these transcription factors in Kupffer cells and alveolar macrophages. Resulting data will establish if an autoregulatory loop involving enhanced COX-2 and CREB activity suppresses postbacteremic cytokine expression by a PGE2-dependent mechanism in an organ-specific manner. The role of activation of the nuclear protein hypoxia inducible
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factor-1 in co-modulating endotoxin-induced-cytokine gene expression during subsequent hypoxia will be assessed. These endpoints will also be analyzed in conscious rats during hypoxic stress, with and without preexisting liver dysfunction following bacteremic infection. In parallel studies, the cis-acting DNA sequences that confer hypoxic suppressibility of endotoxin-induced cytokine promoter activity in RAW 264.7 cells transfected with TNF-alpha and IL-1beta reporter gene constructs will be identified. Results from these vertically-oriented studies should provide novel insights into the transcriptional regulation of cytokine and iNOS expression during gramnegative bacteremic sepsis while identifying mechanistic approaches to ameliorate lung injury and multiple organ failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MACROPHAGE DEATH AND SEPSIS Principal Investigator & Institution: Han, Jiahuai; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006 Summary: (provided by applicant): Overproduction of proinflammatory cytokines by macrophages and other cells is critical in the development of septic shock. On the other hand, immunocompromise of macrophages and lymphocytes that developed during the onset of sepsis was also believed to contribute to the lethality of this disease. The lifespan of macrophages and lymphocytes was modulated in sepsis and is responsible, in part, for the uncontrolled inflammatory response and immunodepression. Recent studies have shown that inhibition of lymphocyte apoptosis increased the survival rate of sepsis in an animal model. However, the effect of macrophage apoptosis on the outcome of sepsis has not been addressed. We found that macrophage apoptosis was induced in the same animal model when caspase inhibitor was administered to prevent lymphocyte death. We also found that Nur77 was induced in apoptotic macrophages and Nur77 induction is required for macrophage death. As reported by others using other types of cells, Nur77 induction requires transactivation of MEF2, but a signaling triggered by bacterial components is also required for macrophage expression of Nur77. This proposal will use the knowledge we have of macrophage apoptosis to promote and inhibit macrophage death in septic mice and thereby determine whether macrophage apoptosis positively or negatively affects the outcome in septic mice. We will also further elucidate the molecular mechanisms underlying the macrophage apoptosis. The proposed study will provide information regarding whether macrophage death should be avoided or enhanced in the treatment of sepsis. Our study will also lead to a better understanding of how macrophage apoptosis is controlled, which is needed to develop therapeutically useful strategies to selectively promote or inhibit macrophage death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISMS OF CELL INJURY IN BURN COMPLICATED BY SEPSIS Principal Investigator & Institution: Horton, Jureta W.; Professor; Surgery; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2003 Summary: (adapted from applicant's abstract): Despite aggressive fluid resuscitation and topical antimicrobial therapy after burn trauma, sepsis frequently results from the loss of dermis; thus sepsis and resultant multiorgan failure are a major cause of death in the burn unit. Studies from the PI's lab and others' have shown that burn trauma and
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sepsis independently alter cardiocirculatory performance, and recent studies suggest that myocardial abnormalities after burn, trauma or sepsis are related to intracellular accumulation of calcium with subsequent cellular injury and dysfunction. Although this field has grown rapidly, much is still unknown about the cellular mechanisms underlying cardiac dysfunction after either trauma or sepsis. The PI's group have focused their attention on a clinically relevant model of burn injury complicated by sepsis (intratracheal administration of S. pneumoniae administered 24 hours postburn) and have shown progressive cardiocirculatory dysfunction in this two-hit model. Specific Aim 1a will determine if burn/sepsis exacerbates the increased [Ca2+] and [Na2+] shown to occur after burn alone and will determine the contribution of altered Na+/Ca2+ to cardiac contractile dysfunction. Specific aim 1b will determine the contribution of transient cellular acidosis and altered H+/Na+ exchange to increased [Na2+], and whether increased [Na+] in turn promotes Na+/Ca2+ exchange in [Ca2+] overload. Specific Aim 2 will determine the contribution of burn/ sepsis-mediated alterations in SR Ca2+ handling (SR Ca2+ efflux, Ca2+-ATPase activity, SERCA, and SR Ca content) to cellular Ca2+ and cardiac contractile deficits and determine the contribution of burn/sepsis induced myofilament Ca2+ insensitivity to cardiac contractile dysfunction. Studies in Specific Aim 3 will examine the role of PKC activation in intracellular Na+/Ca2+ accumulation and cardiac contractile dysfunction in burn sepsis. Studies in Specific Aim 4 will determine the contribution of increased [Ca2+] and reactive oxygen species to apoptosis in burn/sepsis and further determine the contribution of apoptosis to burn/sepsis-induced ionic derangements as well as cardiac contractile dysfunction. Only by understanding the cellular events involved in the postburn inflammatory cascade can adequate prevention and treatment modalities be designed to improve outcome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS OF GROWTH HORMONE RESISTANCE IN SEPSIS Principal Investigator & Institution: Cooney, Robert N.; Staff Physician; Surgery; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390 Timing: Fiscal Year 2003; Project Start 01-MAY-1997; Project End 31-MAR-2007 Summary: (provided by applicant): The catabolism of protein after injury or infection results in multiple complications which prolong recovery and cause death. Nutrient intake is unable to prevent protein catabolism suggesting other factors are important. Growth hormone (GH) induces circulating insulin-like growth factor-I (IGF-I) synthesis by liver, which stimulates muscle protein synthesis. During sepsis, a 2-4 fold increase in circulating GH is seen with a 50% decrease in plasma IGF-I, a 40% reduction in muscle protein synthesis, and decreased muscle mass. The onset of GH resistance and loss of muscle in sepsis is mediated by the inflammatory cytokines, TNF and IL-I. Treating septic rats with IL-1 or TNF antagonists ameliorates the effects of sepsis on plasma IGF-I levels and muscle catabolism. The liver is the major source of circulating IGF-I, and will be the focus of this project to elucidate the mechanisms responsible for GH resistance. Postreceptor defects in GH signaling represent the predominant mechanism for GH resistance in sepsis. The magnitude of the IGF-I response to GH is determined by three distinct processes: the activation/propagation of JAK/STAT and MAP kinase signaling by GH, the regulation of IGF-I gene expression, and the termination of GH signaling. To investigate the mechanisms responsible for GH resistance, we developed a hepatocyte model of cytokine-mediated GH resistance. This novel hepatocyte model uniquely positions us to delineate the mechanisms responsible for defective GH signaling and IGF-I expression. TNF inhibits both the activation and termination of GH signaling by
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the JAK/STAT and MAP kinase pathways. IL-1 also inhibits the induction of IGF-I by GH, but the time course differs from TNF, potentially involving different mechanisms. The mechanisms responsible for GH resistance will be determined with in vitro studies involving TNF and IL-1, and in vivo studies in our rat model of sepsis. Our hypothesis is that cytokine-rnediated alterations in GH signaling mediate hepatic GH resistance and muscle catabolism during sepsis. The specific aims are: (1) to delineate the effects of sepsis, TNF and IL-1 on the activation/propagation of GH signaling; (2) to elucidate the mechanisms by which sepsis, TNF and IL-1 regulate IGF-I gene expression; and (3) to determine the mechanisms by which sepsis, TNF and IL-1 terminate GH signaling. An understanding of how cytokines and growth factors regulate protein catabolism is important for the care of septic patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
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: METALLOPROTEINASES IN VENTILATOR-INDUCED LUNG INJURY Principal Investigator & Institution: Foda, Hussein D.; Medicine; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: Acute, diffuse lung injury often complicates sepsis, gastric acid aspiration, extensive trauma, drug overdose, and other conditions. Clinically, this condition is known as the Adult Respiratory Distress Syndrome (ARDS) that is characterized by catastrophic respiratory failure requiring mechanical ventilation (MV). Although mechanical ventilation is a main stay in managing patients with this condition, several MV-associated complications have been recognized. One of the most serious potential complications of MV is the newly recognized ventilator-induced acute lung injury (VILI). The NIH NHLBI ARDS clinical trials network has just reported that MV strategies employing low tidal volume ventilation reduced mortality in ARDS by 25 percent and lead to a decrease in lung injury and multisystem organ failure. The mechanism by which high volume ventilation causes increased mortality and lung injury is not well understood. In this proposal we will pursue very exciting preliminary results suggesting that matrix metalloproteinases (MMPs) especially gelatinases are responsible for ventilator-induced lung injury in animal lungs subjected to high tidal volume mechanical ventilation. We will also examine the mechanism by which MMPs are up regulated in this type of acute lung injury. Our hypothesis is that Ventilatorinduced lung injury is caused by the release and activation of MMPs especially gelatinases. This increase in MMPs is regulated by the cytokine Extracellular matrix metalloproteinase inducer (EMMPRIN) and is caused by the exposure of lung cells to mechanical stress. To prove this hypothesis we have set several specific aims: 1) To systematically examine the induction, release and activation of MMPs especially gelatinases in an experimental rat model of ventilator-induced lung injury (VILI); 2) To examine if MMP inhibitors can prevent ventilator-induced lung injury in rat lungs; 3) To characterize the role of EMMPRIN in VILI; 4) To investigate the influence of mechanical stress as a mechanism of the increased MMP production. This research has significant implications for the management of patients with acute, severe lung injury requiring mechanical ventilation. By better understanding the mechanisms that lead to ventilatorinduced lung injury, therapeutic strategies may be devised to improve the outcome in this highly fatal condition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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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
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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 vasopressor-induced arteriolar constriction in septic animals. 4. To test the hypothesis that 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 vasopressor-induced 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: MIF AND THE HOST RESPONSE TO INFECTION Principal Investigator & Institution: Bucala, Richard J.; Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-JUN-1998; Project End 31-JAN-2008 Summary: (provided by applicant): Overwhelming infection can lead to massive endorgan damage and death, which is a clinical condition known as septic shock. Current concepts of septic shock pathogenesis emphasize the role of innate immunity and excessive inflammatory cytokine production. Under normal circumstances, these responses are carefully regulated so that the infectious agent is eliminated without causing life-threatening tissue damage. Inhibition of inflammatory cytokines has been studied as a way to treat septic shock, however therapies directed at mediators such as TNF alpha and IL-I have not shown clinical benefit, and in fact have worsened outcome in some studies. We have discovered that macrophage migration inhibitory factor (MIF) is an important mediator of innate immunity and upstream regulator of inflammatory cytokine production. Anti-MIF protects from shock caused by live bacteria in the same models of infection that have demonstrated either a null or a detrimental effect of antiTNF alpha therapy. Interference with MIF action thus offers potential therapeutic advantages that have not been observed with previous anti-cytokine interventions. The objective of this application is to understand the mechanism by which MIF contributes to the overwhelming inflammatory response that produces shock. Our central hypothesis is that septic shock is the result of genetic predisposition to overproduction of MIF, coupled with M1F activation of cells by binding to the surface protein, CD74. We have formulated this hypothesis on the basis of our studies showing, first, that antiMIF prevents shock in relevant models of bacterial sepsis, second, that MIF is encoded by a functionally polymorphic gene, and third, that MIF initiates signal transduction by
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binding to CD74. The rationale for this proposed research is that once it is known how MIF expression leads to septic shock, then new and selective approaches for therapeutic intervention may be devised. We will test our hypothesis by pursuing the following three specific aims: 1) Define the Frequency of the Low and High Expression M/f Alleles in Patients with Pneumonia, and Determine if the High Expression Alleles are Associated with Septic Shock. Our working hypothesis is that high expression M/f alleles wilt be over-represented in patients with pneumonia who develop shock. 2) Define the Mechanism of MIF Signal Transduction. Our working hypothesis is that CD74 transduces MIF signals by recruiting an additional protein(s) into the signaling complex. 3) Determine the Biological Significance of the MIF-CD74 Interaction. Our working hypothesis is that anti-CD74 mAb and soluble CD74 protein (sCD74) will protect mice from lethal septic shock. The proposed research is innovative because it capitalizes on two recent and potentially unifying findings, a polymorphism in the M/fgene that affects its level of expression, and a cell surface protein (CD74) that mediates MIF signal transduction. These results will be significant because they will provide a better understanding of the molecular pathways responsible for the development of sepsis in susceptible individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MODELING THE ACUTE INFLAMMATORY RESPONSE Principal Investigator & Institution: Chow, Carson C.; Assistant Professor; Mathematics; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The acute inflammatory response is a cascade of cellular and molecular events that takes place in the body after a traumatic injury or an infection. This response involves the immune, endocrine and neurological systems and aims to eliminate damaging agents and restore the body back to equilibrium. The clinical manifestation of this response is called the systemic inflammatory response syndrome (SIRS) or sepsis in the case of infection. There are approximately threequarters of a million cases of SIRS severe enough to warrant hospitalization in the United States each year. Although much has been learned in the last several years on the molecular and cellular mechanisms of SIRS, this knowledge has not translated into improved outcome prediction or treatments. We hypothesize that a major reason effective treatments have not been developed is that a good understanding of the global dynamical behavior of the acute inflammatory response is lacking. We propose to address this shortcoming by developing biologically accurate mathematical models of the acute inflammatory response. These models will be tested and calibrated with carefully designed animal experiments in an iterative procedure that relies heavily on detailed statistical analysis. More specifically, we propose to 1) develop a hierarchy of mathematical models, each designed to address a specific set of questions; 2) refine and validate the mathematical models through an iterative process of experimentation, statistical analysis, and model development; and 3) analyze the various modes of behavior in the mathematical models and use these modes to make predictions of outcomes in different experimental scenarios. The long-term goal of this study is to provide a rational basis for the design of therapies to combat SIRS as well as to aid in patient management. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOLECULAR PROBES OF THE MECHANISM 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 2002; Project Start 01-DEC-1985; Project End 31-MAR-2003 Summary: The central theme of this program involves studies of the mechanisms of action of cytochrome P450 enzymes and nitric oxide synthase. The principal approach is the synthesis and characterization of reactive iron porphyrin species that are thought to be intermediates in the catalytic cycles and to relate 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 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 agents. Our effort seeks to provide a foundation of mechanistic and kinetic information which 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 will 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 of NOS and to seek out new oxidation processes that may help with the rational development of NOS inhibitors. Peroxoiron(III) porphyrin 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 mediated processes. Synthetic and semi-synthetic 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 species. Membrane binding by amphiphilic metalloporphyrins is extraordinarily sensitive to pH. This is an unprecedented observation that may have immediate application to the design of metallopharmaceuticals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MUSCLE LACTATE PRODUCTION IN SEPSIS Principal Investigator & Institution: James, J H.; Res Ass Prof; Surgery; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 01-MAY-1997; Project End 31-MAR-2005 Summary: The long-term objective of this work is to understand the changes in metabolism in sepsis in order to improve the therapy of septic patients. Sepsis results in a hypermetabolic state in which many aspects of carbohydrate metabolism are abnormal: enhanced peripheral glucose uptake and utilization, hyperlactacidemia, increased gluconeogenesis, depressed glycogen synthesis, glucose intolerance and insulin resistance. Traditionally, high circulating lactate concentration has been interpreted as tissue hypoxia or mitochondrial dysfunction. However, therapy to improve tissue perfusion does not always prevent lactate accumulation. Current
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understanding of energy metabolism cannot explain persistent glycolysis by welloxygenated tissues. High epinephrine levels in sepsis may cause the characteristic changes in carbohydrate metabolism through stimulation of the Na+-K+ pump in skeletal muscle. The stimulation of glycogen breakdown and lactate production in muscle by epinephrine may be closely tied to stimulation of the Na+, K+-ATPase, implying that muscle energy metabolism takes place in separate glycolytic and oxidative compartments. ATP consumption by the Na+, K+-ATPase appears to be the primary influence on ATP production in the glycolytic compartment. This proposal aims to explore these relationships in greater detail, both in septic and nonsepticrats. Studies will combine in vivo and in vitro assessments of Na+-K+ pump activity, membrane recruitment, glycolysis, glycogenolysis, ATP content and membrane permeability to Na+ and K+. The central role of epinephrine in sepsis-induced metabolic derangements will be examined in two ways (i) chronic infusion of epinephrine using implantable minipumps and (ii) chronic infusion of the beta-adrenergic blockers in sepsis. Studies in vitro will examine the persistence of epinephrine's effects on glycolysis and Na+, K+ATPase activity after beta-blockade has occurred. Results of these studies will clarify metabolic relationships that are important both in health and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MUSCLE PROTEIN TURNOVER AND AMINO ACID UPTAKE IN SEPSIS Principal Investigator & Institution: Hasselgren, Per-Olof J.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 01-JAN-1987; Project End 31-JUL-2004 Summary: Previous studies suggest that sepsis-induced muscle catabolism reflects ubiquitin-proteasome-dependent degradation of myofibrillar proteins regulated by glucocorticoids. Because intact myofibrils are not degraded by the proteasome, it is possible that actin and myosin are dissociated from the myofibrils before they are ubiquitinated and degraded by the proteasome. We will test the hypotheses: 1) sepsis results in glucocorticoid-mediated calcium/calpain-dependent Z-band disintegration and release of myofilaments in skeletal muscle; 2) sepsis results in increased N-end rule pathway-dependent ubiquitination and breakdown of muscle proteins and upregulated expression and activity of the ubiquitin- conjugating enzyme E2/14k and ubiquitin ligase E3alpha; 3) sepsis- induced muscle cachexia can be inhibited by proteasome blocker in vivo; 4) muscle cachexia in patients with sepsis is associated with increased expression and activity of calpains, release of myofilaments and upregulated protein breakdown in the N-end rule pathway. A septic model in rats consisting of cecal ligation and puncture is used in the majority of experiments. Total and myofibrillar protein breadkdown rates are measured in incubated muscles by determining net release of tyrosine and 3-methylhistidine respectively. Integrity of sarcomeric Z-bands is studied by electron microscopy. Gene and protein expression of calpain and calpastatin are determined by Northern and Western blot analysis, respectively. The role of calcium/calpain-dependent proteolysis is assessed by the effect of dantrolene and diltiazem on sepsis-induced morphologic and metabolic changes. The role of glucocorticoids in sepsis- induced changes in muscle calcium levels and release of myofilaments is determined by the glucocorticoid receptor antagonist RU38486. To test the role of the N-end rule pathway, expression and activity of E2/14k and E3alpha are determined and specific E3albha inhibitors are used in a cell- free system. Similar determinations are performed in muscle from patients with sepsis. The proposal is novel because it suggests that muscle cachexia during sepsis is caused by two distinct
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mechanisms, i.e., calcium/calpain-dependent release of myofilaments from the sarcomere followed by ubiquitination of myofilaments in the N-end rule pathway and subsequent degradation of ubiquitinated filaments by the 26S proteasome. The hypothesis implies two levels at which sepsis-induced muscle cachexia may be prevented/treated, i.e., inhibition of myofilament release by treatment with a calcium antagonist and inhibition of ubiquitin/proteasome-dependent degradation of the released myofilaments by a proteasome blocker. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEUTROPHIL ACTIVATION IN ACUTE LUNG INJURY Principal Investigator & Institution: Abraham, Edward; Roger Sherman Mitchell Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 10-JUL-2000; Project End 31-MAY-2005 Summary: (adapted from the application): Acute lung injury is frequently associated with sepsis or blood loss. In preliminary studies, The investigators found that hemorrhage or endotoxemia cause rapid increases in the expression of proinflammatory cytokines IL-1, TNF, and MIP-2, and in activation of the transcriptional regulatory factors NF-kB and CREB in lung neutrophils. After endotoxemia, but not hemorrhage, adrenergic blockade increases expression of proinflammatory cytokines by lung neutrophils, adrenergic blockade increased CREB and decreased NF-kB activation after hemorrhage, but decreased CREB and increased NF-kB activation after endotoxemia. After hemorrhage, but not endotoxemia, the increased expression of proinflammatory cytokines by lung neutrophils was inhibited by blockade of xanthine oxidase. After hemorrhage, but not endotoxemia, blockade of xanthine oxidase increases CREB activation, but does not prevent NF-kB activation in lung neutrophils. They hypothesize that distinct mechanisms lead to activation of activation of NF-kB and CREB in lung neutrophils after hemorrhage or endotoxemia, modulating their ability to affect subsequent transcription of proinflammatory cytokines involved in the development of acute lung injury. The specific aims are to determine: 1) the mechanisms involving alterations in nuclear and cytoplasmic I-kBs, NF-kB relevant kinases, and NF-kB subunit composition, which lead to hemorrhage or endotoxemia-induced activation of NF-kB in lung neutrophils; 2) the mechanisms involving CREB relevant kinases, CREB phosphorylation, CREM and ICER expression, which lead to hemorrhage or endotoxemia-induced activation of CREB in lung neutrophils; 3) the effects of hemorrhage or endotoxemia on binding interactions between CREB, NF-kB, and CBP in lung neutrophils; and 4) the mechanisms by which reactive oxygen intermediates or catecholamines modulate NF-kB and CREB activations as well as their interactions with CBP in lung neutrophils after hemorrhage or endotoxemia, and the effects of such modulation of NF-kB and CREB activity on the development of acute lung injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEUTROPHILS AND STAPHYLOCOCCUS AUREUS Principal Investigator & Institution: Gresham, Hattie D.; Associate Professor; Molecular Genetics & Microbiol; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-MAY-2005 Summary: Description (Adapted from applicant's abstract): Staphylococcus aureus is a major human pathogen causing significant morbidity and mortality in both community-
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and hospital-acquired infections. Concern over the emergence of multidrug resistant strains, particularly strains which lack sensitivity to all currently available antibiotics, has renewed interest in understanding the virulence mechanisms of this pathogen at the molecular level and in elucidating host defense elements which either provide protection from or which limit infection. Neutrophils (PMN) have long been thought to provide significant host defense against S. aureus infection. However, our studies of S. aureus-induced peritonitis and sepsis in mice have suggested that PMN have both a protective and a deleterious role. In order to demonstrate that PMN contribute to the pathogenesis of S. aureus infection, we have used multiple approaches which either limit or promote PMN migration into the infectious site. Our data indicate that excessive numbers of PMN and elevated levels of a C-X-C chemokine, MIP-2, at the site of a S. aureus infection create an environment which leads to enhanced extracellular replication of the pathogen and its intracellular survival in PMN to the detriment of the host; that PMN isolated from this environment are sufficient to establish infection in naive animals; that some of the bacteria inside these infected PMN are in endosomes with partially or fully degraded membranes; and that two regulatory loci mutants (agrand sar-) which lack the expression of several virulence factors are less able to survive and/or avoid clearance in the presence of excess PMN and MIP-2. We hypothesize that S. aureus manifests as a virulence determinant the ability to exploit the host's inflammatory response in order to enhance its survival. Moreover, we hypothesize that exogenous modulation of the inflammatory response is sufficient to alter the susceptibility of the host to infection. To test this hypothesis, we will pursue the following specific aims: #1) determine the number of PMN necessary for protection and for their deleterious role in two models of S. aureus infection; #2) define the contribution of C-X-C chemokines, the CXCR2 receptor, and specific virulence factors expressed by S. aureus to the creation of the environment which leads to both enhanced extracellular replication and intracellular survival of the pathogen; #3) elucidate known virulence factors whose genes are activated both in vivo and in vitro specifically in the presence of C-X-C chemokines and PMN; and #4) determine the mechanism of uptake and the intracellular locale of wild-type and isogenic mutants of S. aureus taken up both in vivo and in vitro by C-X-C chemokine-stimulated PMN. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEW POINT OF CARE SYSTEM FOR BURN WOUND TREATMENT Principal Investigator & Institution: Denvir, Adrian J.; Lynntech, Inc. College Station, Tx 77840 Timing: Fiscal Year 2003; Project Start 03-JUN-2003; Project End 31-MAY-2004 Summary: (provided by applicant): Each year in the United States, two million people suffer burn injuries resulting in approximately 100,000 - 300,000 hospitalizations. Of these two million, more than 12,000 will eventually die of burn-related infections. People suffering from burn wounds have lost a portion of their integument, diminishing one of the body's main defenses against bacterial infection. In addition, the necrotic tissue in the burn eschar, combined with the presence of serum proteins, provides a rich culture medium for microorganisms. Added to the loss of integument is the adverse affect of thermal injury on both local and systemic immunity. For these reasons, infections and sepsis are the most common cause of death among hospitalized burn patient. New methods of burn wound management require a cocktail of antimicrobial and antibiotic agents to fight infection however; they are becoming less effective due to resistant strains of microorganisms. In this Phase I effort we will demonstrate the feasibility of a fundamentally new method for burn wound care. The point of care (POC) system will
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be designed to generate sterile saline or water to moisten or wet the dressings for both the eschar as well as the graft after excision and deliver a broad based antimicrobial agent effective, against gram positive and gram-negative bacteria and fungi to the wound surface. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: P20, MOLECULAR SHORTSTOP FOR INFLAMMATORY LUNG DISEASES Principal Investigator & Institution: Brigham, Kenneth L.; Professor of Medicine; Generx+, Inc. 3200 West End Ave, Ste 500 Nashville, Tn 372011322 Timing: Fiscal Year 2002; Project Start 20-MAY-2000; Project End 31-JUL-2004 Summary: (Applicant's abstract): The transcription factor CAAT enhancer binding protein beta (C/EBPbeta) is a key factor orchestrating the inflammatory response. Specifically, expression of the genes encoding the pro-inflammatory cytokines IL-6 and on IL-8 are regulated by C/EBPbeta. C/EBPbeta can be either an activator or an inhibitor of inflammation depending on the dominant isoforms produced. Our data indicate that airway epithelial cells in culture terminate production of IL-6 and IL-8 increasing production of inhibitory C/EBPbeta isoform (p20) and that cells that have an exaggerated inflammatory response produce decreased amounts of this isoform. In addition, when animals are given endotoxin there is a decrease in lung production of the inhibitory C/EBPbeta isoform and an increase in production of the activator isoform. Since IL-6 production correlates with severity of sepsis in humans and interventions that decrease IL-6 improve outcome in that setting, we believe that increasing the inhibitory C/EBPbeta isoform in the lungs could be therapeutic for the pulmonary complications of sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PATHOGENESIS OF ENDOTOXEMIA-INDUCED ACUTE RENAL FAILURE Principal Investigator & Institution: Schrier, Robert W.; Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-MAY-2006 Summary: (provided by applicant): Sepsis and septic shock in-hospital are associated with a high incidence of acute renal failure (ARF) estimated at 20 and 50%, respectively. Moreover, the combination of sepsis and ARF leads to a very high mortality ranging from 50-80%. Understanding the early vasoactive and the later proinflammatory events which cause ARF during endotoxemia would be a major medical advance, thereby allowing the development of pathogenetic-based interventions. This proposal focuses on early vasoactive endotoxemia-related events which cause systemic arterial vasodilation (e.g. nitric oxide, prostaglandins) and the compensatory vasoconstrictors (e.g. norepinephrine, angiotensin, endothelin, thromboxane) which support blood pressure but lead to renal vasoconstriction. This renal vasoconstriction renders the kidney more susceptible to the proinflammatory events of endotoxemia, such as generation of superoxide, peroxynitrite, and cytokines such as interleukin-18. In addition to selective renal denervation, there are now specific inhibitors to test the involvement of inducible nitric oxide synthase, prostaglandin and thromboxane in sepsis. Molecular biological techniques using knockout and transgemc mice will also be used to examine the role of various systemic and renal vasodilators and vasoconstrictors during endotoxemia.
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Understanding the role and interaction between these factors should allow the development of potential interventions in sepsis which could dramatically decrease the incidence of ARF, morbidity and mortality. The availability of potent scavengers of superoxide and antiserum to interleukin-18 also will allow not only the study of early vasoactive events but also the later pro-inflammatory events. Thus, the potential impact of the research on sepsis and sepsis-mediated ARF is substantial. The goal is to unravel the multifaceted events which occur during sepsis, including their interactions, so that effective interventions can be developed and tested in humans with sepsis. The ultimate goal therefore is to understand and prevent the ARF, morbidity and mortality associated with sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PATHOGENIC MECHANISMS OF ANAEROBES IN SEPSIS Principal Investigator & Institution: Kasper, Dennis L.; Associate Director; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-MAY-1997; Project End 31-DEC-2007 Summary: (provided by applicant): Abscess formation is a classic host response to bacteria during sepsis. Certain bacterial species, particularly Bacteroides fragilis and Staphylococcus aureus are predisposed to induce abscesses. The essential bacterial virulence factor required for abscess induction by these two pathogens is a capsular polysaccharide with a zwitterionic charge motif. Zwitterionic polysaccharides (ZPS) induce the host to form abscesses by their ability to activate T cells initiating a proinflammatory Th1 cytokine response. In contrast to the immunologic paradigm defining polysaccharides as T cell independent antigens, ZPS activate T cells in vitro as well as in vivo when incubated with antigen presenting cells (APC). There is currently no immunologic model that describes how purified polysaccharides can activate T cells. ZPS are internalized and can be detected in lysates of intracellular vesicles from the APC. Blocking of endosomal acidification results in the failure of ZPS to activate T cells. ZPS recovered from endosomal vesicles has a substantially reduced molecular size, indicating processing. We have demonstrated that MHC class II DR appears to be the molecule used by the APC to present ZPS to the T cell and that TCR alpha beta( is required for T cell activation. We hypothesize that ZPS are internalized and cycle through the APC, and that this process is required for presentation of the ZPS to the T cell. We intend to define a novel immunologic paradigm that describes how an important class of biologic molecules (carbohydrates) is recognized by the cell-mediated immune system. This will be done by investigating the cellular pathway by which ZPS cycle through the APC and activate CD4+ T cells. We have defined four specific aims: 1) Determine how ZPS are altered within the endocytic pathway and define the molecular requirements for ZPS-mediated T-cell activation; 2) Investigate the vesicular trafficking and intracellular interactions of ZPSs in the endocytic pathway; 3) Characterize the binding interactions of the MHC class II DR molecule with ZPS; 4) Determine whether T-cell activation results from "processed antigen" presentation or superantigen presentation and whether the processing of ZPS uses the same pathway as protein processing. The delineation of a mechanism for carbohydrate processing and presentation has broad relevance to the fields of microbiology and immunology and could lead to new concepts for enhancing T cell recognition of other polysaccharides. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PH CONTROL OF PROTEIN SYNTHESIS Principal Investigator & Institution: Garlick, Peter J.; Professor and Director of Research; Surgery; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: Patients with renal failure, diabetic ketosis, severe trauma or sepsis often become acidotic. Moreover, they are also susceptible to body protein wasting. Experimental acidosis has been shown to result in negative nitrogen balance, and body protein loss in acidotic patients can be alleviated by normalization of pH. Previous work has concentrated on the effects of pH on protein degradation and no systematic studies have been performed on pH and protein synthesis. However, measurements in animals and human volunteers have shown that both metabolic and respiratory acidosis are associated with depressed rates of synthesis of skeletal muscle protein and serum albumin. The purpose of the present proposal is therefore to characterize the relationship between protein synthesis rates in tissues, especially muscle and liver, of rats and humans in relation to changes in intra- and extracellular pH, to confirm the hypotheses: (i) that changes in blood pH, both by metabolic and respiratory means, modify rates of tissue protein synthesis and gene expression and contribute to the protein wasting of patients with acidosis, and (ii) that these effects of pH operate directly via the intracellular pH and do not involve extracellular mediators such as hormones. The studies will employ measurements of rates of protein synthesis in tissues of rats and human volunteers to characterize the responses to changes in intra- and extracellular pH induced by metabolic and respiratory means and to confirm that these effects are rapid, operate over the full range of pH from acidosis to alkalosis and are independent of oxygen supply. In the animals, the responses of gene expression in the liver will be investigated by determining the levels of mRNA for 3 liver proteins. In particular, the treatments studied will produce different changes in the infra- and extracellular pH. Measurements of intracellular pH will be made by nuclear magnetic resonance, to confirm the hypothesis that changes in protein synthesis are determined by the intracellular rather than extracellular pH. A separate set of studies will be performed in isolated tissues and cells, to determine whether responses to changes in pH are direct or act through circulating hormones. The cellular and molecular mechanisms through peptide chain initiation and initiation factors eIF-2 and eIF-4 will also be identified. Finally, the effect of changes in pH on tissue protein synthesis will be measured in human volunteers and hemodialysis patients, to identify the role of pH control of protein synthesis in health and in protein wasting conditions with abnormalities of pH control. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHAGOCYTE RECEPTORS FOR LIPID A Principal Investigator & Institution: Golenbock, Douglas T.; Chief, Division of Infectious Diseases &; Medicine; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-MAR-2004 Summary: Gram-negative bacterial sepsis is a medical catastrophe, claiming the lives of 35-40 percent of affected patients. There has been little progress in improving the poor outcome of sepsis, due to our inadequate understanding of the basic pathophysiology of the syndrome. Sepsis results from a cascade of life-threatening host responses beginning with the interaction of bacterial lipopolysaccharide (LPS) and the LPSreceptor complex on effector cells. CD14 appears to be the LPS-binding component of
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this complex. The exact components of the complex, and the mechanism of signal transduction, are uncertain. Two Toll-like receptors (TLRs), TLR2 and TLR4, function as LPS signal transducers. Expression of TLR4, but not TLR2, is obligatory for sensitive responses to LPS. TLR2 functions as a pattern recognition molecule for bacterial products (including LPS) from multiple types of bacteria. LPS-receptor specificity resides in TLR4: expression of TLR4 defines a highly specific pharmacology to lipid A and its analogs. The central hypothesis of this proposal is that LPS is recognized by a multimeric receptor consisting of CD14 and of a complex of TLRs and accessory molecules. TLR4 is the predominant LPS receptor in most cells; TLR2 may be important for sCD14/LPS recognition. Upon ligand binding, TLRs multimerize and engage signaling molecules similar or identical to those used by the IL-1 receptor. LPS antagonists may function by preventing TLR multimerization. We propose three Aims to test this hypothesis. 1. To analyze available known TLRs (including TLRs 1, 3, 5, 6 and 7) and chimeric TLR constructs as potential LPS receptor components. To identify regions of TLR4 that are necessary for specific ligand recognition. To determine if epitope-tagged TLRs multimerize, and if multimerization is inhibited by LPS antagonists. 2. To use [32P]-lipid IVa to analyze lipid A binding to TLRs, especially TLR4. 3. To identify new genes in the LPS signal transduction pathway using somatic cell mutagenesis and complementation analysis approaches. The discovery of Toll-like receptors as mediators of signal transduction for both Gram-positive and Gram-negative bacteria suggests that there are common signaling elements that can be discovered and targeted for the rational design of novel therapeutic agents for sepsis, an thus reduce the appalling morbidity and mortality associated with this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHYSIOLOGIC REGULATION OF HEMATOPOIESIS BY NOTCH Principal Investigator & Institution: Carlesso, Nadia; Assistant Professor of Medicine; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Little is known about the mechanisms that regulate, at the cellular level, the process of hematopoietic cell self-renewal and differentiation, in particular during physiologic responses to stress, such as inflammation and infection. The overall objective of this project is to study the physiologic role of Notch receptors in maintaining bone marrow homeostasis, in particular during inflammatory stress. The main hypotheses to be tested in our study are: I) whether Notch activation favors the decision of self-renewal over differentiation at the stem and progenitor cell level, and 2) whether this represents an important regulatory function during bone marrow physiologic response to inflammation and infection. We hypothesize that Notch activation may balance the prodifferentiative effects of inflammatory cytokines, permitting expansion of the proliferating pool of progenitor cells required to respond to physiologic stress and preventing the stem cell pool from exhaustion. Specific Aims: to test these hypotheses we plan to: (1) determine the impact of Notch gain-of function and (2) Notch loss-of function, on self-renewal and expansion potential of stem and progenitor cells; (3) evaluate the level of Notch pathway activation in BM cells during inflammatory stress; (4) determine the consequences of Notchi loss-of function during bone marrow response to inflammatory stress. Research Design and Methods: We will use different and complementary in vivo models: a) xenotransplantation experiments of human cells, engineered to express constitutive forms of Notch 1 or the ligand J2, will be carried out into NOD/S CID mice; b) transgenic mice engineered to express the Notch antisense will be used to evaluate the effects of Notch loss-of function; c) the "mouse full
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skin thickness burn model" (sepsis model) will be used as a model of inflammation to evaluate BM response and Notch function. Significance: These studies are intended to yield insight into the physiologic mechanisms that regulate adult hematopoiesis. We believe that a better comprehension of these events is crucial for the understanding of the biology of hematopoietic disorders and essential for the development of novel therapeutic strategies, in particular those targeted to ex-vivo expansion of human hematopoietic stem cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PILOT--MATERNAL ALCOHOL ABUSE AND ITS EFFECTS ON PREMATURE INFANTS Principal Investigator & Institution: Gauthier, Theresa W.; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-DEC-2007 Summary: Despite the well known neurological effects of alcohol on the developing fetus, its use during pregnancy remains a significant problem in our country. Even with modern neonatal intensive care units, chronic lung disease and bacterial sepsis continue to cause significant morbidity and mortality for the very low birth weight premature newborn. We have expanded the traditional focus of fetal alcohol exposure on the central nervous system to two other developing organ systems of the fetus, namely the lung and immune system. Recent prospective data implicates a history of alcohol abuse as the first reported co-morbid variable significantly increasing the incidence and severity of acute respiratory distress syndrome in adults. Additionally, alcohol exposure is associated with a decrease in lung antioxidant status, particularly glutathione. Glutathione is an essential antioxidant in the epithelial lining fluid of the lung. A reduction in alveolar glutathione, as seen in the premature infant, leaves the lung susceptible to increased pulmonary oxidative injury. We have novel experimental data describing reduced pulmonary glutathione, impairment of alveolar type II epithelial cell function and impaired cell function and impaired surfactant homeostasis in fetal guinea pig lungs exposed to alcohol in utero. Additionally, in a logistic regression analysis of 872 term newborns, we have demonstrated that maternal excessive alcohol use of 7 drinks/wk in either the 3 months prior to conception of the 2nd trimester significantly increased the risk of newborn infection by approximately 3 fold. Because of these data implicating adverse effects of fetal alcohol exposure on the developing fetus, we hypothesize the following: (1) alcohol exposure in (CLD), and (2) fetal alcohol exposure impairs fetal immune function thereby increasing the risk of infection, particularly late onset sepsis, in the premature newborn. We will address these hypotheses in the pilot clinical study by 1: Screening all women who deliver premature infants weighing <1500 gms for alcohol use during pregnancy with an extensive questionnaire. 2: Perform outcome analysis of these infants comparing alcohol-exposed to non-exposed premature infants, investigating the primary outcomes of chronic lung disease and late onset sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PREVENTION OF APOPTOTIC CELL DEATH IN SEPSIS BY BCL-2 Principal Investigator & Institution: Hotchkiss, Richard S.; Professor; Anesthesiology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2003
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Summary: (adapted from the abstract): Sepsis is defined as the systemic inflammatory response from infection and is a major cause of morbidity and mortality with an annual death rate of over 175,000 people in the United States alone. The host response to sepsis is an intricate interplay of numerous inflammatory and anti-inflammatory processes including the coagulation cascade, complement system, kinin system, and many others. Immunologic defenses are activated in sepsis as well; and there is recruitment and activation of granulocytes, lymphocytes, and monocytes. Recent studies demonstrate that sepsis causes a marked decrease in circulating lymphocytes which is accompanied by extensive apoptosis of lymphocytes in tissues throughout the body. Although it is speculated that sepsis-induced apoptosis of lymphocytes may be beneficial in sepsis by down-regulating the inflammatory response, it is also possible that loss of lymphocytes is excessive and impairs the ability of the host to eradicate the infection. Recently, the anti- apoptotic protein BCL-2 has been shown to prevent cell death from a remarkable number of diverse stimuli including hypoxia, ionizing radiation, oxidant injury and excitotoxins. The aims of this investigation are to pursue their initial observations demonstrating that transgenic mice which selectively overexpress BCL-2 in T lymphocytes have complete protection against lymphocyte apoptosis and improved survival in sepsis. These findings indicate that strategies which prevent lymphocyte death in sepsis may improve survival. Transgenic mouse constructs in which BCL-2 is selectively overexpressed in T, B, or both T and B lymphocytes will be employed in sepsis. Lymphocyte transfer experiments in Rag-1 mice, which are totally deficient in mature T and B cells, will be examined also. Rag-1 mice will be transfused with T or B lymphocytes that overexpress BCL-2 and effects on apoptosis and survival recorded. Mechanisms of BCL-2's protective effect will be investigated as well. Finally, autopsy sample from patient who died of sepsis or other causes will be examined to correlate BCL-2's expression with lymphocyte apoptosis and gain insight into possible mechanisms of apoptosis such as caspase activation and cytochrome c release. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTEASE ACTIVATED RECEPTOR-1 SIGNALING BY PROTEIN C Principal Investigator & Institution: Riewald, Matthias; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Protein C (PC) is activated on the surface of endothelial cells by the thrombin-thrombomodulin complex and the generated activated PC (APC) inhibits blood coagulation by down regulating prothrombin activation in a negative feedback loop. In addition to its role as an anticoagulant, APC has major antiinflammatory effects that led to its recent approval for treatment of patients with severe sepsis. The molecular basis for APC's important protective effects is incompletely understood. This application is based upon our recent identification of proteaseactivated receptor 1 (PAR1) and endothelial cell PC receptor (EPCR) as part of a novel APC signaling pathway in endothelial cells. The general hypothesis is that PARldependent signaling of the PC system in endothelial cells limits inflammatory responses and reduces lethality in sepsis. PAR1 can be efficiently activated by thrombin and Aim#1 is to define how autocrine PAR1 signaling by APC is linked to PC activation on the cell surface. Experiments will analyze whether activation of EPCR-bound PC by thrombin-thrombomodulin leads to enhanced APC signaling and what the role of membrane compartmentalization of PC pathway components and PAR1 is. Aim#2 is to define the role of PAR1, EPCR, and thrombomodulin in APC-dependent effects on gene expression, including the down regulation of genes involved in inflammatory and
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apoptotic pathways in activated endothelial cells. Micro array analysis will identify downstream targets of protective PC pathway signaling and adenovirus-mediated expression of mutant EPCR and thrombomodulin will define the roles of these cofactors. Aim#3 is to demonstrate an in vivo role of PAR1 activation by the PC pathway. Transgenic mice will be generated with endothelial cell-specific expression of either wild type PAR1 or a variant PAR1 that can be activated by APC but not thrombin. Effects of APC administration on inflammatory responses and lethality in a model of septicemia will be analyzed in the mice and the results are expected to define the role of endothelial PAR1 in systemic inflammation and in mediating protective effects of APC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTEASE-ACTIVATED RECEPTORS IN INFLAMMATION Principal Investigator & Institution: Coughlin, Shaun R.; Professor; Cardiovascular Research Institute; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2003; Project Start 01-JAN-1998; Project End 31-MAR-2007 Summary: (provided by applicant): The long term goal of this proposal is to define the role of protease-activated receptors (PARs) in inflammatory responses. PARs mediate cellular responses triggered by coagulation proteases and other proteases that are generated or released at sites of tissue injury. The effects of PAR activation in different cell types, largely defined in culture, suggest that PARs may help orchestrate a coordinated response to tissue injury that includes hemostasis, inflammation, and perhaps even regulation of the adaptive immune response. Local PAR activation by proteases generated at sites of local bacterial inoculation may protect against spread of bacteria by promoting both recruitment of leukocytes and microvascular thrombosis. However, more regional or systemic activation of PARs as may occur in the setting of tissue ischemia or sepsis may promote tissue damage by the same mechanisms. Toward testing these hypotheses, we have generated knockout mice for the known PARs as well as relevant double knockouts. Par4 -/- mice, for example, have no platelet responses to thrombin. Mice lacking both PAR1 and PAR4 may have lost thrombin signaling in all cell types. Using such mice and cells derived from them, we shall determine which PARs are responsible for mediating responses to coagulation proteases and other proteases in endothelial and other cell types, the extent to which different PARs in the same cell serve redundant functions, and the potential roles for endothelial PAR activation in vivo. We shall then go on to determine the effects of loss of PAR function in models of a) local bacterial infection and dissemination of same, b) systemic inflammatory response syndromes induced by endotoxin and by pancreatitis, and c) ischemia/infarction. Endpoints will include survival; markers of platelet and fibrin deposition and leukocyte accumulation in tissues; vascular permeability and edema; cytokine production; organ histology; and in a hind-limb ischemia-reperfusion model, reflow and infarct size. Lastly, because PARs sense tissue injury and hence "immunological danger," we shall ask whether PARs influence the decision to mount an adaptive immune response. These studies may point to new strategies for modulating injurious inflammatory responses in man. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PROTECTIVE EFFECTS OF ANTI-C5A IN SEPSIS Principal Investigator & Institution: Ward, Peter A.; Godfrey D. Stobbe Professor and Chairman; Pathology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274
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Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-MAY-2006 Summary: (provided by applicant): On the basis of our studies to date using the experimental model of sepsis induced by cecal ligation/puncture (CLP) in rats, serious impairment of innate immunity develops. This results in what appears to be a C5adependent defect in assembly of NADPH oxidase and defective phagocytic function of neutrophils. These defects can be reproduced by in vitro exposure of neutrophils to concentrations of C5a found in sepsis. In the first aim, we will evaluate how in vitro exposure of neutrophils to C5a results in detective signaling pathways: phorbol 12myristate 13-acetate (PMA)-induced activation of phosphokinase C (PKC) which results in assembly of NADPH oxidase; and cell activation by engagement of FcyRs resulting in phagocytic responses. In the second aim, we will evaluate the same signaling pathways in blood neutrophils from CLP animals and determine if treatment with anti-C5a prevents defective signaling. In the third aim, we will determine if treatment of normal rats and mice and CLP rats and mice with anti-C5a compromises innate immunity, as assessed by bacterial clearance (Pseudomonas sp. and Klebsiella sp.) from lungs and evaluate the effects on survival. In the fourth aim, we will employ microarray analysis in CLP rats to define, as a function of time, alterations in global gene expression in organs that are predisposed to injury during sepsis (liver, lungs, kidneys, thymus) and determine if treatment with anti-C5a prevents this pattern of gene expression. It is possible that microarrary analysis will be predictive of organ susceptibility to damage during sepsis. Collectively, these studies should provide important evidence related to the mechanisms by which complement activation during sepsis impairs innate immunity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PSEUDOMONAS' EFFECTS ON THE GUT BARRIER FROM SURGERY Principal Investigator & Institution: Alverdy, John C.; Professor of Surgery; Surgery; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: The mere presence of Pseudomonas aeruginosa in the intestine of critically ill surgical patients is associated with a 70% mortality rate--a 3 fold increase above matched patients who culture negative for this pathogen. We propose that within the intestinal tract of a surgically stressed host, physical and chemical environmental signals cause critical shifts in the virulence phenotype of P. aeruginosa. These effects result in a change in the behavior of intestinal P. aeruginosa, causing this bacteria, upon proper cue, to shift from an indolent colonizer to a life-threatening pathogen. In this proposal we provide strong evidence that a virulence determinant in P. aeruginosa, the PA-I lectin/adhesin, plays a key role in lethal gut- derived sepsis in a surgically stressed host. The hypotheses to be tested in this project are: 1) the PA-I lectin of P. aeruginosa is expressed in vivo in response to environmental cues in the intestinal tract including pH, redox state, and norepinephrine following surgical stress (hepatectomy) 2) the PA-I lectin of P.aeruginosa induces an epithelial permeability defect at the level of the intercellular tight junction resulting in paracellular transport of its lethal cytotoxins, and 3) the PA-I lectin of P. aeruginosa alters epithelial tight junctional permeability by activation of regulatory molecules involved in the expression of occludin, the rate limiting seal of the paracellular pathway. We will test these hypotheses using a novel mouse model of endogenous P. aeruginosa sepsis and cultured intestinal epithelial cells that we have extensively studied. Our specific aims to test these hypotheses are: 1) Determine the expression, location, and function of PA-I in P. aeruginosa harvested
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from different tissue sites in mice following surgical stress (hepatectomy) and cecal injection of live P. aeruginosa and following in vitro manipulation of the its physical microenvironment (pH, redox, osmolality, norepinephrine). 2) Determine the route of transport of the P. aeruginosa cytotoxins, exotoxin A and elastase, across cultured intestinal epithelial cells (Caco-2) in response to purified PA-I and selected mutants of live P. aeurginosa. 3) Explore potential cellular mechanisms of PA-I-induced decreases in intestinal epithelial barrier function. We propose that we should rethink our understanding of the gut theory of sepsis to include mechanisms by which pathogenic bacteria alter their virulence strategies in response to stressful changes in their local environment. Understanding the virulence determinants and cellular mechanisms that pathogens use to adhere to and modify the intestinal epithelial barrier may lead to therapies which can avoid nosocomial infection at a more proximate point in the care of the critically ill. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: QUORUM PATHOGENESIS
SENSING
AND
STAPHYLOCOCCUS
AUREUS
Principal Investigator & Institution: Balaban, Naomi; Assistant Professor; Biomedical Sciences; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): This proposal is responsive to PA-03-080 on "Biodefense and emerging infectious disease research opportunities". Our aim is to better understand how virulence is regulated in Staphylococcus aureus and to further develop immunotherapy to staphylococcal infections. S. aureus cause food poisoning, sepsis, device (Biofilm) related infections, and multiple diseases like endocarditis and pneumonia. The numerous toxins produced by the bacteria are at the heart of these diseases and cause more than 50,000 deaths each year in the US alone. As food and device-associated infectious organism that can survive in multiple environments, S. aureus is a potential target for bioterrorism. Many of the infective strains are resistant to conventional antibiotics and alternative methods to prevent and treat such infections are mandatory. We discovered that the production of toxins is regulated by quorum sensing mechanisms, where proteins such as RNAIIl activating protein (RAP) are secreted by the bacteria and induce virulence. RAP (native or recombinant) activates S. aureus pathogenesis through the histidine-phosphorylation of TRAP in a still unknown manner. TRAP has been shown to be membrane-associated, but it lacks a predicted transmembrane domain and a kinase domain typical of two component system sensors. Our first hypothesis is that TRAP is bound to the membrane through another protein and that this protein acts as the actual receptor to RAP. Studies proposed in Specific Aim 1 are focused on identifying this receptor. RAP has been shown to serve as an effective vaccine to prevent S. aureus infections. Our second hypothesis is that monoclonal anti RAP antibodies may be used for immunotherapy. This will be tested under Specific Aim 2, using a panel of clones already available. Such immune intervention would greatly benefit people suffering from acute drug resistant infections or surgery-related infections often associated with implantable medical devices. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF ALS AND ITS ROLE IN THE IGF SYSTEM Principal Investigator & Institution: Boisclair, Yves R.; Animal Science; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853
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Timing: Fiscal Year 2003; Project Start 26-SEP-1997; Project End 31-MAR-2007 Summary: (provided by applicant): Gene deletion studies have demonstrated the importance of IGF-I and II (IGFs), particularly during fetal life when local IGFs production predominates. After birth, the liver becomes the most important site of IGFs synthesis, resulting in the development of a substantial plasma reservoir. This reservoir is dependent on the postnatal production of the acid labile subunit (ALS), a protein that recruits IGFs and IGF Binding Protein-3 in long-lived ternary complexes. The significance of this reservoir has been uncertain until we showed that ALS and the plasma IGF-I reservoir are required for early postnatal growth and bone development. We now will extend these studies to normal and diseased states of later postnatal life. This is relevant to malnutrition and catabolic illnesses in which decreased plasma IGF-I is associated with erosion of lean mass. Despite this association, IGF-I-based therapies have had limited success, reflecting the need for their incorporation into ternary complexes for effectiveness. Three specific aims wilt be pursued to address the role of ALS and the circulating IGFs reservoir during diseased states. AIM A: IGF-I is a potent positive regulator of skeletal muscle mass. Null ALS mice will be subjected to challenges known to induce changes in plasma IGF-I and to alter the mass of skeletal muscles (i.e., sudden increase in GH, nutritional deficiency or sepsis). AIM B: Humans have 3 times as much plasma IGF-II than IGF-I. In contrast, mice have little IGF-II and null ALS mice have normal carbohydrate homeostasis. To determine the role of ALS in containing the metabolic effects of IGF-II, we will study null ALS mice over-expressing human IGF-II. AIM C: GH stimulates ALS synthesis by increasing transcription. In vitro, this effect is conveyed by STAT5, but the importance of this mechanism remains to be established in vivo. Using null STAT5 mice and liver cells, we will evaluate the contribution of direct and indirect mechanisms mediating the effects of GH on ALS synthesis. Studying the GH-regulation of ALS transcription will provide clues to mechanisms responsible for development of hepatic GH resistance during catabolic diseases. Overall, these studies will significantly advance our understanding of the roles played by ALS and the circulating IGF reservoir in diseases of postnatal life. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MONOCYTES
REGULATION
OF
INDUCIBLE
GENE
EXPRESSION
IN
Principal Investigator & Institution: Mackman, Nigel; Associate Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 01-JUL-1992; Project End 31-MAR-2006 Summary: Gram-negative sepsis is a major cause of death in intensive care units in the United States. Sepsis is induced by the presence of pathogenic bacteria in the blood. Monocytes of the host innate immune system orchestrate a rapid response to bacterial lipopolysaccharide (LPS [endotoxin]) by expressing various cytokines and by expressing the procoagulant protein tissue factor (TF), which initiates disseminated intravascular coagulation. Recent studies indicate that administration of anticoagulants reduces mortality in patients with severe sepsis. The long-term objectives of this proposal are to elucidate the mechanism by which coagulation proteases contribute to inflammation during sepsis. Our central hypothesis is that FXa activation of protease activated receptor 2 (PAR-2) enhances IL-6 expression and increases lethality during sepsis. We will also determine the role of thrombin (FIIa) -PAR- 1 signaling in sepsis. We will employ selective inhibitors of FXa and FIIa and analyze PAR-1- and PAR-2-dependent mice in a lethal mouse model of sepsis. In addition, we will use bone marrow transplantation to determine the role of TF and PAR-1 expression on monocytes versus
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endothelial cells in sepsis. Finally, we will generate mice that constitutively or inducibly express PAR-2 in endothelial cells to directly test our central hypothesis that PAR-2 is a key component of a pathogenic pathway involved in lethal sepsis. These studies should define the mechanism by which coagulation proteases enhance inflammation during sepsis. The clinical relevance of these studies is that they may provide new insight that can be used to develop improved therapeutic strategies for the treatment of patients with severe sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF MACROPHAGE FUNCTION IN SURGICAL SEPSIS Principal Investigator & Institution: West, Michael A.; Professor; Surgery; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-AUG-1990; Project End 31-JUL-2003 Summary: (adapted from the abstract.): Sepsis and multiple organ dysfunction syndrome (MODS) are the leading causes of mortality in critically ill surgical patients. TNF and IL-1 are pro-inflammatory cytokines produced by endotoxin- stimulated macrophages and are known to be important mediators in sepsis. The PI proposes that this regulated production of pro-inflammatory cytokines is a cardinal feature of sepsis leading to MODS. This is the result of sequential exposure to multiple inflammatory insults over time. The PI hypothesizes that a tolerant macrophage phenotype is the relevant macrophage response to inflammatory stimuli in patients with sepsis or MODS. Using an in vitro mouse macrophage model, they have previously demonstrated profound modifications in LPS-activated macrophage functions following LPS pretreatment. These LPS-tolerant alterations include: 1) an inhibition of TNF secretion; 2) augmentation of IL-1 secretion; 3) impaired activation of ERK1 and 2 and T38 mitogen activated kinase (MAPK); and 4) altered regulation of NF-kB. The present studies are designed to systematically investigate: 1) the mechanisms by which LPS pretreatment induces LPS tolerance; 2) the specific defects responsible for the altered response to LPS; and 3) to characterize the signal transduction alterations present in monocytes of patients with trauma, sepsis, or burns. The PI will focus on LPS signal transduction pathways that can be stimulated in the absence of serum or CD14, and do not require protein tyrosine kinases, MAPK, or NF-kB activation. They propose to extend previous investigations using mouse macrophages, human monocytic cell lines, and monocytes from clinical trauma patients, burn patients, or patients with sepsis. The previous results suggest that relatively early LPS activation signaling events depend on upstream MAPK activation and act by changes in both pre- and post-translational transcriptional processing. The PI will use specific agonists and antagonists to delineate the precise signal transduction alterations present in LPS-tolerant cells compared to naive macrophages. They hope that using monocytes from patients will help them to determine when and how alterations in signal transduction arise and how they can develop approaches to counteract or modulate macrophage-regulated cytokine production. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF PROTEIN TURNOVER IN SEPSIS Principal Investigator & Institution: Vary, Thomas C.; Professor; Cellular/Molecular Physiology; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390
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Timing: Fiscal Year 2002; Project Start 01-JUL-1989; Project End 31-JUL-2003 Summary: The objectives of the studies described herein are to identify the loci responsible for the inhibition of protein synthesis in skeletal muscle during sepsis and to establish the mechanism(s) by which the inhibition can be reversed in order to develop treatment strategies to combat the severe muscle wasting associated with the septic process. Sustained muscle wasting contributes to the morbidity and mortality associated with sepsis. The defect in protein synthesis is localized to an impaired translation of mRNA at the level of peptide-chain initiation. Translation initiation is regulated at two steps: formation of the 43S pre-initiation complex (controlled by eukaryotic initiation factor 2 (eIF2) and eIF2B); and the binding of mRNA to the 40S ribosome (controlled by elF4E). We have identified a decreased activity of eIF2B as one defect in peptide-chain initiation and have shown that the muscle content of eIF2B protein is diminished 40 percent by sepsis. Therefore, reduced expression of eIF2B appeared a likely cause of the sepsis-induced inhibition of peptide-chain initiation in muscles of septic rats. However, protein synthesis can be stimulated 2-fold by perfusion of muscles from septic rats with buffer containing either IGF-I or elevated concentrations of amino acids by accelerating peptide-chain initiation without increasing the muscle content of eIF2B. Thus, effects of a reduced eIF2B expression on protein synthesis can be overridden, but the mechanisms responsible remain unknown. The hypothesis to be tested is that altered regulation of eIF2B and/or eIF4E mediates the changes in protein synthesis in sepsis. The specific aims of the studies proposed for the next project period are: (1) to evaluate the role of altered phosphorylation of eIF2B activity in controlling translation initiation during sepsis; (2) to investigate the effect of sepsis on eIF4E by measuring the amount of eIF4E found in the inactive 4E-BPI eIF4E complex and the active eIF4G eIF4E complex in muscle; (3) to investigate the mechanisms by which IGF-I stimulates translation initiation and contrast the response of skeletal muscle protein synthesis to IGF-I with that of insulin during sepsis; (4) to investigate the mechanisms by which amino acids stimulate translation initiation, and hence protein synthesis, during sepsis; and (5) to investigate the mechanisms by which chronic infusion of TNF or IL-1 cause an inhibition of protein synthesis in skeletal muscle. The research design will be to correlate changes in eukaryotic factor activity with rates of protein synthesis to establish which control mechanisms are important for regulating protein synthesis in skeletal muscle during sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF THE (POLY) SIALIC VIRULENCE FACTOR Principal Investigator & Institution: Vimr, Eric R.; Associate Professor; Pathobiology; University of Illinois Urbana-Champaign Henry Administration Bldg Champaign, Il 61820 Timing: Fiscal Year 2004; Project Start 01-JUL-1998; Project End 31-DEC-2008 Summary: (provided by applicant): Bacterial sepsis and meningitis are the leading causes of mortality and hospitalization by infectious agents in the United States. Sepsis alone accounts for >700,000 life-threatening infections each year and over 200,000 deaths, with economic losses greatly exceeding one billion annually. Extraintestinal pathogenic Escherichia coli (ExPEC) are the predominant agents of these infections, with one serotype, E. coli O18:K1:H7, emerging as the leading cause of gram-negative neonatal meningitis and the most prevalent isolate from uncomplicated cystitis in women, thus making it a useful model of ExPEC infections in general. How ExPEC breach the host's mucosa and reach the systemic concentration (bacteremia) necessary for triggering sepsis and meningitis is not understood, although cell-surface
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modification with sialic acid is an important determinant. In this continuation application, we propose to complete our studies to determine how the sialic and polysialic acid virulence factors are synthesized, and then to identify other gene products required for systemic disease using a functional genomic approach. Specific Aim 1 will complete the analysis of sialic acid biosynthesis and the regulation of sialate metabolism. Preliminary data indicate that the synthesis of N-acetylmannosamine (ManNAc), the first committed step in sialate biosynthesis, does not involve ManNAc 6phosphate. X-ray crystallography and NMR spectroscopy will complement the objectives of this aim. In Specific Aim 2, the structural basis for PSA biosynthesis will be determined by analyzing chimeric polysialyltransferases (polySTs) and using sitedirected mutagenesis to understand catalytic mechanism. Our preliminary data indicate that these important enzymes are structurally and functionally distinct from mammalian polySTs, suggesting wide therapeutic potential for specific polyST inhibitors. Specific Aim 3 will apply signature-tagged mutagenesis to identify disease traits that are either distinct from PSA or function in concert with this capsule to define ExPEC virulence. Our objective in this aim is to establish the minimal systemic ExPEC "pathotype". The proposed studies have direct application to the development of new therapeutic approaches by identifying novel targets for non-antibiotic drug or vaccine design. New approaches are urgently needed to prevent or treat ExPEC infections in the rapidly aging US population, the very young and the increasingly large number of immunocompromised patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF THE HUMAN INOS GENE IN SEPSIS AND TRAUMA Principal Investigator & Institution: Geller, David A.; Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JUN-1995; Project End 31-MAY-2004 Summary: Sepsis, trauma, and infection initiate systemic responses regulated by cytokines and other inflammatory mediators. In extreme conditions, this response can progress to multiple organ failure, a major cause of mortality in surgical patients. Advances in our understanding of this syndrome are based on the discovery that the inducible nitric oxide synthase (iNOS) gene is expressed in nearly every organ and tissue during the septic response. While NO synthesis has beneficial effects during acute inflammation, over-production of NO during sepsis can be detrimental with massive vasodilation and hypotension. Chronic expression of iNOS has been implicated in NOmediated cytotoxicity leading to diabetes, arthritis, neurode generative disorders, and certain cancers. Our laboratory has cloned the human iNOS gene from cytokinestimulated human hepatocytes. We then isolated the promoter region of the human iNOS gene and have shown that the cytokine-responsive DNA elements are located upstream from -4.7 kb. Recently we have characterized a novel NF-kappaB enhancer region that regulates iNOS transcription in response to TNFalpha or IL-1beta, and have shown a role for STAT1alpha in mediating IFNgamma induction. We have also identified extracellular signals that down-regulate iNOS expression including p53 tumor suppressor protein, steroids, heat shock, certain growth factors, and NO itself. Since the human iNOS gene is tightly regulated, we hypothesize that several mechanisms are working jointly to control the expression of this gene. We predict that this will include cytokine-stimulated nuclear factors that exert either positive or negative control over transcription, as well as post-transcriptional mechanisms that regulate iNOS mRNA stability and translational efficiency. In this proposal, we will pursue two interrelated
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specific aims. AIM I: TO DEFINE THE TRANSCRIPTIONAL MECHANISMS AND FUNCTIONAL PROMOTER ELEMENTS RESPONSIBLE FOR INDUCTION AND SUPPRESSION OF THE HUMAN iNOS GENE. Additional promoter regions will be fully sequenced and characterized in transfection experiments. DNA elements will be analyzed that are required for cytokine- responsiveness, with an initial focus on the interactions between NF-kappaB and STAT1alpha. Specific mechanisms for gene suppression by p53, steroids, heat shock, TGF-beta, and NO will be sought. Positive and negative transcription will be identified by gel shifts and in vivo footprinting assays. AIM II. TO DETERMINE THE POST-TRANSCRIPTIONAL MECHANISMS INVOLVED IN REGULATION OF THE HUMAN iNOS GENE. Post-transcriptional changes in mRNA stability or translational efficiency can also regulate gene expression. Cytokines will be tested for effects on human iNOS mRNA stability. Changes in translational efficiency in response to these agents will be measured by pulse-chase experiments. The 3'-untranslated region of the human iNOS gene will be analyzed for elements that mediate these effects. At the completion of our studies, we will have characterized the molecular regulation of the human iNOS gene. The information gained will increase our understanding of the control of iNOS transcription, describe novel mechanisms of cytokine-synergy in signal transduction, and help in designing therapeutic strategies for pathophysiological disease states where cytokine expression is relevant. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF S-NITROSOHEMOGLOBIN IN SEPSIS Principal Investigator & Institution: Patel, Rakesh P.; Pathology; 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: (provided by applicant): Septic shock is a leading cause of mortality in hospitalized patients and is defined as the systemic inflammatory response to infection. This disease is characterized by hypotension and inflammatory damage to organs including the lung and which ultimately leads to multiple organ failure and death. Nitric oxide (NO) has a critical role in this disease with NO produced from iNOS receiving much attention. However, the role of NO in sepsis remains unclear with both detrimental and beneficial roles reported. An important regulator of NO function in the vasculature is Hemoglobin (Hb). Recent insights into the reactions between NO and Hb have shown that in addition to reactions with the heme, NO also interacts with a critical cysteine residue forming S-nitrosohemoglobin (SNOHb). SNOHb can elicit NO dependent effects and has been investigated principally in the context of physiological regulation of blood flow. The potential role of SNOHb in pathology has not been considered however. Recent studies show that SNOHb is elevated during endotoxemia and in this proposal, the novel concept that SNOHb mediates endotoxin induced hypotensive and inflammatory responses, by modulating production of different redox congeners of NO is put forward. The biological role of redox derivatives of NO, including nitroxyl anion (N0-) in disease remains largely unexplored although functions in promoting vasodilatation and stimulation of inflammatory responses have been suggested. Preliminary data presented herein suggest that SNOHb dependent vasorelaxation occurs via formation of N0- and vasorelaxing effects of red blood cells purified from endotoxin treated rats are demonstrated. These observations have led to the hypothesis that systemic hypotension and inflammation observed in sepsis are mediated by SNOHb. This hypothesis will be tested by pursuit of the following specific aims: 1) Determine the mechanism of SNOHb formation in endotoxic shock; 2) Determine the vasodilatory mechanisms of SNOHb; and 3) Investigate the role of
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SNOHb as a mediator of inflammatory damage in the lung. Accomplishment of these aims will yield novel insights into both the molecular mechanisms by which NO impacts upon the pathogenesis of septicemia and on possible therapeutic strategies to treat this inflammatory disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF T CELLS IN SELF-LIMITED MUCOSAL INFECTIONS Principal Investigator & Institution: Bry, Lynn; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): We have found that the early adaptive serum immunoglobulin response plays an important role in surviving infection with noninvasive mucosal pathogens. B cells and CD4+ T cells are required to survive infection with Citrobacter rodentium, the mouse homolog for the enteropathogenic E. coli (EPEC). Wild-type mice develop small breaks in epithelial integrity during infection, allowing C. rodentium and members of the normal flora a direct portal of entry into the host. However, immunocompetent mice develop an early and robust serum IgM response and have few colony forming units (CFU) in end organs including liver and spleen. In contrast, infection proves lethal in mice lacking B cells or CD4+ T cells. Colonic infection leads to significant polymicrobial sepsis with damage to end organs. Unlike wild-type mice, CD4-deficient animals fail to mount pathogen-specific serum IgM or IgG responses during active infection. These results implicate a critical role for the systemic adaptive immune response in surviving and eventually clearing a mucosal infection. This research plan outlines a strategy to (1) establish the protective capacity of serum immunoglobulins during active infection, (2) establish the function and location(s) where CD4+ T cells stimulate a pathogen-specific humoral response in adoptively transferred CD4-deficient mice, (3) determine the location, immunophenotype, and cytokine secretion profiles of adoptively transferred CD4+ T cells, and (4) identify T cell co-stimulatory molecules and Th cytokines important in this response. In conjunction with these aims the candidate proposes a curriculum to further training in immunology, lymphocyte biology, pathology and ethical conduct in research. The candidate has completed the core clinical training as a resident in pathology and will devote at least 75% effort towards research. This training provides a necessary step in the candidate's goal to become an independent researcher investigating questions in mucosal immunology and host-microbial cross-talk in intestinal environments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ROLE OF TRAJ IN NEONATAL E. COLI SEPSIS AND MENINGITIS Principal Investigator & Institution: Badger, Julie L.; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 900276062 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Despite the use of modern therapeutics and diagnostic measures, neonatal bacterial sepsis and meningitis continues to be a disease with unacceptable rates of morbidity and mortality. The fatality rate of this disease is 1575 percent; furthermore, approximately 50 percent of meningitis survivors have significant neurological and developmental abnormalities. The primary, route of infection for E. coli K1 (the most common causative agent of gram-negative meningitis) is oral. Following intestinal colonization, bacteria translocate through the GI tract to
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extra-intestinal sites of mesenteric lymph nodes (MLN), liver, spleen, and the blood. E. coli K1 then multiply systemically within the bloodstream reaching a necessary threshold of bacteremia to gain access to the central nervous system (CNS). Recently we identified an E. coli K1 plasmid-encoded blood-brain barrier (BBB) invasion gene, traJ, with homology to traJ of various F-like plasmid tra operons. Our preliminary data indicate that the traJ mutation specifically attenuates dissemination from the MLN to the liver, spleen, blood, and the CNS in the neonatal rat. In addition, although animals orally infected with the traJ mutant demonstrated a decrease or no recoverable bacteria in the liver or spleen, these tissues showed a significant inflammatory response. In vitro studies determined that the traJ mutant is taken-up less by macrophages and shows a loss of a 55 kDa-secreted protein. The central hypothesis of this application is that TraJ controls the expression of a set of genes whose products (i.e., 55 kDa secreted protein) are involved in E. coli K1 dissemination, systemic infection and crossing the BBB, and these events within the disease process occur via TraJ-dependent interactions with professional phagocytes. The following proposed experiments are designed to test and substantiate our hypotheses. We aim to 1) Elucidate the genetic and molecular characteristics of the traJ region and plasmid, evaluate the ability of the endogenous plasmid to self-transfer, and determine the potential role of the traJ-containing plasmid in E. coli K1 neonatal rat virulence, 2) Evaluate the function of the TraJ-regulated proteins (i.e., 55 kDa-secreted protein) in E. coli K1 systemic dissemination and meningitis, and 3) Determine the mechanism of TraJ-dependent host inflammatory response in the neonatal rat. Improved knowledge of molecular mechanisms for early systemic dissemination and the exact interplay of the host inflammatory response during these events will assist in achieving our long-term goal of identifying novel rational approaches to development of new treatments and preventive strategies for E. coli K1 sepsis and meningitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SALT AND WATER TRANSPORT IN THE ALCOHOLIC LUNG Principal Investigator & Institution: Eaton, Douglas C.; Professor and Deputy Chairman of Physiol; 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): Salt and water transport by lung epithelial cells is critical for normal clearance of fluid in the developing and mature lungs. A delicate balance between alveolar fluid secretion and absorption results in a thin fluid layer on the surface of the airways that helps promote pulmonary gas exchange and mucociliary clearance of foreign particles from the lung. The alveolar epithelial barrier formed by lung epithelial cells and tight junctions between the cells play a key role in this process, and disruption of the barrier function can result in alveolar flooding. Chronic alcohol exposure appears to compromise the alveolar barrier. Nonetheless, compensatory increases in salt transport in the alcoholic lung appear to be sufficient to maintain approximately normal levels of airway surface fluid. However, alcoholic lungs when challenged by any significant stress (like major trauma or sepsis) are much more likely to develop edema implying that the salt and water transport mechanisms cannot respond to increased demand as nonalcoholic lungs can. It is hypothesized that alcoholinduced changes in epithelial barrier function and transport mechanisms predispose the lungs to acute edematous lung injury. While there is now substantial evidence that the maintenance of salt and water transport is a strongly regulated, energy-dependent process, the pathways for salt and water transport are not clearly defined in the normal lung, let alone how they are modified in the alcoholic lung. It does seem likely that some
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regulatory mechanism controlling the response of lung salt and water transport stress is abnormal in alcoholic lungs. It is hypothesized that abnormal glucocorticoid and TGFbeta responsiveness of lung epithelial cells prevents stress-induced increases in lung salt and water transport in alcoholic lungs.There are three specific aims of this proposal. The first aim is to determine if transport characteristics of the alcoholic lung are different from normal lung. The second aim is to determine how transport in stressed alcoholic lung differs from normal and alcoholic lung. The third aim to elucidate the cellular mechanisms responsible for alcohol-induced changes in lung transport. These experiments will improve our understanding of how chronic alcohol exposure alters alveolar fluid balance under normal and stressful conditions, and help in devising therapeutic strategies to prevent edematous lung injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SENSITIVITY OF TCR SIGNALING TO GSH LOSS IN HIV DISEASE Principal Investigator & Institution: Herzenberg, Leonore A.; Genetics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2006 Summary: (provided by applicant): Previous work in our laboratory and elsewhere has established that intracellular redox status measured in terms of intracellular glutathione (GSH) levels regulates T cell function. Inflammatory responses such as the activation of NF-kappaB are up-regulated under oxidative stress (when GSH is depleted) whereas activation events required for T cell (TCR) signaling, including tyrosine kinase phosphorylations and calcium influx, are down-regulated under these conditions but favored when intracellular GSH levels are normal. Consistent with these findings, intracellular GSH tends to be depleted in a wide variety of diseases (e.g., HIV infection, sepsis, diabetes, neoplasia) in which T cell function is often impaired. To define the biochemical mechanisms that underlie the redox regulation of TCR signaling, we propose here to combine the 11-color Fluorescent Activated Cell Sorter (Hi-D FACS) technology that we have developed to measure intracellular redox status in human T cell subsets with Hi-D FACS methods to quantitate phosphorylation of individual kinases in these T cell subsets. By examining the functional consequences of altering redox status (depleting/repleting GSH) in freshly isolated T cells from healthy donors, and by probing the relationship between redox status and T cell function in patients with various diseases, we contribute significantly to basic and clinical understanding of the impact of GSH depletion on immune function. Further, since treatment with nontoxic cysteine pro-drugs can replenish GSH, our findings may open the way to introduction of adjunct therapies to increase immune surveillance and bolster responses to infection. Finally, the technology we develop here will provide new and better ways to monitor disease progress and evaluate therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SYSTEMS APPROACH TO INNATE IMMUNITY-INFLAMMATIONSEPSIS Principal Investigator & Institution: Ulevitch, Richard J.; Chairman & Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: In the United States, recent estimates suggest that more than 750,000 patients per year are at high risk for developing septic shock with mortality rates reaching 60%. Thus there are huge societal and financial costs associated with this syndrome. Because
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of its high incidence and poor prognosis, we propose basic research focused on the innate immune system and its interface with the adaptive immune system. We acknowledge that the pathophysiology of severe sepsis/shock is exceedingly complex. There is little doubt, however, that there is often a progression from infection --) normal systemic response (sepsis) --) severe sepsis --) shock and that the primary event in this sequence is infection. There is also important evidence that the intensity of the inflammatory process at the site(s) of infection determine the severity of the systemic reaction to infection, and thus the occurrence of severe sepsis and shock. It is our contention that the only means to approach such a complex system is to use appropriate cellular and animal model systems and apply the principles of systems biology in their analysis. To accomplish this we have brought together investigators with many different scientific backgrounds and specialties that include cutting-edge bioinformatics, genomic and proteomic analyses, cell biology, studies of innate and adaptive immunity, biological network modeling etc. Most importantly, we have combined experts in the field of innate immunity with "new scientific blood" such as experts in the fields of genomics, proteomics and bioinformatics. It is our contention that in the context of this GLUE GRANT this combination of investigators will, in our highly interactive and interdependent setting, substantially expand the formulation of new concepts for this field. This effort will form the basis for a great many hypothesis-driven studies by the scientific community at-large, both basic and clinical. These studies will also identify potential new drug targets that could lead to new therapies for sepsis and shock. This would directly impact the clinical outcome of these critically ill patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TARGETED INTERLEUKIN-10 GENE THERAPY IN SEPSIS SYNDROMES Principal Investigator & Institution: Moldawer, Lyle L.; Professor; Surgery; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (Verbatim from the applicant's abstract) The treatment of the hospitalized patient with sepsis remains a clinical conundrum, due in large part to the complexity of the host response to infection and tissue injury. Pro- and antiinflammatory cytokines play critical roles in the development of sepsis syndromes, but their production is often localized to individual tissues, rather than the systemic circulation. Current therapeutic approaches for the treatment of sepsis syndromes involve the systemic administration of biological response modifiers, such as cytokine antagonists or antiinflammatory agents. To date, none of these agents has proven effective, and one explanation may be that their systemic administration is an inefficient or even inappropriate means to treat a more localized inflammatory or immunosuppressive response. We have proposed that he targeted delivery of protein-based therapies using a recombinant adenoviral vector can directly modulate the inflammatory or apoptotic processes occurring in the target tissue, without systemic immune suppression or activation. Therefore, the overall objective of these studies is to determine the feasibility of adenovirus gene transfer as a herapeutic modality. More specifically, the goals of this proposal are to determine whether the forced overexpression of initially IL-10, but also in later years, a dominant negative I-KB super-repressor, will blunt the sepsis responses in arget organs without producing systemic immune suppression. The two specific aims of the current application are: 1) To determine whether targeted expression of IL- 10 in the lungs of mice with an adenoviral vector can prevent the development of respiratory distress syndrome in a zymosan-induced model of multisystem organ failure, without increased
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expression in other organs or the induction of T-cell hyporesponsiveness and immune suppression, and 2) To determine the mechanisms by which targeted expression of IL10 in the thymus of mice can reduce caspase-3 iependent thymocyte apoptosis and improve outcome in a cecal ligation and puncture model of a compensatory mtiinflammatory response syndrome. The studies proposed in this application will ultimately determine the utility and safety ofadenovirus based gene therapy as a means of targeting protein-based therapies to individual tissues and organs in sepsis syndromes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE LPS RESPONSIVENESS OF TLR2 AN TLR4 IN THE NEUTROPHIL Principal Investigator & Institution: Arndt, Patrick G.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 15-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) The sepsis syndrome and sepsis induced Acute Respiratory Distress Syndrome (ARDS), associated with expo- sure to LPS, are important clinical entities without available specific therapies. The recent identification of the Toll- like receptors (TLRs), in particular TLR2 and TLR4 as LPS receptors has advanced our understanding of the initiation of signaling after LPS exposure. We hypothesize that TLR4 is the predominant receptor responsible for LPS induced NF-KB and/or p38 activation in the neutrophil with the signaling pathway involving IRAK 2 and M, syk and Rac2. Although, alternatively, LPS signaling may occur through TLR2 with less avidity and with involvement of other IRAK sub-species, tyrosine kinases, or small G proteins. We show here that human neutro- phils and PLB-985 cells express mRNA for TLRI-6 and express TLR2 protein. In addition, we show here in PLB-985 cells, that IRAK, the tyrosine kinase syk, and the small protein Rac2 associate with TLR2 at baseline and after LPS exposure, suggesting their involvement in LPS signaling through TLR2. We propose to investigate in neutrophils, both human and murine, and the PLB985 cell line: 1. the role of TLR2 and TLR4 in NF-KB and p38 activation, including their interdependence, 2. the macromolecular complex which associate with TLR2 or TLR4 after LPS exposure, and 3. the role and activation of IRAK 2 & M, the tyrosine kinases syk and lyn, and the small G proteins Rac2 and Cdc42 in LPS signaling. To accomplish these goals, we will develop inducible antisense retroviral techniques for the creation of antisense TLR2, TLR4, and IRAK ex- pressing cell lines, dominant negatives for TLR2, TLR4, and IRAK M, and novel immunoprecipitation techniques for 2D gel electrophoresis to examine the macromolecular complexes associated with TLR2, TLR4, and the IRAK subspecies. I will also develop techniques in 2D gel electrophoresis and protein identification by mass spec- trometry which will benefit future investigations into signaling pathways. An improved understanding of the recognition of LPS, and the signaling pathways initiated by LPS, in the neu- trophil are important to improve the understanding of the underlying pathophysiology of sepsis syndrome and sepsis induced ARDS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE ROLE OF MICROBIAL ORGANISMS IN ACUTE LUNG INJURY Principal Investigator & Institution: Doerschug, Kevin C.; Cardiovascular Center; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008
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Summary: This application is to support the development of Dr. Kevin Doerschug so that he will become an accomplished clinician-scientist and independent researcher. Dr. Gary Hunninghake will assume responsibility as mentor to ensure the success of the career development plan. The focus of the proposal is an intensive research experience in studies of human lung injury and sepsis. To achieve this, Dr. Doerschug will continue formal training in the design and analysis of human studies, as well as scientific techniques to analyze specimens from human patients with acute lung injury and sepsis. Dr. Doerschug will complete didactic training in these areas including classes in epidemiology, statistics, cell biology, and microbiology. Dr. Doerschug's classes will culminate in a Master's Degree in Translational Biomedical Research. The research mentorship will involve active development of and participation in studies designed to identify factors involved in the pathogenesis of acute lung injury and sepsis. Specifically, Dr. Doerschug will focus on the role of circulating microorganisms as the stimulus for the inflammation that characterizes these diseases. Initial studies will include identifying bacteremia or fungemia in patients with SIRS (a common risk factor for sepsis and acute lung injury), using PCR to detect previously undetectable organisms. Additionally, Dr. Doerschug will investigate the relationships between circulating microorganisms and the development of acute lung injury, focusing on patient physiology and outcomes. Once completed, these preliminary studies will more accurately describe the relationships between infection and inflammation in these disorders. Further studies can then focus on the modification of host responses to these infections. Throughout Dr. Doerschug's career development, he will interface with trainees in clinical research, pulmonary medicine, and microbiology. This intellectually rich environment will help foster the career development of Dr. Doerschug, providing ample opportunity for critical review throughout the period of this award. Both the mentor and the institution are highly committed to Dr. Doerschug's scientific development and academic success. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF TISSUE FACTOR IN TRAUMA Principal Investigator & Institution: Armstead, Valerie E.; Anesthesiology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: (Adapted from the applicant's abstract) Trauma is a serious health problem in the United States and the leading cause of death in young people. Trauma causes tissue injury, resulting in disruption of normal barriers, leading to dysfunction of physiologic systems and organs. Significant damage to the vasculature results in abnormalities in blood flow and coagulation that further compromise vital organ function. Tissue factor (TF) is a transmembrane glycoprotein that is normally expressed in epithelial cells, glial cells, mucosal cells and adventitia. TF binds to factor VII and active VIIa to trigger the extrinsic and intrinsic coagulation pathways. Activation of TF expression in cells where it is normally not expressed, such as endothelium, results in thrombosis and coagulation abnormalities. Inhibition of TF activity has been shown to increase survival in animal models of sepsis. Inappropriate activity of the coagulation cascade during trauma may be, in part due, to a potent activator such as TF. The proposed research focuses on studying the expression and activity of TF in trauma. The major hypothesis to be tested is that TF expression is an important mechanism of endothelial dysfunction and tissue damage in trauma. The specific aims of this proposal involve four areas of investigation. The first aim is to characterize TF gene expression following trauma. This goal will be accomplished by utilizing a well-recognized model of soft tissue trauma and murine
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traumatic shock (Noble-Collip drum trauma). After soft tissue trauma is induced in anesthetized rats, vital signs will be monitored and TF expression measured in vital organ mRNA, tissue extracts, and plasma. Coagulation activity will be measured with standard assays. The second aim will be to determine the relationship between TF and two other important mediators of leukocyte-endothelial-platelet interaction, P-selectin and nitric oxide (NO). This goal will be achieved by using Noble-Collip drum trauma, as well as cultured monocytes, macrophages, and vascular cells, and determining TF expression while manipulating experimental conditions with NO and P-selectin agonists and antagonists. The third aim will be to investigate the effect of inhibition of TF activity in traumatic shock by administering tissue factor pathway inhibitor, TF antibody and inhibitors of early activation of TF gene transcription. The fourth aim is to analyze the regulatory mechanisms of the induction of TF gene expression related to trauma by administering analogs of potential TF regulatory factors to our experimental models. The long-term objective is to determine if modulation of TF subsequent to trauma changes the natural course of traumatic shock. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THERAPEUTIC USE OF INTER-ALPHA INHIBITOR IN SEPSIS Principal Investigator & Institution: Lim, Yow-Pin; Prothera Biologics, Llc 87 Walmer Ave East Providence, Ri 02914 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-MAR-2003 Summary: The primary goal of this proposed research is targeted towards demonstrating the commercial utilization of human plasma derived inter- alpha inhibitor proteins (IaIp) an effective therapy of sepsis. IaIp are serine protease inhibitors found normally at high levels in human plasma. The fact that no person with complete absence of IaIp has ever been detected suggests an essential physiological role for these proteins. In patients with severe sepsis, the plasma level of IaIp decrease significantly and the decrease correlates with mortality. We propose that administration of IaIp to restore the imbalance between these natural protective inhibitors and destructive proteases will prevent organ injuries and ultimately reduce sepsis related mortality. Our preliminary animal studies in a sepsis rat model of cecal ligation and puncture (CLP) have demonstrated the beneficial effects of IaIp in maintaining hemodynamic stability, preventing organ injury, and improving survival during sepsis. In this study, we propose to optimize a protocol for purification of IaIp from human crude plasma and to evaluate and confirm the beneficial effects of the purified IaIp in the CLP rat model. The ultimate goal of these studies is to develop a novel plasma derived therapeutic that is safe and effective for sepsis. PROPOSED COMMERCIAL APPLICATIONS: There is a serious unmet medical need for more than 1.5 million people worldwide annually who suffer from sepsis. Since there are currently no agents effective for sepsis, treatment is limited to antibiotic and supportive therapy. The magnitude of the need for an effective novel therapeutic agent in reducing sepsis mortality and morbidity is immense and it creates an enormous market potential estimated at $10-25 billion/year in the US alone. Inter-alpha inhibitor proteins appear to be an effective therapeutic agent of sepsis. The proposed study is expected to lead to the development of novel human plasma derived protein that is safe and effective for sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THERMAL INJURY INDUCED ALTERATIONS IN IMMUNE FUNCTION Principal Investigator & Institution: Schwacha, Martin G.; Assistant Professor of Surgery; Surgery; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-JUL-1999; Project End 31-JUL-2004 Summary: Immune dysfunction, susceptibility to sepsis and multiple organ failure are complications associated with thermal injury. Evidence suggests that activation of a proinflammatory cascade after burn injury plays an important role in their development. With regards to this, macrophages (Mphi) are major producers of pro-inflammatory mediators with increased productive capacity being observed post-burn. Thus, Mphi hyperactivity (as defined by increased productive capacity for pro-inflammatory mediators) may be of fundamental importance in the development of these complications. Nonetheless, the precise mechanisms responsible for the alterations in Mphi activity are unclear. We have utilized a murine scald burn model (3rd degree, 25 percent total body surface area) and our preliminary results indicated that at 4-7 days post-burn Mphi were "hyperactive" as increased productive capacity for nitric oxide, TNF-alpha, IL-6 and PGE2 was observed. Furthermore, at 4-7 days post-burn, but not earlier, Mphi hyperactivity was responsible for the suppression of T cell function and at 7 days post-burn mice were significantly more susceptible to the lethal effects of sepsis. With regards to T cells, we have observed significant mortality (approximately 75 percent) during the initial 48 hr. post-burn period in mice lacking gamma/delta T cells (gamma/delta T cell knock-out mice) and Mphi isolated from surviving mice at 7 days post-burn appear not to be "hyperactive". These findings suggest a dual role for gamma/delta T cells in burn injury pathogenesis; 1) survival early and; 2) induction of Mphi hyperactivity later. Our preliminary results suggest that Mphi hyperactivity postburn is related to alterations in sensitivity to CAMP, however, the mediators and mechanisms responsible for Mphi hyperactivity post-burn and its role in immune dysfunction remain to elucidated. Moreover, the impact of burn excision, a common clinical practice, on Mphi hyperactivity and susceptibility to sepsis post-burn is unknown. It is our hypothesis that Mphi hyperactivity post-burn is mediated by gamma/delta T cells and altered cAMP responses leading to the development of immune dysfunction. Therefore, we propose to determine the following: 1) The relationship between gamma/delta T cells, Mphi and survival early (initial 48 hr.) postburn; 2) The role of gamma/delta T cells in the induction of Mphi hyperactivity late (7 days) post-burn; 3) The mechanisms responsible for Mphi hyperactivity post-burn; and 4) The effect of burn wound excision on Mphi hyperactivity and increased susceptibility to sepsis. A more comprehensive understanding of the relationship between Mphi activity, T cell function, and the development of immune dysfunction following thermal injury should hopefully provide the basis for improved therapeutic regimes in the treatment of burn patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THROMBIN, SEPSIS AND MECHANISMS OF INFLAMMATION Principal Investigator & Institution: Tiruppathi, Chinnaswamy; Associate Professor; Pharmacology; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-FEB-1999; Project End 31-JAN-2007 Summary: (provided by applicant): The overall objective of this renewal application is to test the hypothesis that the activation of Trp channel-mediated Ca2+ entry in
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endothelial cells increases lung microvascular permeability and promotes lung edema. We have shown that thrombin activation of Proteinase-Activated Receptor-1 (PAR-1) expressed on endothelial cell surface induces an increase in intracellular Ca2+, which is critical in the mechanism of increased endothelial permeability. The increase in intracellular Ca2+ concentration ([Ca2+]i) is dependent on both Ca2+ store depletion and the Ca2+ store depletion-mediated Ca2+ influx. We showed that the prevention of Ca2+ influx drastically reduced the thrombin-induced increase in endothelial permeability. We also show that the Ca2+ influx due to store depletion occurs through activation of the transient receptor potential (Trp) gene family of channels expressed in endothelial cells. Our supporting data show that Trp1 (Trp gene homologue) is predominantly expressed in human endothelial cells and increased expression of Trp1 augments the Ca2+ influx in endothelial cells. Further, we show that Src kinase activation plays an important role in the regulation of Ca2+ influx via Trp channels. Deletion of Trp4 gene (predominant Trp isoform expressed in mouse endothelial cells) in mouse impairs thrombin-induced increase in lung microvascular permeability. The association of Trp1 with caveolin-1 (the principal protein of caveolae) in response to thrombin is required for the Ca2+ influx in endothelial cells. We also show that the inflammatory cytokine, tumor necrosis factor-alpha (TNFa) increases Trp1 expression in endothelial cells. Based on these supporting data, we propose to (i) determine the role of Src kinase signaling in the mechanism of Ca2+ influx in endothelial cells via Trp channels (ii) study the role of caveolin-1 in the mechanism of Ca2+ influx through Trp channels and its role in the mechanism of increased endothelial permeability, and (iii) investigate the effects of inflammatory mediators, TNFa and lipopolysaccharide, on the functional expression of Trp channels and its role in the mechanism of increase in endothelial permeability. The proposed studies will utilize cell and in vivo approaches involving Src null (Src -/-), caveolin-1 null (cav1 -/-), and Trp4 null (Trp4 -/-) mice to address the role of Trp channels in activating Ca2+ influx in endothelial cells and in the mechanism of increased endothelial permeability. With the achievement of these studies, we will be able to provide new molecular insight into understanding the mechanism of vascular injury and tissue inflammation associated with states of hypercoagulation such as with sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TREATMENT FOR GBS COLONIZATION IN PREGNANT WOMEN Principal Investigator & Institution: Bhatt, Bakul M.; Biomedical Development Corporation 500 Sandau, Ste 200 San Antonio, Tx 78216 Timing: Fiscal Year 2001; Project Start 20-SEP-1997; Project End 31-MAY-2004 Summary: (Adapted from Applicant's Abstract): The goal of this project is to further develop Iocide, a novel iodine-based antimicrobial technology, for use as a topical bacteriocide for group B streptococci (GBS) in the vaginal tract of pregnant women during the intrapartum period. GBS is the leading cause of neonatal bacterial disease and death, and most frequently occurs in neonates as sepsis, meningitis, and pneumonia. Despite clinical advances to date, GBS continues to be a major cause of illness and death among newborns. Due to the limitations of current clinical strategies, a need exists for alternate approaches to prevent GBS-related neonatal disease. The following specific aims have been designed to achieve this goal: 1) to optimize the formulation of the Iocide vaginal gel, 2) to determine the effective range of Iocide in vitro, 3) to demonstrate safety and efficacy to the Iocide in animals, and 4) to determine safety and efficacy of Iocide in human clinical trials. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE
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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 “sepsis” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for sepsis in the PubMed Central database: •
A Double-Blind Placebo-Controlled Study of an Infusion of Lexipafant (PlateletActivating Factor Receptor Antagonist) in Patients with Severe Sepsis. by Suputtamongkol Y, Intaranongpai S, Smith MD, Angus B, Chaowagul W, Permpikul C, Simpson JA, Leelarasamee A, Curtis L, White NJ.; 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89748
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A Model of Infected Burn Wounds Using Escherichia coli O18:K1:H7 for the Study of Gram-Negative Bacteremia and Sepsis. by Busch NA, Zanzot EM, Loiselle PM, Carter EA, Allaire JE, Yarmush ML, Warren HS.; 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97598
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Actinobacillus equuli Septicemia: an Unusual Zoonotic Infection. by Ashhurst-Smith C, Norton R, Thoreau W, Peel MM.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105212
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Activity of lipopolysaccharide-binding protein-bactericidal/permeability-increasing protein fusion peptide in an experimental model of Pseudomonas sepsis. by Opal SM, Palardy JE, Jhung JW, Donsky C, Romulo RL, Parejo N, Marra MN.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163038
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Application of 16S rRNA Gene Sequencing To Identify Bordetella hinzii as the Causative Agent of Fatal Septicemia. by Kattar MM, Chavez JF, Limaye AP, Rassoulian-Barrett SL, Yarfitz SL, Carlson LC, Houze Y, Swanzy S, Wood BL, Cookson BT.; 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86205
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Assessment of a new hub design and the semiquantitative catheter culture method using an in vivo experimental model of catheter sepsis. by Segura M, Alia C, Valverde J, Franch G, Torres Rodriguez JM, Sitges-Serra A.; 1990 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268222
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Assessment of Neutrophil Function in Patients with Septic Shock: Comparison of Methods. by Wenisch C, Fladerer P, Patruta S, Krause R, Horl W.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96030
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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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Bacteriological and Serological Findings in a Further Case of Transfusion-Mediated Yersinia enterocolitica Sepsis. by Strobel E, Heesemann J, Mayer G, Peters J, MullerWeihrich S, Emmerling P.; 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87034
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Balance of inflammatory cytokines related to severity and mortality of murine sepsis. by Walley KR, Lukacs NW, Standiford TJ, Strieter RM, Kunkel SL.; 1996 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174439
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Bench-to-bedside review: Toll-like receptors and their role in septic shock. by Opal SM, Huber CE.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137294
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Blood Cultures Positive for Coagulase-Negative Staphylococci: Antisepsis, Pseudobacteremia, and Therapy of Patients. by Souvenir D, Anderson DE Jr, Palpant S, Mroch H, Askin S, Anderson J, Claridge J, Eiland J, Malone C, Garrison MW, Watson P, Campbell DM.; 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104953
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Brevibacterium casei Sepsis in an 18-Year-Old Female with AIDS. by Brazzola P, Zbinden R, Rudin C, Schaad UB, Heininger U.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87423
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Case of Sepsis Caused by Bifidobacterium longum. by Ha GY, Yang CH, Kim H, Chong Y.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88684
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Catheter Sepsis Due to Mycobacterium chelonae. by Wallace RJ Jr, Brown BA.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105357
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Catheter-Related Sepsis Due to Rhodotorula glutinis. by Hsueh PR, Teng LJ, Ho SW, Luh KT.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149691
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CD40 Contributes to Lethality in Acute Sepsis: In Vivo Role for CD40 in Innate Immunity. by Gold JA, Parsey M, Hoshino Y, Hoshino S, Nolan A, Yee H, Tse DB, Weiden MD.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155725
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Central Line Sepsis in a Child Due to a Previously Unidentified Mycobacterium. by Hogg GG, Schinsky MF, McNeil MM, Lasker BA, Silcox VA, Brown JM.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88674
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Chemokine C10 Promotes Disease Resolution and Survival in an Experimental Model of Bacterial Sepsis. by Steinhauser ML, Hogaboam CM, Matsukawa A, Lukacs NW, Strieter RM, Kunkel SL.; 2000 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97687
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Circulating complement proteins in patients with sepsis or systemic inflammatory response syndrome. by Stove S, Welte T, Wagner TO, Kola A, Klos A, Bautsch W, Kohl J.; 1996 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170271
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Clinical correlations of serial quantitative blood cultures determined by lysiscentrifugation in patients with persistent septicemia. by Whimbey E, Wong B, Kiehn TE, Armstrong D.; 1984 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=271182
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Complement Activation in Relation to Capillary Leakage in Children with Septic Shock and Purpura. by Hazelzet JA, de Groot R, van Mierlo G, Joosten KF, van der Voort E, Eerenberg A, Suur MH, Hop WC, Hack CE.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108669
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Concordance of endotoxemia with gram-negative bacteremia in patients with gramnegative sepsis: a meta-analysis. by Hurley JC.; 1994 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=263953
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Critical advances in septicemia and septic shock. by Das UN.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137258
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Critical Role of CD14 for Production of Proinflammatory Cytokines and Cytokine Inhibitors during Sepsis with Failure To Alter Morbidity or Mortality. by Ebong SJ, Goyert SM, Nemzek JA, Kim J, Bolgos GL, Remick DG.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98135
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Dantrolene Ameliorates the Metabolic Hallmarks of Sepsis in Rats and Improves Survival in a Mouse Model of Endotoxemia. by Hotchkiss RS, Karl IE.; 1994 Apr 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43510
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DF-2 septicemia following whirlpool spa immersion. by Holmes RL, Kozinn WP.; 1986 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=268709
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Differential Host Inflammatory Responses to Viable Versus Antibiotic-Killed Bacteria in Experimental Microbial Sepsis. by Silverstein R, Wood JG, Xue Q, Norimatsu M, Horn DL, Morrison DC.; 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97417
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Effect of Interleukin-10 on Gut-Derived Sepsis Caused by Pseudomonas aeruginosa in Mice. by Matsumoto T, Tateda K, Miyazaki S, Furuya N, Ohno A, Ishii Y, Hirakata Y, Yamaguchi K.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105955
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Effective Immunomodulatory Treatment of Escherichia coli Experimental Sepsis with Thalidomide. by Giamarellos-Bourboulis EJ, Poulaki H, Kostomitsopoulos N, Dontas I, Perrea D, Karayannacos PE, Giamarellou H.; 2003 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166096
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Effects of Specific Antibodies against Streptococcus pneumoniae on Pharmacodynamic Parameters of [beta]-Lactams in a Mouse Sepsis Model. by Casal J, Aguilar L, Jado I, Yuste J, Gimenez MJ, Prieto J, Fenoll A.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127147
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Elevated Levels of Lipopolysaccharide-Binding Protein and Soluble CD14 in Plasma in Neonatal Early-Onset Sepsis. by Berner R, Furll B, Stelter F, Drose J, Muller HP, Schutt C.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=119928
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Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. by Ulloa L, Ochani M, Yang H, Tanovic M, Halperin D, Yang R, Czura CJ, Fink MP, Tracey KJ.; 2002 Sep 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129448
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Expression of the C5a receptor (CD88) on granulocytes and monocytes in patients with severe sepsis. by Furebring M, Hakansson LD, Venge P, Nilsson B, Sjolin J.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125318
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Fatal sepsis caused by Corynebacterium amycolatum in a premature infant. by Berner R, Pelz K, Wilhelm C, Funke A, Leititis JU, Brandis M.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229725
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Genetic Characterization of Resistance to Extended-Spectrum [beta]-Lactams in Klebsiella oxytoca Isolates Recovered from Patients with Septicemia at Hospitals in the Stockholm Area. by Wu SW, Dornbusch K, Kronvall G.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89264
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Gram-negative sepsis: a dilemma of modern medicine. by Bone RC.; 1993 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=358266
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Heat stress is associated with decreased lactic acidemia in rat sepsis. by Deshpande GG, Heidemann SM, Sarnaik AP.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29035
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Hemofiltration in sepsis: where do we go from here? by Kellum JA, Bellomo R.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137329
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Highly sensitive immunoassay for direct diagnosis of viral hemorrhagic septicemia which uses antinucleocapsid monoclonal antibodies. by Mourton C, Romestand B, de Kinkelin P, Jeffroy J, Le Gouvello R, Pau B.; 1992 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265503
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Hot new therapy for sepsis and the acute respiratory distress syndrome. by Slutsky AS.; 2002 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151137
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Immunomodulating effect of fosfomycin on gut-derived sepsis caused by Pseudomonas aeruginosa in mice. by Matsumoto T, Tateda K, Miyazaki S, Furuya N, Ohno A, Ishii Y, Hirakata Y, Yamaguchi K.; 1997 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163706
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Immunopathologic Alterations in Murine Models of Sepsis of Increasing Severity. by Ebong S, Call D, Nemzek J, Bolgos G, Newcomb D, Remick D.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97073
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Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock. by Macarthur H, Westfall TC, Riley DP, Misko TP, Salvemini D.; 2000 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16937
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Increased C5a receptor expression in sepsis. by Riedemann NC, Guo RF, Neff TA, Laudes IJ, Keller KA, Sarma VJ, Markiewski MM, Mastellos D, Strey CW, Pierson CL, Lambris JD, Zetoune FS, Ward PA.; 2002 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151030
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Infection of Neonatal Mice with Sindbis Virus Results in a Systemic Inflammatory Response Syndrome. by Klimstra WB, Ryman KD, Bernard KA, Nguyen KB, Biron CA, Johnston RE.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113094
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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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Interleukin-10 Controls the Onset of Irreversible Septic Shock. by Latifi SQ, O'Riordan MA, Levine AD.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128185
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Interleukin-8 in sepsis: relation to shock and inflammatory mediators. by Hack CE, Hart M, van Schijndel RJ, Eerenberg AJ, Nuijens JH, Thijs LG, Aarden LA.; 1992 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=257242
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Levels of Inhibitors of Tumor Necrosis Factor Alpha and Interleukin 1[beta] in Urine and Sera of Patients with Urosepsis. by Olszyna DP, Prins JM, Buis B, van Deventer SJ, Speelman P, van der Poll T.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108383
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Lipopolyamines: Novel Antiendotoxin Compounds That Reduce Mortality in Experimental Sepsis Caused by Gram-Negative Bacteria. by David SA, Silverstein R, Amura CR, Kielian T, Morrison DC.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89225
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Mass transfer, clearance and plasma concentration of procalcitonin during continuous venovenous hemofiltration in patients with septic shock and acute oliguric renal failure. by Level C, Chauveau P, Guisset O, Cazin MC, Lasseur C, Gabinsky C, Winnock S, Montaudon D, Bedry R, Nouts C, Pillet O, Benissan GG, Favarel-Guarrigues JC, Castaing Y.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=374372
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Mast cell dipeptidyl peptidase I mediates survival from sepsis. by Mallen --St. Clair J, Pham CT, Villalta SA, Caughey GH, Wolters PJ.; 2004 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=338261
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Mechanisms Involved in the Pathogenesis of Sepsis Are Not Necessarily Reflected by In Vitro Cell Activation Studies. by Amura CR, Silverstein R, Morrison DC.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108672
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Modulation of Release of Proinflammatory Bacterial Compounds by Antibacterials: Potential Impact on Course of Inflammation and Outcome in Sepsis and Meningitis. by Nau R, Eiffert H.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=118062
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Molecular Cloning and Characterization of the afa-7 and afa-8 Gene Clusters Encoding Afimbrial Adhesins in Escherichia coli Strains Associated with Diarrhea or Septicemia in Calves. by Lalioui L, Jouve M, Gounon P, Le Bouguenec C.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96852
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Neutrophils employ the myeloperoxidase system to generate antimicrobial brominating and chlorinating oxidants during sepsis. by Gaut JP, Yeh GC, Tran HD, Byun J, Henderson JP, Richter GM, Brennan ML, Lusis AJ, Belaaouaj A, Hotchkiss RS, Heinecke JW.; 2001 Oct 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59821
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Nosocomial septicemia caused by Serratia plymuthica. by Domingo D, Limia A, Alarcon T, Sanz JC, Del Rey MC, Lopez-Brea M.; 1994 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=263083
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papG Alleles among Escherichia coli Strains Causing Urosepsis: Associations with Other Bacterial Characteristics and Host Compromise. by Johnson JR.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108561
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Pasteurella multocida septicemia and subsequent Pasteurella dagmatis septicemia in a diabetic patient. by Fajfar-Whetstone CJ, Coleman L, Biggs DR, Fox BC.; 1995 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=227908
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Pathogenicity of an Escherichia coli O115:K"V165" mutant negative for F165(1) fimbriae in septicemia of gnotobiotic pigs. by Ngeleka M, Jacques M, Martineau-Doize B, Daigle F, Harel J, Fairbrother JM.; 1993 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302809
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Pattern of cytokines and pharmacomodulation in sepsis induced by cecal ligation and puncture compared with that induced by endotoxin. by Villa P, Sartor G, Angelini M, Sironi M, Conni M, Gnocchi P, Isetta AM, Grau G, Buurman W, van Tits LJ.; 1995 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170198
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Phylogenetic Analysis and Prevalence of Urosepsis Strains of Escherichia coli Bearing Pathogenicity Island-Like Domains. by Bingen-Bidois M, Clermont O, Bonacorsi S, Terki M, Brahimi N, Loukil C, Barraud D, Bingen E.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128014
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Physiological-dose steroid therapy in sepsis [ISRCTN36253388]. by Yildiz O, Doganay M, Aygen B, Guven M, Kelestimur F, Tutus A.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125315
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Potential Therapeutic Role of Cationic Peptides in Three Experimental Models of Septic Shock. by Giacometti A, Cirioni O, Ghiselli R, Mocchegiani F, Del Prete MS, Viticchi C, Kamysz W, Lempicka E, Saba V, Scalise G.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=127283
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Predictive Value of Nuclear Factor [kappa]B Activity and Plasma Cytokine Levels in Patients with Sepsis. by Arnalich F, Garcia-Palomero E, Lopez J, Jimenez M, Madero R, Renart J, Vazquez JJ, Montiel C.; 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=97370
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Prevalence of Molecular Types and mecA Gene Carriage of Coagulase-Negative Staphylococci in a Neonatal Intensive Care Unit: Relation to Nosocomial Septicemia. by Krediet TG, Jones ME, Janssen K, Gerards LJ, Fleer A.; 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88351
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Prevention of lymphocyte cell death in sepsis improves survival in mice. by Hotchkiss RS, Tinsley KW, Swanson PE, Chang KC, Cobb JP, Buchman TG, Korsmeyer SJ, Karl IE.; 1999 Dec 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24472
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Primary Shewanella alga Septicemia in a Patient on Hemodialysis. by Iwata M, Tateda K, Matsumoto T, Furuya N, Mizuiri S, Yamaguchi K.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85050
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Pro/con clinical debate: Is high-volume hemofiltration beneficial in the treatment of septic shock? by Reiter K, Bellomo R, Ronco C, Kellum JA.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137392
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Pulmonary and Hepatic Gene Expression following Cecal Ligation and Puncture: Monophosphoryl Lipid A Prophylaxis Attenuates Sepsis-Induced Cytokine and Chemokine Expression and Neutrophil Infiltration. by Salkowski CA, Detore G, Franks A, Falk MC, Vogel SN.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108388
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Quality of life effects of antithrombin III in sepsis survivors: results from the KyberSept trial [ISRCTN22931023]. by Rublee D, Opal SM, Schramm W, Keinecke HO, Knaub S.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125322
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Quantitative aspects of septicemia. by Yagupsky P, Nolte FS.; 1990 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=358159
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Reappraisal with meta-analysis of bacteremia, endotoxemia, and mortality in gramnegative sepsis. by Hurley JC.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228145
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Risk factors for early onset neonatal group B streptococcal sepsis: case-control study. by Oddie S, Embleton ND.; 2002 Aug 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117770
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Role of endotoxemia in cardiovascular dysfunction and lethality: virulent and nonvirulent Escherichia coli challenges in a canine model of septic shock. by Hoffman WD, Danner RL, Quezado ZM, Banks SM, Elin RJ, Hosseini JM, Natanson C.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173778
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Role of IL-12 in Staphylococcus aureus-triggered arthritis and sepsis. by Hultgren OH, Stenson M, Tarkowski A.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17823
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Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis. by Bernard GR, Macias WL, Joyce DE, Williams MD, Bailey J, Vincent JL.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=270661
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Sepsis, Multiple Organ Failure, and Death Due to Pandoraea pnomenusa Infection after Lung Transplantation. by Stryjewski ME, LiPuma JJ, Messier, Jr. RH, Reller LB, Alexander BD.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154699
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Septic Shock Due to Helicobacter fennelliae in a Non-Human Immunodeficiency Virus-Infected Heterosexual Patient. by Hsueh PR, Teng LJ, Hung CC, Chen YC, Yang PC, Ho SW, Luh KT.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85042
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Septicemia caused by the gram-negative bacterium CDC IV c-2 in an immunocompromised human. by Dan M, Berger SA, Aderka D, Levo Y.; 1986 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=362844
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Septicemia Due to Acinetobacter junii. by Linde HJ, Hahn J, Holler E, Reischl U, Lehn N.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=120562
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Septicemia Due to Pasteurella pneumotropica: 16S rRNA Sequencing for Diagnosis Confirmation. by Frebourg NB, Berthelot G, Hocq R, Chibani A, Lemeland JF.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153411
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Septicemia in Neutropenic Patients Infected with Clostridium tertium Resistant to Cefepime and Other Expanded-Spectrum Cephalosporins. by Steyaert S, Peleman R, Vaneechoutte M, De Baere T, Claeys G, Verschraegen G.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85761
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Serial Granulocyte Transfusions as a Treatment for Sepsis Due to MultidrugResistant Pseudomonas aeruginosa in a Neutropenic Patient. by Lin YW, Adachi S, Watanabe KI, Umeda K, Nakahata T.; 2003 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=254381
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Severe sepsis: variation in resource and therapeutic modality use among academic centers. by Yu DT, Black E, Sands KE, Schwartz JS, Hibberd PL, Graman PS, Lanken PN, Kahn KL, Snydman DR, Parsonnet J, Moore R, Platt R, Bates DW.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=270675
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Severe Serratia liquefaciens Sepsis following Vitamin C Infusion Treatment by a Naturopathic Practitioner. by Engelhart S, Saborowski F, Krakau M, ScherholzSchlosser G, Heyer I, Exner M.; 2003 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=179848
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Simultaneous Detection of Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae in Suspected Cases of Meningitis and Septicemia Using Real-Time PCR. by Corless CE, Guiver M, Borrow R, Edwards-Jones V, Fox AJ, Kaczmarski EB.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87969
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STAT4 Is Required for Antibacterial Defense but Enhances Mortality during Polymicrobial Sepsis. by Godshall CJ, Lentsch AB, Peyton JC, Scott MJ, Cheadle WG.; 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96223
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Susceptibility testing of macrolide antibiotics against Haemophilus influenzae and correlation of in vitro results with in vivo efficacy in a mouse septicemia model. by Fernandes PB, Hardy D, Bailer R, McDonald E, Pintar J, Ramer N, Swanson R, Gade E.; 1987 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=174912
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Synergistic effect of a recombinant N-terminal fragment of bactericidal/permeabilityincreasing protein and cefamandole in treatment of rabbit gram-negative sepsis. by Lin Y, Leach WJ, Ammons WS.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163058
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Targeted adenovirus-induced expression of IL-10 decreases thymic apoptosis and improves survival in murine sepsis. by Oberholzer C, Oberholzer A, Bahjat FR, Minter RM, Tannahill CL, Abouhamze A, LaFace D, Hutchins B, Clare-Salzler MJ, Moldawer LL.; 2001 Sep 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58759
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The effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis [ISRCTN28863830]. by Tugrul S, Ozcan PE, Akinci O, Seyhun Y, Cagatay A, Cakar N, Esen F.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125317
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The enigma of sepsis. by Riedemann NC, Guo RF, Ward PA.; 2003 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=171398
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The level of lipopolysaccharide-binding protein is significantly increased in plasma in patients with the systemic inflammatory response syndrome. by Myc A, Buck J, Gonin J, Reynolds B, Hammerling U, Emanuel D.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=170487
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The role of staphylococcal polysaccharide microcapsule expression in septicemia and septic arthritis. by Nilsson IM, Lee JC, Bremell T, Ryden C, Tarkowski A.; 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=175605
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The Surviving Sepsis Campaign: raising awareness to reduce mortality. by Slade E, Tamber PS, Vincent JL.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154124
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Tissue distribution of migration inhibitory factor and inducible nitric oxide synthase in falciparum malaria and sepsis in African children. by Clark IA, Awburn MM, Whitten RO, Harper CG, Liomba NG, Molyneux ME, Taylor TE.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154094
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Transfusion-associated bacterial sepsis. by Wagner SJ, Friedman LI, Dodd RY.; 1994 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=358326
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Treatment of Klebsiella pneumoniae septicemia in normal and leukopenic mice by liposome-encapsulated muramyl tripeptide phosphatidylethanolamide. by Melissen PM, van Vianen W, Bakker-Woudenberg IA.; 1994 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=284413
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Use of Lytic Bacteriophage for Control of Experimental Escherichia coli Septicemia and Meningitis in Chickens and Calves. by Barrow P, Lovell M, Berchieri A Jr.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=104512
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Usefulness of gram staining of blood collected from total parenteral nutrition catheter for rapid diagnosis of catheter-related sepsis. by Moonens F, el Alami S, Van Gossum A, Struelens MJ, Serruys E.; 1994 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=264041
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Usefulness of procalcitonin for diagnosis of sepsis in the intensive care unit. by BalcI C, Sungurtekin H, Gurses E, Sungurtekin U, Kaptanoglu B.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154110
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Utilization of 16S Ribosomal DNA Sequencing for Diagnosis of Septicemia Due to Neisseria elongata subsp. glycolytica in a Neutropenic Patient. by Hombrouck-Alet C, Poilane I, Janoir-Jouveshomme C, Fain O, Cruaud P, Thomas M, Collignon A.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165362
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 sepsis, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “sepsis” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for sepsis (hyperlinks lead to article summaries): •
A case of Pasteurella haemolytica sepsis in a patient with mitral valve disease who developed a splenic abscess. Author(s): Takeda S, Arashima Y, Kato K, Ogawa M, Kono K, Watanabe K, Saito T. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(10): 764-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14606620
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A definite role for treatment with activated protein C in sepsis? Standard use is premature. Author(s): Girbes AR, Polderman KH. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 December; 1(12): 2469-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675079
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PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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A definite role for treatment with activated protein C in sepsis? Yes. Author(s): Wiel E, Vallet B. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 December; 1(12): 2466-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675078
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A new weapon against severe sepsis related to necrotizing fasciitis. Author(s): Purnell D, Hazlett T, Alexander SL. Source: Dimensions of Critical Care Nursing : Dccn. 2004 January-February; 23(1): 18-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14734896
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A patient with E. coli-induced pyelonephritis and sepsis who transiently exhibited symptoms associated with primary biliary cirrhosis. Author(s): Ohno N, Ota Y, Hatakeyama S, Yanagimoto S, Morisawa Y, Tsukada K, Koike K, Kimura S. Source: Intern Med. 2003 November; 42(11): 1144-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14686759
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A readers' guide to the interpretation of diagnostic test properties: clinical example of sepsis. Author(s): Fischer JE, Bachmann LM, Jaeschke R. Source: Intensive Care Medicine. 2003 July; 29(7): 1043-51. Epub 2003 May 07. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12734652
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Abdominal sepsis and communication breakdown. Author(s): McCoy R. Source: Aust Fam Physician. 2003 May; 32(5): 345-6. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12772367
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Acute acalculous cholecystitis associated with systemic sepsis and visceral arterial hypoperfusion: a case series and review of pathophysiology. Author(s): McChesney JA, Northup PG, Bickston SJ. Source: Digestive Diseases and Sciences. 2003 October; 48(10): 1960-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627341
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Adequacy of early empiric antibiotic treatment and survival in severe sepsis: experience from the MONARCS trial. Author(s): MacArthur RD, Miller M, Albertson T, Panacek E, Johnson D, Teoh L, Barchuk W. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2004 January 15; 38(2): 284-8. Epub 2003 December 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14699463
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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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Adrenocortical hormones in survivors and nonsurvivors of severe sepsis: diverse time course of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol. Author(s): Marx C, Petros S, Bornstein SR, Weise M, Wendt M, Menschikowski M, Engelmann L, Hoffken G. Source: Critical Care Medicine. 2003 May; 31(5): 1382-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12771606
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Aminoglycoside and vancomycin serum concentration monitoring and mortality due to neonatal sepsis in Saudi Arabia. Author(s): El Desoky ES, Sheikh AA, Al Hammadi AY. Source: Journal of Clinical Pharmacy and Therapeutics. 2003 December; 28(6): 479-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14651671
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Analysis of sepsis in allogeneic bone marrow transplant recipients: a single-center study. Author(s): Mitsui H, Karasuno T, Santo T, Fukushima K, Matsunaga H, Nakamura H, Hiraoka A. Source: Journal of Infection and Chemotherapy : Official Journal of the Japan Society of Chemotherapy. 2003 September; 9(3): 238-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14513392
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Analysis of the efficacy of urine culture as part of sepsis evaluation in the premature infant. Author(s): Tamim MM, Alesseh H, Aziz H. Source: The Pediatric Infectious Disease Journal. 2003 September; 22(9): 805-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14506372
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Antibody to enterobacterial common antigen and gram-negative sepsis. Author(s): Bayardelle P, Albertson TE, MacArthur RD. Source: Critical Care Medicine. 2004 February; 32(2): 617-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14758202
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Anti-complement strategies in experimental sepsis. Author(s): Ward PA, Riedemann NC, Guo RF, Huber-Lang M, Sarma JV, Zetoune FS. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(9): 601-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14620141
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Antioxidant therapy for severe sepsis: promise and perspective. Author(s): Pinsky MR. Source: Critical Care Medicine. 2003 November; 31(11): 2697-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14605544
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Arterial hypertension and sepsis. Author(s): Nunes JP. Source: Rev Port Cardiol. 2003 November; 22(11): 1375-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14768492
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Assessment of six mortality prediction models in patients admitted with severe sepsis and septic shock to the intensive care unit: a prospective cohort study. Author(s): Arabi Y, Al Shirawi N, Memish Z, Venkatesh S, Al-Shimemeri A. Source: Critical Care (London, England). 2003 October; 7(5): R116-22. Epub 2003 August 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12974979
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Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome. Author(s): Garred P, J Strom J, Quist L, Taaning E, Madsen HO. Source: The Journal of Infectious Diseases. 2003 November 1; 188(9): 1394-403. Epub 2003 October 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14593599
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Bacillus Calmette-Guerin sepsis: shift of an intended local toward a detrimental systemic cytotoxic immune response. Author(s): Zeerleder S, Hack CE, Caliezi C, Hebeisen R, Wuillemin WA. Source: Blood. 2001 August 1; 98(3): 890-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11468141
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Bacteremia and sepsis due to Prevotella oris from dentoalveolar abscesses. Author(s): Bein T, Brem J, Schusselbauer T. Source: Intensive Care Medicine. 2003 May; 29(5): 856. Epub 2003 March 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12664220
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Bacteremic sepsis in intensive care: temporal trends in incidence, organ dysfunction, and prognosis. Author(s): Hugonnet S, Harbarth S, Ferriere K, Ricou B, Suter P, Pittet D. Source: Critical Care Medicine. 2003 February; 31(2): 390-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12576941
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Bacteria in blood smears: overwhelming sepsis or trivial contamination. Author(s): van der Meer W, Verwiel JM, Gidding CE, de Metz M, de Keijzer MH. Source: Acta Haematologica. 2002; 107(4): 220-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12053150
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Bad and good news in prevention and management of sepsis and MODS. Author(s): Baue AE. Source: Minerva Anestesiol. 2001 November; 67(11): 773-83. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11753221
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Balance of inflammation in sepsis. Author(s): Pravinkumar E. Source: American Journal of Respiratory and Critical Care Medicine. 2004 March 1; 169(5): 655-6; Author Reply 656. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14982827
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Bench-to-bedside review: endothelial cell dysfunction in severe sepsis: a role in organ dysfunction? Author(s): Vallet B. Source: Critical Care (London, England). 2003 April; 7(2): 130-8. Epub 2003 January 06. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12720559
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Bench-to-bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis. Author(s): Opal SM, Esmon CT. Source: Critical Care (London, England). 2003 February; 7(1): 23-38. Epub 2002 December 20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12617738
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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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Best evidence in anesthetic practice: prevention: recombinant human activated protein C reduces mortality in severe sepsis. Author(s): Butler R, Laufer B. Source: Canadian Journal of Anaesthesia = Journal Canadien D'anesthesie. 2002 February; 49(2): 207-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11823403
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Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. Author(s): Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Source: Bmj (Clinical Research Ed.). 2004 March 20; 328(7441): 668. Epub 2004 Mar 02. Review. Erratum In: Bmj. 2004 April 10; 328(7444): 884. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14996699
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Beyond the complete blood cell count and C-reactive protein: a systematic review of modern diagnostic tests for neonatal sepsis. Author(s): Malik A, Hui CP, Pennie RA, Kirpalani H. Source: Archives of Pediatrics & Adolescent Medicine. 2003 June; 157(6): 511-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796229
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Bilateral endogenous endophthalmitis as a complication of late-onset sepsis in a premature infant. Author(s): Matasova K, Hudecova J, Zibolen M. Source: European Journal of Pediatrics. 2003 May; 162(5): 346-7. Epub 2003 February 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692717
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Biliary sepsis in a patient on anti-TNFalpha therapy. Author(s): McNamara DA, Molony D, Mulsow J, O'Connell PR. Source: Ir J Med Sci. 2001 July-September; 170(3): 210-1. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12120982
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Biochemical markers of neonatal sepsis: value of procalcitonin in the emergency setting. Author(s): Guibourdenche J, Bedu A, Petzold L, Marchand M, Mariani-Kurdjian P, Marie-Fran, Hurtaud-Roux O, Aujard Y, Porquet D. Source: Annals of Clinical Biochemistry. 2002 March; 39(Pt 2): 130-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11928760
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Biomarkers of sepsis: is procalcitonin ready for prime time? Author(s): Pugin J. Source: Intensive Care Medicine. 2002 September; 28(9): 1203-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12400563
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Blood purification in sepsis: an idea whose time has come? Author(s): Kellum JA, Venkataraman R. Source: Critical Care Medicine. 2002 June; 30(6): 1387-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12072702
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Both gram positive and gram negative organisms complicate neutropaenic sepsis in children with leukemia. A unit audit study and recommendation. Author(s): Lee KY, Chan WS, Koay LS, Huang F, Tan LM, Yeoh AE. Source: Ann Acad Med Singapore. 2003 September; 32(5 Suppl): S37-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14968729
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Breast gangrene as a complication of puerperal sepsis. Author(s): Rege SA, Nunes Q, Rajput A, Dalvi AN. Source: Archives of Surgery (Chicago, Ill. : 1960). 2002 December; 137(12): 1441-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12470116
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Brevibacterium casei bacteremia and line sepsis in a patient with AIDS. Author(s): Janda WM, Tipirneni P, Novak RM. Source: The Journal of Infection. 2003 January; 46(1): 61-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12504612
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Carcinoma of the colon presenting as Streptococcus salivarius sepsis. Author(s): Afek S, Sperber AD, Almog Y. Source: Journal of Clinical Gastroenterology. 2004 January; 38(1): 86-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14679337
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Caspase-3 and -8 activation and cytokine removal with a novel cellulose triacetate super-permeable membrane in an in vitro sepsis model. Author(s): Bordoni V, Bolgan I, Brendolan A, Crepaldi C, Gastaldon F, D'intini V, Pilotto L, Inguaggiato P, Bonello M, Galloni E, Everard P, Bellomo R, Ronco C. Source: Int J Artif Organs. 2003 October; 26(10): 897-905. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14636005
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Cellular changes in association with defense mechanisms in intra-abdominal sepsis. Author(s): Pavlidis TE. Source: Minerva Chir. 2003 December; 58(6): 777-81. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14663404
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Characterization of a novel rapidly growing Mycobacterium species associated with sepsis. Author(s): Hong T, Butler WR, Hollis F, Floyd MM, Toney SR, Tang YW, Steele C, Leggiadro RJ. Source: Journal of Clinical Microbiology. 2003 December; 41(12): 5650-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14662956
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Circulating adrenocorticotropic hormone (ACTH) and cortisol concentrations in normal, appropriate-for-gestational-age newborns versus those with sepsis and respiratory distress: Cortisol response to low-dose and standard-dose ACTH tests. Author(s): Soliman AT, Taman KH, Rizk MM, Nasr IS, Alrimawy H, Hamido MS. Source: Metabolism: Clinical and Experimental. 2004 February; 53(2): 209-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14767873
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Clinical prognostic markers in patients with severe sepsis: a prospective analysis of 139 consecutive cases. Author(s): Gogos CA, Lekkou A, Papageorgiou O, Siagris D, Skoutelis A, Bassaris HP. Source: The Journal of Infection. 2003 November; 47(4): 300-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14556754
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Clinical review: Drotrecogin alfa (activated) as adjunctive therapy for severe sepsis-practical aspects at the bedside and patient identification. Author(s): Laterre PF, Wittebole X. Source: Critical Care (London, England). 2003 December; 7(6): 445-50. Epub 2003 June 30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624684
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Clinical review: extracorporeal blood purification in severe sepsis. Author(s): Venkataraman R, Subramanian S, Kellum JA. Source: Critical Care (London, England). 2003 April; 7(2): 139-45. Epub 2003 February 21. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12720560
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Clinical trial design and outcomes in patients with severe sepsis. Author(s): Opal SM. Source: Shock (Augusta, Ga.). 2003 October; 20(4): 295-302. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14501941
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Clostridium difficile colitis causing toxic megacolon, severe sepsis and multiple organ dysfunction syndrome. Author(s): Dobson G, Hickey C, Trinder J. Source: Intensive Care Medicine. 2003 June; 29(6): 1030. Epub 2003 May 07. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12734650
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Coagulation cascade in sepsis: getting from bench to bedside? Author(s): Brown G. Source: Critical Care (London, England). 2003 April; 7(2): 117-8. Epub 2002 November 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12720555
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Coagulation disorders in patients with cirrhosis and severe sepsis. Author(s): Plessier A, Denninger MH, Consigny Y, Pessione F, Francoz C, Durand F, Francque S, Bezeaud A, Chauvelot-Moachon L, Lebrec D, Valla DC, Moreau R. Source: Liver International : Official Journal of the International Association for the Study of the Liver. 2003 December; 23(6): 440-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15002397
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Colistin for Klebsiella pneumoniae-associated sepsis. Author(s): Karabinis A, Paramythiotou E, Mylona-Petropoulou D, Kalogeromitros A, Katsarelis N, Kontopidou F, Poularas I, Malamou-Lada H. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2004 January 1; 38(1): E7-9. Epub 2003 December 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14679468
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Comparison of surface swab cultures and quantitative tissue biopsy cultures to predict sepsis in burn patients: a prospective study. Author(s): Sjoberg T, Mzezewa S, Jonsson K, Robertson V, Salemark L. Source: The Journal of Burn Care & Rehabilitation. 2003 November-December; 24(6): 365-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14610420
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Contact activation by pathogenic bacteria: a virulence mechanism contributing to the pathophysiology of sepsis. Author(s): Herwald H, Morgelin M, Bjorck L. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(9): 604-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14620142
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Cortisol levels and mortality in severe sepsis. Author(s): Sam S, Corbridge TC, Mokhlesi B, Comellas AP, Molitch ME. Source: Clinical Endocrinology. 2004 January; 60(1): 29-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678284
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Cost-effectiveness of recombinant human activated protein C and the influence of severity of illness in the treatment of patients with severe sepsis. Author(s): Fowler RA, Hill-Popper M, Stasinos J, Petrou C, Sanders GD, Garber AM. Source: Journal of Critical Care. 2003 September; 18(3): 181-91; Discussion 191-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14595571
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CpG DNA: trigger of sepsis, mediator of protection, or both? Author(s): Krieg AM. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(9): 653-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14620150
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Crazy-paving appearance associated with Streptococcus pneumoniae sepsis. Author(s): Ngo MH, Chen HT, Stark P. Source: Seminars in Respiratory Infections. 2003 September; 18(3): 220-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14505284
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Cytokine cascade in sepsis. Author(s): Cavaillon JM, Adib-Conquy M, Fitting C, Adrie C, Payen D. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(9): 535-44. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14620132
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Detection of circulating lipopolysaccharide-bound monocytes in children with gramnegative sepsis. Author(s): Takeshita S, Nakatani K, Tsujimoto H, Kawamura Y, Sekine I. Source: The Journal of Infectious Diseases. 2000 November; 182(5): 1549-52. Epub 2000 October 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11015235
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Development of an anti-core lipopolysaccharide vaccine for the prevention and treatment of sepsis. Author(s): Cross AS, Opal S, Cook P, Drabick J, Bhattacharjee A. Source: Vaccine. 2004 February 17; 22(7): 812-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15040932
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Diagnosis of neonatal sepsis: a clinical and laboratory challenge. Author(s): Chiesa C, Panero A, Osborn JF, Simonetti AF, Pacifico L. Source: Clinical Chemistry. 2004 February; 50(2): 279-87. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14752012
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Diagnostic value of cytokines and C-reactive protein in the first 24 hours of neonatal sepsis. Author(s): Laborada G, Rego M, Jain A, Guliano M, Stavola J, Ballabh P, Krauss AN, Auld PA, Nesin M. Source: American Journal of Perinatology. 2003 November; 20(8): 491-501. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14703598
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Dismutating the superoxide ion in sepsis. Author(s): Bar-Or D. Source: Critical Care Medicine. 2003 January; 31(1): 329-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12545049
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Disseminated intravascular coagulation in meningococcal sepsis. Case 7. Author(s): Zeerleder S, Zurcher Zenklusen R, Hack CE, Wuillemin WA. Source: Hamostaseologie. 2003 August; 23(3): 125-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12923582
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Do circulating cytokines really matter in sepsis? Author(s): Tetta C, Bellomo R, D'Intini V, De Nitti C, Inguaggiato P, Brendolan A, Ronco C. Source: Kidney International. Supplement. 2003 May; (84): S69-71. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12694313
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Do pancreatic duct stents cause or prevent pancreatic sepsis? Author(s): Kozarek R, Hovde O, Attia F, France R. Source: Gastrointestinal Endoscopy. 2003 October; 58(4): 505-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14520281
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Does arginine become a "near" essential amino acid during sepsis? Author(s): Carcillo JA. Source: Critical Care Medicine. 2003 February; 31(2): 657-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12576990
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Does blocking cytokines in sepsis work? Author(s): Dinarello CA, Abraham E. Source: American Journal of Respiratory and Critical Care Medicine. 2002 November 1; 166(9): 1156-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12403683
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Does immunonutrition in patients with sepsis do more harm than good? Author(s): Heyland DK, Samis A. Source: Intensive Care Medicine. 2003 May; 29(5): 669-71. Epub 2003 March 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12664222
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Doppler ultrasonographic evaluation of hepatic blood flow in clinical sepsis. Author(s): Varsamidis K, Varsamidou E, Mavropoulos G. Source: Ultrasound in Medicine & Biology. 2003 September; 29(9): 1241-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14553799
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Drotrecogin alfa (activated) (recombinant human activated protein C) for the treatment of severe sepsis. Author(s): Bernard GR. Source: Critical Care Medicine. 2003 January; 31(1 Suppl): S85-93. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12544981
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Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Author(s): Ely EW, Laterre PF, Angus DC, Helterbrand JD, Levy H, Dhainaut JF, Vincent JL, Macias WL, Bernard GR; PROWESS Investigators. Source: Critical Care Medicine. 2003 January; 31(1): 12-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12544987
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Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multipleorgan dysfunction: data from the PROWESS trial. Author(s): Dhainaut JF, Laterre PF, Janes JM, Bernard GR, Artigas A, Bakker J, Riess H, Basson BR, Charpentier J, Utterback BG, Vincent JL; Recombinant Human Activated Protein C Worldwide Evaluation in Sepsis (PROWESS) Study Group. Source: Intensive Care Medicine. 2003 June; 29(6): 894-903. Epub 2003 April 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12712239
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Drotrecogin alfa (activated) treatment of older patients with severe sepsis. Author(s): Ely EW, Angus DC, Williams MD, Bates B, Qualy R, Bernard GR. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 July 15; 37(2): 187-95. Epub 2003 Jul 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12856210
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Drotrecogin alfa (activated): a novel therapeutic strategy for severe sepsis. Author(s): Pastores SM. Source: Postgraduate Medical Journal. 2003 January; 79(927): 5-10. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12566544
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Drotrecogin alfa (recombinant human activated protein C) for the treatment of severe sepsis. Author(s): McCoy C, Matthews SJ. Source: Clinical Therapeutics. 2003 February; 25(2): 396-421. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12749504
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Drotrecogin alfa (recombinant human activated protein C) in severe sepsis--a New Zealand viewpoint. Author(s): Liang J, Streat S, Torrance J, Sleigh J, Freebairn R, Ramsay M. Source: N Z Med J. 2003 September 12; 116(1181): U586. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14581969
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Duration of empiric antibiotics for suspected early-onset sepsis in extremely low birth weight infants. Author(s): Cordero L, Ayers LW. Source: Infection Control and Hospital Epidemiology : the Official Journal of the Society of Hospital Epidemiologists of America. 2003 September; 24(9): 662-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14510248
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Early enteral immunonutrition in patients with severe sepsis: results of an interim analysis of a randomized multicentre clinical trial. Author(s): Bertolini G, Iapichino G, Radrizzani D, Facchini R, Simini B, Bruzzone P, Zanforlin G, Tognoni G. Source: Intensive Care Medicine. 2003 May; 29(5): 834-40. Epub 2003 April 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12684745
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Early markers of late-onset sepsis in premature neonates: clinical, hematological and cytokine profile. Author(s): Gonzalez BE, Mercado CK, Johnson L, Brodsky NL, Bhandari V. Source: Journal of Perinatal Medicine. 2003; 31(1): 60-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12661146
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Echovirus 11 sepsis in a neonate: report of one case. Author(s): Hsiao CC, Tsao LY, Chen HN. Source: Acta Paediatr Taiwan. 2003 March-April; 44(2): 104-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12845853
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Ecthyma gangrenosum as a manifestation of Pseudomonas sepsis in a previously healthy child. Author(s): Mull CC, Scarfone RJ, Conway D. Source: Annals of Emergency Medicine. 2000 October; 36(4): 383-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11020689
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Effect of estradiol administration on splanchnic perfusion after trauma-hemorrhage and sepsis. Author(s): Yokoyama Y, Schwacha MG, Bland KI, Chaudry IH. Source: Current Opinion in Critical Care. 2003 April; 9(2): 137-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12657977
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Effect of polymyxin B immobilized fiber on encephalopathy in hemodialysis patients with sepsis. Author(s): Nakamura T, Ushiyama C, Suzuki S, Shoji H, Shimada N, Ebihara I, Koide H. Source: Renal Failure. 2000; 22(5): 653-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11041298
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Effect of polymyxin B-immobilized fiber hemoperfusion on sepsis-induced rhabdomyolysis with acute renal failure. Author(s): Nakamura T, Ushiyama C, Suzuki S, Shoji H, Shimada N, Sekizuka K, Ebihara I, Koide H. Source: Nephron. 2000 October; 86(2): 210. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11015003
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Effective immunomodulatory treatment of Escherichia coli experimental sepsis with thalidomide. Author(s): Giamarellos-Bourboulis EJ, Poulaki H, Kostomitsopoulos N, Dontas I, Perrea D, Karayannacos PE, Giamarellou H. Source: Antimicrobial Agents and Chemotherapy. 2003 August; 47(8): 2445-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12878503
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Effects of antenatal antibiotics on the incidence and bacteriological profile of earlyonset neonatal sepsis. A retrospective study over five years. Author(s): Laugel V, Kuhn P, Beladdale J, Donato L, Escande B, Astruc D, Messer J. Source: Biology of the Neonate. 2003; 84(1): 24-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12890932
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Effects of early excision and aggressive enteral feeding on hypermetabolism, catabolism, and sepsis after severe burn. Author(s): Hart DW, Wolf SE, Chinkes DL, Beauford RB, Mlcak RP, Heggers JP, Wolfe RR, Herndon DN. Source: The Journal of Trauma. 2003 April; 54(4): 755-61; Discussion 761-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12707540
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Effects of functional Toll-like receptor-4 mutations on the immune response to human and experimental sepsis. Author(s): Feterowski C, Emmanuilidis K, Miethke T, Gerauer K, Rump M, Ulm K, Holzmann B, Weighardt H. Source: Immunology. 2003 July; 109(3): 426-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12807489
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Effects of intrapartum antimicrobial prophylaxis for prevention of group-Bstreptococcal disease on the incidence and ecology of early-onset neonatal sepsis. Author(s): Moore MR, Schrag SJ, Schuchat A. Source: The Lancet Infectious Diseases. 2003 April; 3(4): 201-13. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679263
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Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. Author(s): Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, Beale R, Svoboda P, Laterre PF, Simon S, Light B, Spapen H, Stone J, Seibert A, Peckelsen C, De Deyne C, Postier R, Pettila V, Artigas A, Percell SR, Shu V, Zwingelstein C, Tobias J, Poole L, Stolzenbach JC, Creasey AA; OPTIMIST Trial Study Group. Source: Jama : the Journal of the American Medical Association. 2003 July 9; 290(2): 23847. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12851279
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Elevated nucleosome levels in systemic inflammation and sepsis. Author(s): Zeerleder S, Zwart B, Wuillemin WA, Aarden LA, Groeneveld AB, Caliezi C, van Nieuwenhuijze AE, van Mierlo GJ, Eerenberg AJ, Lammle B, Hack CE. Source: Critical Care Medicine. 2003 July; 31(7): 1947-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12847387
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Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Author(s): Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K. Source: Critical Care Medicine. 2003 September; 31(9): 2332-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14501964
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Esophageal erosion as a possible bacterial entry site in an acute lymphoblastic leukemia patient with sepsis. Author(s): Ikegaya S, Yoshida A, Iwasaki H, Naiki H, Ueda T. Source: International Journal of Hematology. 2003 May; 77(4): 395-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12774931
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Evaluation of different blood culture media in neonatal sepsis. Author(s): Lee CS, Tang RB, Chung RL, Chen SJ. Source: J Microbiol Immunol Infect. 2000 September; 33(3): 165-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11045379
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Exocrine pancreatic dysfunction in sepsis. Author(s): Tribl B, Sibbald WJ, Vogelsang H, Spitzauer S, Gangl A, Madl C. Source: European Journal of Clinical Investigation. 2003 March; 33(3): 239-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12641542
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Extracellular role of HMGB1 in inflammation and sepsis. Author(s): Wang H, Yang H, Tracey KJ. Source: Journal of Internal Medicine. 2004 March; 255(3): 320-31. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14871456
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Extracorporeal endotoxin removal for the treatment of sepsis: endotoxin adsorption cartridge (Toraymyxin). Author(s): Shoji H. Source: Therap Apher Dial. 2003 February; 7(1): 108-14. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12921125
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Familial isolated congenital asplenia: a rare, frequently hereditary dominant condition, often detected too late as a cause of overwhelming pneumococcal sepsis. Report of a new case and review of 31 others. Author(s): Gilbert B, Menetrey C, Belin V, Brosset P, de Lumley L, Fisher A. Source: European Journal of Pediatrics. 2002 July; 161(7): 368-72. Epub 2002 June 04. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12111187
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Fascial dehiscence after trauma laparotomy: a sign of intra-abdominal sepsis. Author(s): Tillou A, Weng J, Alkousakis T, Velmahos G. Source: The American Surgeon. 2003 November; 69(11): 927-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627249
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Fas-ligand mediated apoptosis in severe sepsis and shock. Author(s): Ayala A, Lomas JL, Grutkoski PS, Chung S. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(9): 593-600. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14620140
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Fatal Bacillus cereus sepsis following resolving neutropenic enterocolitis during the treatment of acute leukemia. Author(s): Ginsburg AS, Salazar LG, True LD, Disis ML. Source: American Journal of Hematology. 2003 March; 72(3): 204-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12605393
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Fatal case of inhalational anthrax mimicking intra-abdominal sepsis. Author(s): Quintiliani R Jr, Quintiliani R. Source: Conn Med. 2002 May; 66(5): 261-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12071107
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Fatal clostridial sepsis after spontaneous abortion. Author(s): Barrett JP, Whiteside JL, Boardman LA. Source: Obstetrics and Gynecology. 2002 May; 99(5 Pt 2): 899-901. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11975951
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Fatal Pasteurella sepsis and hairy-cell leukemia. Author(s): Athar MK, Karim MS, Mannam S, Ahmed M. Source: American Journal of Hematology. 2003 April; 72(4): 285. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12666145
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Fatal puerperal sepsis with necrotising fasciitis due to Streptococcus pneumoniae. Author(s): Clad A, Orlowska-Volk M, Karck U. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2003 February; 110(2): 213-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12618169
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Fatal sepsis after uterine artery embolization with microspheres. Author(s): de Blok S, de Vries C, Prinssen HM, Blaauwgeers HL, Jorna-Meijer LB. Source: Journal of Vascular and Interventional Radiology : Jvir. 2003 June; 14(6): 779-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12817046
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Fatal sepsis associated with acute pancreatitis caused by Moraxella catarrhalis in a child. Author(s): Ohkusu K, Nakamura A, Horie H, Udagawa A. Source: The Pediatric Infectious Disease Journal. 2001 September; 20(9): 914-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11734777
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Fatal sepsis due to mycobacterium tuberculosis after allogeneic bone marrow transplantation. Author(s): Kindler T, Schindel C, Brass U, Fischer T. Source: Bone Marrow Transplantation. 2001 January; 27(2): 217-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11281394
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Fatal sepsis in a patient with rheumatoid arthritis treated with etanercept. Author(s): Baghai M, Osmon DR, Wolk DM, Wold LE, Haidukewych GJ, Matteson EL. Source: Mayo Clinic Proceedings. 2001 June; 76(6): 653-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11393506
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Fatal sepsis in an AIDS patient during therapy for Pneumocystis carinii pneumonia. Author(s): Piso RJ, Rossi M, Oehler T, Nguyen XM, Tauber MG. Source: Infection. 2002 October; 30(5): 314-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12382094
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Finger sepsis in two poorly controlled diabetic patients with reuse of lancets. Author(s): Monami M, Mannucci E, Masotti G. Source: Diabetes Care. 2002 June; 25(6): 1103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12032130
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First sepsis drug nears market. Author(s): DeFrancesco L. Source: Nature Medicine. 2001 May; 7(5): 516-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11329033
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Flagellin from gram-negative bacteria is a potent mediator of acute pulmonary inflammation in sepsis. Author(s): Liaudet L, Szabo C, Evgenov OV, Murthy KG, Pacher P, Virag L, Mabley JG, Marton A, Soriano FG, Kirov MY, Bjertnaes LJ, Salzman AL. Source: Shock (Augusta, Ga.). 2003 February; 19(2): 131-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12578121
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Fluid therapy in sepsis with capillary leakage. Author(s): Marx G. Source: European Journal of Anaesthesiology. 2003 June; 20(6): 429-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12803259
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Fournier's gangrene: an unusual presentation of sepsis. Author(s): Rotondo N. Source: The Journal of Emergency Medicine. 2002 November; 23(4): 413-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12480026
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Frequency and timing of symptoms in infants screened for sepsis: effectiveness of a sepsis-screening pathway. Author(s): Madan A, Adams MM, Philip AG. Source: Clinical Pediatrics. 2003 January-February; 42(1): 11-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12635976
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From phenomenon to phenotype and from phenotype to gene: forward genetics and the problem of sepsis. Author(s): Beutler B, Du X, Hoebe K. Source: The Journal of Infectious Diseases. 2003 June 15; 187 Suppl 2: S321-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12792846
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Gastrointestinal disorders of the critically ill. Cholestasis of sepsis. Author(s): Gilroy RK, Mailliard ME, Gollan JL. Source: Best Practice & Research. Clinical Gastroenterology. 2003 June; 17(3): 357-67. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12763501
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Gender differences in sepsis: genetically determined? Author(s): Schroder J, Kahlke V, Book M, Stuber F. Source: Shock (Augusta, Ga.). 2000 September; 14(3): 307-10; Discussion 310-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11028548
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Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy. Author(s): Holmes CL, Russell JA, Walley KR. Source: Chest. 2003 September; 124(3): 1103-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12970043
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Genetic variation and risk of sepsis. Author(s): Kellum JA, Angus DC. Source: Minerva Anestesiol. 2003 April; 69(4): 245-53. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766715
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Genetics of sepsis and pneumonia. Author(s): Wunderink RG, Waterer GW. Source: Current Opinion in Critical Care. 2003 October; 9(5): 384-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14508151
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Genomic polymorphisms in sepsis. Author(s): Lin MT, Albertson TE. Source: Critical Care Medicine. 2004 February; 32(2): 569-79. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14758181
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Genotypic and phenotypic properties of coagulase-negative staphylococci causing dialysis catheter-related sepsis. Author(s): Spare MK, Tebbs SE, Lang S, Lambert PA, Worthington T, Lipkin GW, Elliott TS. Source: The Journal of Hospital Infection. 2003 August; 54(4): 272-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12919757
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Glucocorticoid insufficiency in patients who present to the hospital with severe sepsis: a prospective clinical trial. Author(s): Manglik S, Flores E, Lubarsky L, Fernandez F, Chhibber VL, Tayek JA. Source: Critical Care Medicine. 2003 June; 31(6): 1668-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12794402
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Glucose-insulin-potassium infusion in sepsis and septic shock: no hard evidence yet. Author(s): van der Horst IC, Ligtenberg JJ, Bilo HJ, Zijlstra F, Gans RO. Source: Critical Care (London, England). 2003 February; 7(1): 13-5. Epub 2002 October 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12617733
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Granulocyte colony-stimulating factor as the expecting sword for the treatment of severe sepsis. Author(s): Murata A. Source: Current Pharmaceutical Design. 2003; 9(14): 1115-20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12769751
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Granulocyte macrophage-colony stimulating factor augmentation therapy in sepsis: is there a role? Author(s): Trapnell BC. Source: American Journal of Respiratory and Critical Care Medicine. 2002 July 15; 166(2): 129-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12119219
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Green teeth associated with cholestasis caused by sepsis: a case report and review of the literature. Author(s): Guimaraes LP, Silva TA. Source: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 2003 April; 95(4): 446-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12686928
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Group A streptococcal hydrocele infection and sepsis in a renal transplant recipient. Author(s): Beiko DT, Watterson JD, Cook AJ, Denstedt JD. Source: Can J Urol. 2003 February; 10(1): 1768-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12625858
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Group A streptococcal sepsis secondary to peritonitis and acute pelvic inflammatory disease. Author(s): Borgia SM, Low DE, Andrighetti S, Rau NV. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2001 June; 20(6): 437-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11476452
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Group B streptococcal sepsis. Author(s): Gamble VR. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 2002 July-August; 22(5): 428-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12082484
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Group B streptococcus: prevention of early-onset neonatal sepsis. Author(s): Platt JS, O'Brien WF. Source: Obstetrical & Gynecological Survey. 2003 March; 58(3): 191-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12612459
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Growth stimulation of intestinal commensal Escherichia coli by catecholamines: a possible contributory factor in trauma-induced sepsis. Author(s): Freestone PP, Williams PH, Haigh RD, Maggs AF, Neal CP, Lyte M. Source: Shock (Augusta, Ga.). 2002 November; 18(5): 465-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12412628
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Guess what! Pseudomonas aeruginosa sepsis. Author(s): Bugatti L, Nicolini M, Filosa A, Filosa G. Source: European Journal of Dermatology : Ejd. 2002 May-June; 12(3): 291-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11978576
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Gut overgrowth with abnormal flora: the missing link in parenteral nutrition-related sepsis in surgical neonates. Author(s): van Saene HK, Taylor N, Donnell SC, Glynn J, Magnall VL, Okada Y, Klein NJ, Pierro A, Lloyd DA. Source: European Journal of Clinical Nutrition. 2003 April; 57(4): 548-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12700616
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Gut oxygenation in sepsis: still a matter of controversy? Author(s): Vallet B. Source: Critical Care (London, England). 2002 August; 6(4): 282-3. Epub 2002 May 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12225596
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Haematological findings in neonates with sepsis. Author(s): Manucha V, Rusia U, Sikka M, Faridi MM, Madan N. Source: Indian J Pathol Microbiol. 2001 January; 44(1): 73. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12562005
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Heart rate variability in emergency department patients with sepsis. Author(s): Barnaby D, Ferrick K, Kaplan DT, Shah S, Bijur P, Gallagher EJ. Source: Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. 2002 July; 9(7): 661-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12093705
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Hemoadsorption therapy for sepsis syndromes. Author(s): Kellum JA. Source: Critical Care Medicine. 2003 January; 31(1): 323-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12545045
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Hemodynamic instability in sepsis: bedside assessment by Doppler echocardiography. Author(s): Vieillard-Baron A, Prin S, Chergui K, Dubourg O, Jardin F. Source: American Journal of Respiratory and Critical Care Medicine. 2003 December 1; 168(11): 1270-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14644922
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Hemofiltration, adsorption, sieving and the challenge of sepsis therapy design. Author(s): Honore PM, Matson JR. Source: Critical Care (London, England). 2002 October; 6(5): 394-6. Epub 2002 September 04. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12398774
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Hepatocellular dysfunction induced by nitric oxide production in hepatocytes isolated from rats with sepsis. Author(s): Tu W, Satoi S, Zhang Z, Kitade H, Okumura T, Kwon AH, Kamiyama Y. Source: Shock (Augusta, Ga.). 2003 April; 19(4): 373-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12688550
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Herpes simplex virus esophagitis in an immunocompetent host with sepsis. Author(s): Pamuk ON, Pamuk GE, Celik AF, Ozturk R, Aktuglu Y. Source: The American Journal of Gastroenterology. 2001 July; 96(7): 2264-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11467669
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Herpes simplex virus-associated sepsis in a previously infected immunocompetent adult. Author(s): Zahariadis G, Jerome KR, Corey L. Source: Annals of Internal Medicine. 2003 July 15; 139(2): 153-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12859170
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High and low response in relation to nitric oxide formation but not to lipid peroxidation in patients with sepsis. Author(s): Schimke I, Richter N, Wauer H, Rohr U, Petersson AS, Wennmalm A, Kuppe H, Kox WJ. Source: Critical Care Medicine. 2003 January; 31(1): 65-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12544995
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High circulating levels of the IL-1 type II decoy receptor in critically ill patients with sepsis: association of high decoy receptor levels with glucocorticoid administration. Author(s): Muller B, Peri G, Doni A, Perruchoud AP, Landmann R, Pasqualini F, Mantovani A. Source: Journal of Leukocyte Biology. 2002 October; 72(4): 643-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12377932
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High-dose antithrombin therapy for sepsis: mechanisms of action. Author(s): Iba T, Kidokoro A. Source: Shock (Augusta, Ga.). 2002 November; 18(5): 389-94. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12412615
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Highly purified vitamin B2 presents a promising therapeutic strategy for sepsis and septic shock. Author(s): Toyosawa T, Suzuki M, Kodama K, Araki S. Source: Infection and Immunity. 2004 March; 72(3): 1820-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14977995
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High-molecular-weight polyethylene glycol prevents lethal sepsis due to intestinal Pseudomonas aeruginosa. Author(s): Wu L, Zaborina O, Zaborin A, Chang EB, Musch M, Holbrook C, Shapiro J, Turner JR, Wu G, Lee KY, Alverdy JC. Source: Gastroenterology. 2004 February; 126(2): 488-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14762786
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HMGB1 in sepsis. Author(s): Andersson U, Tracey KJ. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(9): 577-84. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14620138
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Human antibody response during sepsis against targets expressed by methicillin resistant Staphylococcus aureus. Author(s): Lorenz U, Ohlsen K, Karch H, Hecker M, Thiede A, Hacker J. Source: Fems Immunology and Medical Microbiology. 2000 October; 29(2): 145-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11024354
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Human leukocyte antigen-DR expression in peripheral blood mononuclear cells from healthy donors influenced by the sera of injured patients prone to severe sepsis. Author(s): Mueller A, Kreuzfelder E, Nyadu B, Lindemann M, Rebmannn V, Majetschak M, Obertacke U, Schade UF, Nast-Kolb D, Grosse-Wilde H. Source: Intensive Care Medicine. 2003 December; 29(12): 2285-90. Epub 2003 September 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12955176
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Human leukocyte antigen-DR expression on peripheral monocytes as a predictive marker of sepsis during acute pancreatitis. Author(s): Satoh A, Miura T, Satoh K, Masamune A, Yamagiwa T, Sakai Y, Shibuya K, Takeda K, Kaku M, Shimosegawa T. Source: Pancreas. 2002 October; 25(3): 245-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12370535
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Hypertonic saline resuscitation in sepsis. Author(s): Wade CE. Source: Critical Care (London, England). 2002 October; 6(5): 397-8. Epub 2002 August 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12398775
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Hypocholesterolemia in sepsis and critically ill or injured patients. Author(s): Wilson RF, Barletta JF, Tyburski JG. Source: Critical Care (London, England). 2003 December; 7(6): 413-4. Epub 2003 October 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624677
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Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis. Ibuprofen in Sepsis Study Group. Author(s): Mangialardi RJ, Martin GS, Bernard GR, Wheeler AP, Christman BW, Dupont WD, Higgins SB, Swindell BB. Source: Critical Care Medicine. 2000 September; 28(9): 3137-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11008971
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IL-10 polymorphism is associated with increased incidence of severe sepsis. Author(s): Shu Q, Fang X, Chen Q, Stuber F. Source: Chinese Medical Journal. 2003 November; 116(11): 1756-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14642153
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IL-18 promoter polymorphisms correlate with the development of post-injury sepsis. Author(s): Stassen NA, Breit CM, Norfleet LA, Polk HC Jr. Source: Surgery. 2003 August; 134(2): 351-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12947340
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Immature granulocyte measurement using the Sysmex XE-2100. Relationship to infection and sepsis. Author(s): Ansari-Lari MA, Kickler TS, Borowitz MJ. Source: American Journal of Clinical Pathology. 2003 November; 120(5): 795-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14608908
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Immunohistochemical detection of sepsis-induced lung injury in human autopsy material. Author(s): Tsokos M. Source: Legal Medicine (Tokyo, Japan). 2003 June; 5(2): 73-86. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12935535
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Immunonutrition: increased mortality is associated with immunonutrition in sepsis. Author(s): Knight DJ. Source: Bmj (Clinical Research Ed.). 2003 September 20; 327(7416): 682-3; Author Reply 683. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14510000
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Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Author(s): Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, JimenezJimenez FJ, Perez-Paredes C, Ortiz-Leyba C. Source: Critical Care Medicine. 2003 December; 31(12): 2742-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14668610
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Impact of antibiotic resistance on the treatment of sepsis. Author(s): Turnidge J. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(9): 677-82. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14620154
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Impact of intrapartum chemoprophylaxis on neonatal sepsis. Author(s): Schuchat A. Source: The Pediatric Infectious Disease Journal. 2003 December; 22(12): 1087-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14688571
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Impaired energy metabolism during neonatal sepsis: the effects of glutamine. Author(s): Eaton S. Source: The Proceedings of the Nutrition Society. 2003 August; 62(3): 745-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14692610
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Improving survival for sepsis: on the cutting edge. Author(s): Rello J, Rodriguez A. Source: Critical Care Medicine. 2003 December; 31(12): 2807-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14668621
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Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Author(s): Harbarth S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D. Source: The American Journal of Medicine. 2003 November; 115(7): 529-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14599631
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Influence of acute hyperglycemia in human sepsis on inflammatory cytokine and counterregulatory hormone concentrations. Author(s): Yu WK, Li WQ, Li N, Li JS. Source: World Journal of Gastroenterology : Wjg. 2003 August; 9(8): 1824-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12918129
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Injury, sepsis, and the regulation of Toll-like receptor responses. Author(s): Murphy TJ, Paterson HM, Mannick JA, Lederer JA. Source: Journal of Leukocyte Biology. 2004 March; 75(3): 400-7. Epub 2003 October 13. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14557385
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Inter-alpha inhibitor proteins in infants and decreased levels in neonatal sepsis. Author(s): Baek YW, Brokat S, Padbury JF, Pinar H, Hixson DC, Lim YP. Source: The Journal of Pediatrics. 2003 July; 143(1): 11-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12915817
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Interpreting the mechanisms of continuous renal replacement therapy in sepsis: the peak concentration hypothesis. Author(s): Ronco C, Tetta C, Mariano F, Wratten ML, Bonello M, Bordoni V, Cardona X, Inguaggiato P, Pilotto L, d'Intini V, Bellomo R. Source: Artificial Organs. 2003 September; 27(9): 792-801. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12940901
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Intraabdominal sepsis: newer interventional and antimicrobial therapies for infected necrotizing pancreatitis. Author(s): Solomkin JS, Umanskiy K. Source: Current Opinion in Critical Care. 2003 October; 9(5): 424-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14508156
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Intrathecal baclofen withdrawal mimicking sepsis. Author(s): Kao LW, Amin Y, Kirk MA, Turner MS. Source: The Journal of Emergency Medicine. 2003 May; 24(4): 423-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12745045
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Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative bacilli in critically ill patients. Author(s): Markou N, Apostolakos H, Koumoudiou C, Athanasiou M, Koutsoukou A, Alamanos I, Gregorakos L. Source: Critical Care (London, England). 2003 October; 7(5): R78-83. Epub 2003 July 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12974973
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Intravenous immunoglobulin adjunctive therapy in sepsis, with special emphasis on severe invasive group A streptococcal infections. Author(s): Norrby-Teglund A, Ihendyane N, Darenberg J. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(9): 683-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14620155
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Intravenous lines-related sepsis in newborn babies admitted to NICU in a developing country. Author(s): Bakr AF. Source: Journal of Tropical Pediatrics. 2003 October; 49(5): 295-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14604163
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Jaks, STATs, Cytokines, and Sepsis. Author(s): Scott MJ, Godshall CJ, Cheadle WG. Source: Clinical and Diagnostic Laboratory Immunology. 2002 November; 9(6): 1153-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12414743
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Karyotyping of Candida albicans and Candida glabrata from patients with Candida sepsis. Author(s): Klempp-Selb B, Rimek D, Kappe R. Source: Mycoses. 2000; 43(5): 159-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10948811
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Keep in contact: the role of the contact system in infection and sepsis. Author(s): Levi M. Source: Critical Care Medicine. 2000 November; 28(11): 3765-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11098995
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Late-onset neonatal sepsis due to Hafnia alvei. Author(s): Casanova-Roman M, Sanchez-Porto A, Casanova-Bellido M. Source: Scandinavian Journal of Infectious Diseases. 2004; 36(1): 70-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15000567
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Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Author(s): Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, Lemons JA, Donovan EF, Stark AR, Tyson JE, Oh W, Bauer CR, Korones SB, Shankaran S, Laptook AR, Stevenson DK, Papile LA, Poole WK. Source: Pediatrics. 2002 August; 110(2 Pt 1): 285-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12165580
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Lemierre's syndrome: an unusual cause of sepsis and abdominal pain. Author(s): Hoehn S, Dominguez TE. Source: Critical Care Medicine. 2002 July; 30(7): 1644-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12130992
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Lemierre's syndrome: the forgotten disease. An unusual presentation of sepsis. Author(s): Ritter M, Tebbe J, Battmann A, Gorg C. Source: Ultraschall in Der Medizin (Stuttgart, Germany : 1980). 2004 February; 25(1): 703. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14961428
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Lethal fulminate S. aureus sepsis in M. Behcet overnight cold exposure. Author(s): Finsterer J, Schmidbauer M. Source: Acta Medica Austriaca. 2002; 29(4): 143-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12424941
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Leukocytosis after posttraumatic splenectomy: a physiologic event or sign of sepsis? Author(s): Toutouzas KG, Velmahos GC, Kaminski A, Chan L, Demetriades D. Source: Archives of Surgery (Chicago, Ill. : 1960). 2002 August; 137(8): 924-8; Discussion 928-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12146991
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Lipid unites disparate syndromes of sepsis. Author(s): Wang H, Czura CJ, Tracey KJ. Source: Nature Medicine. 2004 February; 10(2): 124-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14760415
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Lipopolysaccharide-binding protein serum levels in patients with severe sepsis due to gram-positive and fungal infections. Author(s): Blairon L, Wittebole X, Laterre PF. Source: The Journal of Infectious Diseases. 2003 January 15; 187(2): 287-91. Epub 2002 December 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12552453
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Lipoprotein metabolism in patients with severe sepsis. Author(s): van Leeuwen HJ, Heezius EC, Dallinga GM, van Strijp JA, Verhoef J, van Kessel KP. Source: Critical Care Medicine. 2003 May; 31(5): 1359-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12771603
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Listeria monocytogenes sepsis in patients treated with anti-tumor necrosis factoralpha. Author(s): Tweezer-Zaks N, Shiloach E, Spivak A, Rapoport M, Novis B, Langevitz P. Source: Isr Med Assoc J. 2003 November; 5(11): 829-30. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14650115
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Liver in sepsis and systemic inflammatory response syndrome. Author(s): Szabo G, Romics L Jr, Frendl G. Source: Clinics in Liver Disease. 2002 November; 6(4): 1045-66, X. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12516206
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Long-term mortality and medical care charges in patients with severe sepsis. Author(s): Weycker D, Akhras KS, Edelsberg J, Angus DC, Oster G. Source: Critical Care Medicine. 2003 September; 31(9): 2316-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14501962
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Low-dose heparin for severe sepsis. Author(s): Freebairn R, Ramsay S, Gomersall C. Source: The New England Journal of Medicine. 2003 March 20; 348(12): 1185-6; Author Reply 1185-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12646683
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Low-dose heparin for severe sepsis. Author(s): Davidson BL, Geerts WH, Lensing AW. Source: The New England Journal of Medicine. 2002 September 26; 347(13): 1036-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12324565
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Lps2 and signal transduction in sepsis: at the intersection of host responses to bacteria and viruses. Author(s): Beutler B, Hoebe K, Du X, Janssen E, Georgel P, Tabeta K. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(9): 563-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14620135
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Lymphocyte subset numbers depend on the bacterial origin of sepsis. Author(s): Holub M, Kluckova Z, Helcl M, Prihodov J, Rokyta R, Beran O. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2003 March; 9(3): 202-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12667252
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Management of severe sepsis: integration of multiple pharmacologic interventions. Author(s): Micek ST, Shah RA, Kollef MH. Source: Pharmacotherapy. 2003 November; 23(11): 1486-96. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14620394
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Managing patients with sepsis in the general ward environment. Author(s): Nassau J. Source: Prof Nurse. 2003 July; 18(11): 618-20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12861813
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Mcl-1 correlates with reduced apoptosis in neutrophils from patients with sepsis. Author(s): Harter L, Mica L, Stocker R, Trentz O, Keel M. Source: Journal of the American College of Surgeons. 2003 December; 197(6): 964-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14644285
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Measures, markers, and mediators: toward a staging system for clinical sepsis. A report of the Fifth Toronto Sepsis Roundtable, Toronto, Ontario, Canada, October 2526, 2000. Author(s): Marshall JC, Vincent JL, Fink MP, Cook DJ, Rubenfeld G, Foster D, Fisher CJ Jr, Faist E, Reinhart K. Source: Critical Care Medicine. 2003 May; 31(5): 1560-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12771633
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Mediator modulation therapy of severe sepsis and septic shock: does it work? Author(s): Phillip Dellinger R, Parrillo JE. Source: Critical Care Medicine. 2004 January; 32(1): 282-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14707593
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Meeting unmet needs in patients with sepsis: the role of drotrecogin alfa (activated). Author(s): McEvoy M. Source: American Journal of Critical Care : an Official Publication, American Association of Critical-Care Nurses. 2003 September; 12(5): 398; Author Reply 398. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503421
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Metabolic alterations in sepsis and vasoactive drug-related metabolic effects. Author(s): Trager K, DeBacker D, Radermacher P. Source: Current Opinion in Critical Care. 2003 August; 9(4): 271-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883281
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Molecular basis of endothelial dysfunction in sepsis. Author(s): Peters K, Unger RE, Brunner J, Kirkpatrick CJ. Source: Cardiovascular Research. 2003 October 15; 60(1): 49-57. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14522406
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Molecular comparison of bacterial isolates from blood with strains colonizing pharynx and intestine in immunocompromised patients with sepsis. Author(s): Murono K, Hirano Y, Koyano S, Ito K, Fujieda K. Source: Journal of Medical Microbiology. 2003 June; 52(Pt 6): 527-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12748274
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Molecular epidemiology of coagulase-negative staphylococci causing sepsis in a neonatal intensive care unit over an 11-year period. Author(s): Krediet TG, Mascini EM, van Rooij E, Vlooswijk J, Paauw A, Gerards LJ, Fleer A. Source: Journal of Clinical Microbiology. 2004 March; 42(3): 992-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15004043
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Neonatal sepsis and meningitis in Haiti. Author(s): Desinor OY, Silva JL, Menos MJ. Source: Journal of Tropical Pediatrics. 2004 February; 50(1): 48-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14984170
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Neonatal sepsis caused by Streptococcus bovis variant (biotype II/2): report of a case and review. Author(s): Gavin PJ, Thomson RB Jr, Horng SJ, Yogev R. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 3433-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12843113
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Neonatal sepsis in hospital-born babies: bacterial isolates and antibiotic susceptibility patterns. Author(s): Aurangzeb B, Hameed A. Source: J Coll Physicians Surg Pak. 2003 November; 13(11): 629-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14700488
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New approaches to the treatment of sepsis. Author(s): O'Brien JM Jr, Abraham E. Source: Clinics in Chest Medicine. 2003 December; 24(4): 521-48, V. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14710689
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New mode of intervention in sepsis treatment. Author(s): Foubister V. Source: Drug Discovery Today. 2003 July 15; 8(14): 610-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12867140
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New treatment strategies for severe sepsis and septic shock. Author(s): Patel GP, Gurka DP, Balk RA. Source: Current Opinion in Critical Care. 2003 October; 9(5): 390-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14508152
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Novel strategies for the treatment of sepsis. Author(s): Riedemann NC, Guo RF, Ward PA. Source: Nature Medicine. 2003 May; 9(5): 517-24. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12724763
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Nuclear factor-kappaB: is it a therapeutic target for the adjuvant treatment of sepsis? Author(s): Fink MP. Source: Critical Care Medicine. 2003 September; 31(9): 2400-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14501975
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Nuclear fallout in sepsis. Author(s): Alston TA. Source: Critical Care Medicine. 2003 July; 31(7): 2076-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12847409
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Nutritional support in sepsis and multiple organ failure. Author(s): Nitenberg G. Source: Nestle Nutr Workshop Ser Clin Perform Programme. 2003; (8): 223-40; Discussion 240-4. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12968457
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Of mice and men (and rats): implications of species and stimulus differences for the interpretation of studies of nitric oxide in sepsis. Author(s): Reade MC, Young JD. Source: British Journal of Anaesthesia. 2003 February; 90(2): 115-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12538363
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On the mechanism of the reduction in the ECG QRS amplitudes in patients with sepsis. Author(s): Madias JE, Bazaz R. Source: Cardiology. 2003; 99(3): 166-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12824725
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Only activated protein C treatment and not protein C has demonstrated an improvement in survival in severe sepsis. Author(s): Yan SB, Dhainaut JF, Schwarz HP, Ehrlich HJ. Source: Critical Care Medicine. 2004 February; 32(2): 618; Author Reply 618-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14758203
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Open abdomen management of intra-abdominal sepsis. Author(s): Adkins AL, Robbins J, Villalba M, Bendick P, Shanley CJ. Source: The American Surgeon. 2004 February; 70(2): 137-40; Discussion 140. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15011916
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Opening the microcirculation: can vasodilators be useful in sepsis? Author(s): Buwalda M, Ince C. Source: Intensive Care Medicine. 2002 September; 28(9): 1208-17. Epub 2002 July 27. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12209267
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Optimal antimicrobial therapy for sepsis. Author(s): Fish DN. Source: American Journal of Health-System Pharmacy : Ajhp : Official Journal of the American Society of Health-System Pharmacists. 2002 February 15; 59 Suppl 1: S13-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11885408
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Outbreak of nosocomial sepsis and pneumonia in a newborn intensive care unit by multiresistant extended-spectrum beta-lactamase-producing Klebsiella pneumoniae: high impact on mortality. Author(s): Martinez-Aguilar G, Alpuche-Aranda CM, Anaya C, Alcantar-Curiel D, Gayosso C, Daza C, Mijares C, Tinoco JC, Santos JI. Source: Infection Control and Hospital Epidemiology : the Official Journal of the Society of Hospital Epidemiologists of America. 2001 November; 22(11): 725-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11842997
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Overexpression of the high-affinity Fcgamma receptor (CD64) is associated with leukocyte dysfunction in sepsis. Author(s): Hirsh M, Mahamid E, Bashenko Y, Hirsh I, Krausz MM. Source: Shock (Augusta, Ga.). 2001 August; 16(2): 102-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11508860
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Oxidative stress and gene expression in sepsis. Author(s): Macdonald J, Galley HF, Webster NR. Source: British Journal of Anaesthesia. 2003 February; 90(2): 221-32. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12538380
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Oxidized lipid protects against sepsis. Author(s): Riedemann NC, Ward PA. Source: Nature Medicine. 2002 October; 8(10): 1084-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12357242
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Peptidoglycan is an important pathogenic factor of the inflammatory response in sepsis. Author(s): Zingarelli B. Source: Critical Care Medicine. 2004 February; 32(2): 613-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14758200
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Peroxisome proliferator-activated receptor-gamma ligands: a pluripotent class of pharmacological agents that may prove to be useful for adjuvant treatment of sepsis and multiple organ dysfunction syndrome. Author(s): Fink MP. Source: Critical Care Medicine. 2004 February; 32(2): 604-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14758194
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Pharmacologic treatment of acute renal failure in sepsis. Author(s): De Vriese AS, Bourgeois M. Source: Current Opinion in Critical Care. 2003 December; 9(6): 474-80. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14639066
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Platelet count and sepsis in very low birth weight neonates: is there an organismspecific response? Author(s): Guida JD, Kunig AM, Leef KH, McKenzie SE, Paul DA. Source: Pediatrics. 2003 June; 111(6 Pt 1): 1411-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12777561
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Pneumococcal surface protein A is expressed in vivo, and antibodies to PspA are effective for therapy in a murine model of pneumococcal sepsis. Author(s): Swiatlo E, King J, Nabors GS, Mathews B, Briles DE. Source: Infection and Immunity. 2003 December; 71(12): 7149-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638806
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Prevention of early-onset GBS sepsis: evaluation of a changing paradigm. Author(s): Brozanski BS. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 2003 June; 23(4): 263-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12774130
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Procalcitonin as a diagnostic and prognostic biomarker of sepsis in critically ill children. Author(s): Leclerc F, Cremer R, Noizet O. Source: Pediatric Critical Care Medicine : a Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2003 April; 4(2): 264-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12749670
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Procalcitonin in pediatric burn patients: an early indicator of sepsis? Author(s): Neely AN, Fowler LA, Kagan RJ, Warden GD. Source: The Journal of Burn Care & Rehabilitation. 2004 January-February; 25(1): 76-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14726743
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Progress in clinical neurosciences: sepsis-associated encephalopathy: evolving concepts. Author(s): Wilson JX, Young GB. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2003 May; 30(2): 98-105. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12774948
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Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing? Author(s): Netea MG, van der Meer JW, van Deuren M, Kullberg BJ. Source: Trends in Immunology. 2003 May; 24(5): 254-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12738419
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Quantification of antithrombin isoform proportions in plasma samples of healthy subjects, sepsis patients, and in antithrombin concentrates. Author(s): Romisch J, Donges R, Stauss H, Inthorn D, Muhlbayer D, Jochum M, Hoffmann JN. Source: Pathophysiology of Haemostasis and Thrombosis. 2002 May-June; 32(3): 143-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12372930
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Recent developments in the identification of novel therapeutic targets for the treatment of patients with sepsis and septic shock. Author(s): Cohen J. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(9): 690-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14620156
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Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebocontrolled, clinical trial. Author(s): Opal S, Laterre PF, Abraham E, Francois B, Wittebole X, Lowry S, Dhainaut JF, Warren B, Dugernier T, Lopez A, Sanchez M, Demeyer I, Jauregui L, Lorente JA, McGee W, Reinhart K, Kljucar S, Souza S, Pribble J; Controlled Mortality Trial of Platelet-Activating Factor Acetylhydrolase in Severe Sepsis Investigators. Source: Critical Care Medicine. 2004 February; 32(2): 332-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14758145
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Reducing mortality in sepsis: new directions. Author(s): Vincent JL, Abraham E, Annane D, Bernard G, Rivers E, Van den Berghe G. Source: Critical Care (London, England). 2002 December; 6 Suppl 3: S1-18. Epub 2002 December 05. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12720570
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Relationship of pulmonary artery catheter use to mortality and resource utilization in patients with severe sepsis. Author(s): Yu DT, Platt R, Lanken PN, Black E, Sands KE, Schwartz JS, Hibberd PL, Graman PS, Kahn KL, Snydman DR, Parsonnet J, Moore R, Bates DW; AMCC Sepsis Project Working Group. Source: Critical Care Medicine. 2003 December; 31(12): 2734-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14668609
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Re-operation for complicated secondary peritonitis - how to identify patients at risk for persistent sepsis. Author(s): Holzheimer RG, Gathof B. Source: European Journal of Medical Research. 2003 March 27; 8(3): 125-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12730034
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Repair of an abdominal wall defect after a salvage laparotomy for sepsis. Author(s): Hirsch EF. Source: Journal of the American College of Surgeons. 2004 February; 198(2): 324-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14759790
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Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Author(s): Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, Susarla SM, Ulloa L, Wang H, DiRaimo R, Czura CJ, Wang H, Roth J, Warren HS, Fink MP, Fenton MJ, Andersson U, Tracey KJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 2004 January 6; 101(1): 296-301. Epub 2003 December 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14695889
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Ringer's ethyl pyruvate solution: a novel resuscitation fluid for the treatment of hemorrhagic shock and sepsis. Author(s): Fink MP. Source: The Journal of Trauma. 2003 May; 54(5 Suppl): S141-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12768116
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Role of activated protein C in the pathophysiology of severe sepsis. Author(s): Dettenmeier P, Swindell B, Stroud M, Arkins N, Howard A. Source: American Journal of Critical Care : an Official Publication, American Association of Critical-Care Nurses. 2003 November; 12(6): 518-24; Quiz 525-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14619357
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Role of apoptotic cell death in sepsis. Author(s): Hotchkiss RS, Tinsley KW, Karl IE. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(9): 585-92. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14620139
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Safety and efficacy of molgramostim as an adjunctive therapy in critically ill patients with severe sepsis. Author(s): Myrianthefs PM, Karabatsos EG, Karatzas SP, Boutzouka EG, Venetsanou KF, Evagelopoulou PL, Fildissis GA, Legakis NJ, Baltopoulos GJ. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(3): 175-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12751712
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Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis. Author(s): Bernard GR, Macias WL, Joyce DE, Williams MD, Bailey J, Vincent JL. Source: Critical Care (London, England). 2003 April; 7(2): 155-63. Epub 2003 February 28. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12720562
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Science review: role of coagulation protease cascades in sepsis. Author(s): Riewald M, Ruf W. Source: Critical Care (London, England). 2003 April; 7(2): 123-9. Epub 2002 October 01. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12720558
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Sepsis and neurology. Author(s): Chakravarty A, Chatterjee SK. Source: J Assoc Physicians India. 2003 April; 51: 385-90. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12723655
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Sepsis clinical knowledge: a role of steroid treatment. Author(s): Annane D. Source: Minerva Anestesiol. 2003 April; 69(4): 254-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766716
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Sepsis, multiple organ failure, and death due to Pandoraea pnomenusa infection after lung transplantation. Author(s): Stryjewski ME, LiPuma JJ, Messier RH Jr, Reller LB, Alexander BD. Source: Journal of Clinical Microbiology. 2003 May; 41(5): 2255-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12734295
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Sepsis, related terms cause confusion for coders. Author(s): Prophet-Bowman S. Source: J Ahima. 2003 May; 74(5): 81-3. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12747157
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Serum procalcitonin in children with suspected sepsis: a comparison with C-reactive protein and neutrophil count. Author(s): Casado-Flores J, Blanco-Quiros A, Asensio J, Arranz E, Garrote JA, Nieto M. Source: Pediatric Critical Care Medicine : a Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2003 April; 4(2): 190-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12749651
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Should we treat severe sepsis with activated protein C? Author(s): Mackillop A. Source: Hosp Med. 2003 May; 64(5): 316. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12789748
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Such stuff as dreams are made on: mediator-directed therapy in sepsis. Author(s): Marshall JC. Source: Nature Reviews. Drug Discovery. 2003 May; 2(5): 391-405. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12750742
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The dark side of C5a in sepsis. Author(s): Ward PA. Source: Nature Reviews. Immunology. 2004 February; 4(2): 133-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15040586
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The lived experience of nurses caring for newborns with sepsis. Author(s): Rubarth LB. Source: Journal of Obstetric, Gynecologic, and Neonatal Nursing : Jognn / Naacog. 2003 May-June; 32(3): 348-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12774877
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The problems and challenges of immunotherapy in sepsis. Author(s): Nasraway SA. Source: Chest. 2003 May; 123(5 Suppl): 451S-9S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12740228
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The puzzle of sepsis: fitting the pieces of the inflammatory response with treatment. Author(s): Cunneen J, Cartwright M. Source: Aacn Clinical Issues. 2004 January-March; 15(1): 18-44. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14767363
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The risk factors and time course of sepsis and organ dysfunction after burn trauma. Author(s): Fitzwater J, Purdue GF, Hunt JL, O'Keefe GE. Source: The Journal of Trauma. 2003 May; 54(5): 959-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12777910
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The role of extracorporeal therapies in sepsis. Author(s): Ronco C, Inguaggiato P, D'Intini V, Cole L, Bellomo R, Poulin S, Bordoni V, Crepaldi C, Gastaldon F, Brendolan A, Trairak P, Khajohn T. Source: Journal of Nephrology. 2003 November-December; 16 Suppl 7: S34-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14733299
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Therapeutic benefits of antioxidants during sepsis: is protection against oxidantmediated tissue damage only half the story? Author(s): Crouser ED. Source: Critical Care Medicine. 2004 February; 32(2): 589-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14758185
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Toxic shock syndrome due to Staphylococcus aureus sepsis following diagnostic laparotomy for Hodgkin's disease. Author(s): Goksugur N, Ozaras R, Tahan V, Mert A, Soysal T, Aydemir E, Tabak F. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 2003 November; 17(6): 732-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14761154
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Treatment of severe sepsis with Xigris: implications for the clinical nurse specialist. Author(s): Powers J, Jacobi J. Source: Clinical Nurse Specialist Cns. 2003 May; 17(3): 128-30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12792186
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Treatment with recombinant human activated protein C obviates additional anticoagulation during continuous venovenous hemofiltration in patients with severe sepsis. Author(s): de Pont AC, Bouman CS, de Jonge E, Vroom MB, Buller HR, Levi M. Source: Intensive Care Medicine. 2003 July; 29(7): 1205. Epub 2003 May 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12761613
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Unraveling severe sepsis: why did OPTIMIST fail and what's next? Author(s): Angus DC, Crowther MA. Source: Jama : the Journal of the American Medical Association. 2003 July 9; 290(2): 2568. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12851282
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Urinary diversion in infants with primary high-grade vesicoureteric reflux, urinary sepsis and renal function impairment. Author(s): Mattioli G, Buffa P, Torre M, Carlini C, Pini Prato A, Castagnetti M, Betti E, Manzara A, Piaggio G, Perfumo F, Jasonni V. Source: Urologia Internationalis. 2003; 71(3): 275-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14512648
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Use of antibiotic-loaded polymethyl methacrylate beads in the management of musculoskeletal sepsis--a retrospective study. Author(s): Mohanty SP, Kumar MN, Murthy NS. Source: Journal of Orthopaedic Surgery (Hong Kong). 2003 June; 11(1): 73-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12810976
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Use of drotrecogin alfa (activated) in two patients with severe sepsis. Author(s): Mikaszewska-Sokolewicz M, Nierebinska M, Mayzner-Zawadzka E. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 August; 9(8): Cs80-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12942037
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Use of prostacyclin in the treatment of sepsis-induced organ failure. Author(s): Imperatore F, Borrelli LM, Liguori G, Marsilia PF, Munciello F, Occhiochiuso L. Source: Medgenmed [electronic Resource] : Medscape General Medicine. 2003 July 31; 5(3): 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14600652
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Use of quantitative and semiquantitative procalcitonin measurements to identify children with sepsis and meningitis. Author(s): Prat C, Dominguez J, Rodrigo C, Gimenez M, Azuara M, Blanco S, Ausina V. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2004 February; 23(2): 1368. Epub 2003 December 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14689316
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Use of transcriptome data to unravel the fine structure of genes involved in sepsis. Author(s): Stevenson BJ, Iseli C, Beutler B, Jongeneel CV. Source: The Journal of Infectious Diseases. 2003 June 15; 187 Suppl 2: S308-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12792844
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Utility of activated partial thromboplastin time waveform analysis for identification of sepsis and overt disseminated intravascular coagulation in patients admitted to a surgical intensive care unit. Author(s): Dempfle CE, Lorenz S, Smolinski M, Wurst M, West S, Houdijk WP, Quintel M, Borggrefe M. Source: Critical Care Medicine. 2004 February; 32(2): 520-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14758173
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Utility of complete blood count and blood culture screening to diagnose neonatal sepsis in the asymptomatic at risk newborn. Author(s): Ottolini MC, Lundgren K, Mirkinson LJ, Cason S, Ottolini MG. Source: The Pediatric Infectious Disease Journal. 2003 May; 22(5): 430-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12792384
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Utility of sepsis evaluation in infants 90 days of age or younger with fever and clinical bronchiolitis. Author(s): Melendez E, Harper MB. Source: The Pediatric Infectious Disease Journal. 2003 December; 22(12): 1053-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14688564
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Variability of splanchnic blood flow in patients with sepsis. Author(s): Sakka SG, Reinhart K, Wegscheider K, Meier-Hellmann A. Source: Intensive Care Medicine. 2001 August; 27(8): 1281-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11511940
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Variability of splanchnic blood flow measurements in patients with sepsis-physiology, pathophysiology or measurement errors? Author(s): Jakob SM, Takala J. Source: Intensive Care Medicine. 2001 November; 27(11): 1692-5. Epub 2001 October 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11810111
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Variation in sepsis care: a wake-up call. Author(s): Hartman ME, Angus DC. Source: Critical Care (London, England). 2003 June; 7(3): 211-3. Epub 2003 May 01. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12793867
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Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Author(s): Aird WC. Source: Critical Care Medicine. 2001 July; 29(7 Suppl): S28-34; Discussion S34-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11445731
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Vena caval filter use in patients with sepsis: results in 175 patients. Author(s): Greenfield LJ, Proctor MC. Source: Archives of Surgery (Chicago, Ill. : 1960). 2003 November; 138(11): 1245-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14609875
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Venous gangrene of lower extremities and Staphylococcus aureus sepsis. Author(s): Ibrahim H, Krouskop R, Jeroudi M, McCulloch C, Parupia H, Dhanireddy R. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 2001 March; 21(2): 136-40. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11324361
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Vibrio vulnificus sepsis. Author(s): Pressly KB, Quattlebaum LS. Source: Critical Care Nurse. 2000 October; 20(5): 78-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11878490
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Viridans streptococcal sepsis: clinical features and complications in childhood acute myeloid leukemia. Author(s): Okamoto Y, Ribeiro RC, Srivastava DK, Shenep JL, Pui CH, Razzouk BI. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 September; 25(9): 696-703. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12972804
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Virulence factors of Escherichia coli isolated from female reproductive tract infections and neonatal sepsis. Author(s): Cook SW, Hammill HA, Hull RA. Source: Infectious Diseases in Obstetrics and Gynecology. 2001; 9(4): 203-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11916176
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Volume expansion using pentastarch does not change gastric-arterial CO2 gradient or gastric intramucosal pH in patients who have sepsis syndrome. Author(s): Forrest DM, Baigorri F, Chittock DR, Spinelli JJ, Russell JA. Source: Critical Care Medicine. 2000 July; 28(7): 2254-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10921549
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Waterhouse-Friderichsen syndrome and bilateral renal cortical necrosis in meningococcal sepsis. Author(s): Agraharkar M, Fahlen M, Siddiqui M, Rajaraman S. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2000 August; 36(2): 396-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10922319
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Weaning from mechanical ventilation by long-term nasal positive pressure ventilation in two patients with acute respiratory distress syndrome associated with pneumococcal sepsis. Author(s): Windisch W, Storre JH, Matthys H, Sorichter S, Virchow JC Jr. Source: Respiration; International Review of Thoracic Diseases. 2002; 69(5): 464-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12232458
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What are the microbial components implicated in the pathogenesis of sepsis? Report on a symposium. Author(s): Horn DL, Morrison DC, Opal SM, Silverstein R, Visvanathan K, Zabriskie JB. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2000 October; 31(4): 851-8. Epub 2000 October 11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11049761
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What is sepsis, and why is it life threatening? Author(s): Rosen DS. Source: Health News. 2001 April; 7(4): 10. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11303476
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What's your assessment? Streptococcal sepsis. Author(s): Bielan B. Source: Dermatology Nursing / Dermatology Nurses' Association. 1999 February; 11(1): 48, 51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10670325
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When sepsis is only an appearance. Author(s): Cloutier RL. Source: Pediatric Annals. 2001 October; 30(10): 626-32. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11641856
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Which infants need lumbar puncture for suspected sepsis? Author(s): Wilhelm S, Kelsberg G, Safranek S. Source: The Journal of Family Practice. 2003 October; 52(10): 806-8; Discussion 808. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14529609
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Whole blood platelet deposition on extracellular matrix under flow conditions in preterm neonatal sepsis. Author(s): Finkelstein Y, Shenkman B, Sirota L, Vishne TH, Dardik R, Varon D, Linder N. Source: European Journal of Pediatrics. 2002 May; 161(5): 270-4. Epub 2002 March 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12012223
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Xigris: reducing mortality in adult patients with severe sepsis. Author(s): Larson AM. Source: Urologic Nursing : Official Journal of the American Urological Association Allied. 2002 June; 22(3): 200-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12087796
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Yersinia enterocolitica sepsis in an adolescent with Cooley's anemia. Author(s): Chiu S, Huang YC, Su LH, Lin TY. Source: J Formos Med Assoc. 2003 March; 102(3): 202-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12783140
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CHAPTER 2. NUTRITION AND SEPSIS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and sepsis.
Finding Nutrition Studies on Sepsis 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 “sepsis” (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 information is typical of that found when using the “Full IBIDS Database” to search for “sepsis” (or a synonym): •
Anti-TNF therapies in rheumatoid arthritis, Crohn's disease, sepsis, and myelodysplastic syndromes. Author(s): Rush Cancer Institute, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612-3515,
[email protected] Source: Raza, A Microsc-Res-Tech. 2000 August 1; 50(3): 229-35 1059-910X
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Clinically-oriented therapies in sepsis: a review. Author(s): Department of Intensive Care, Erasme Hospital, Free University of Brussels, Belgium. Source: Dubois, M J Vincent, J L J-Endotoxin-Res. 2000; 6(6): 463-9 0968-0519
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Design of clinical trials in sepsis: problems and pitfalls. Author(s): Department of Microbiology and Infectious Diseases, City Hospital, UK. Source: Finch, R G J-Antimicrob-Chemother. 1998 January; 41 Suppl A95-102 0305-7453
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Effect of L-NAME, an inhibitor of nitric oxide synthesis, on plasma levels of IL-6, IL8, TNF alpha and nitrite/nitrate in human septic shock. Author(s): Department of Surgery, University Hospital Rotterdam, The Netherlands. Source: Avontuur, J A Stam, T C Jongen Lavrencic, M van Amsterdam, J G Eggermont, A M Bruining, H A Intensive-Care-Med. 1998 July; 24(7): 673-9 0342-4642
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Evolving strategies in the treatment of sepsis and systemic inflammatory response syndrome (SIRS). Author(s): Department of Pathology, University of Pittsburgh Medical Center, PA 15213-2582, USA. Source: Horn, K D QJM. 1998 April; 91(4): 265-77 1460-2725
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Frequency of sepsis after local corticosteroid injection (an inquiry on 1160000 injections in rheumatological private practice in France). Author(s): 146 Av Ledru Rollin, 75011 Paris, 28 rue Pauline, 94120 Fontenay sous-Bois, 15 rue M. Renault, 75017 Paris, 56 Av du Pdt Kennedy, 92160 Antony and 17 J. Jaures, 93130 Noisy le sec, France. Source: Seror, P Pluvinage, P d'Andre, F L Benamou, P Attuil, G Rheumatology(Oxford). 1999 December; 38(12): 1272-4 1462-0324
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Growth hormone does not attenuate the inhibitory effects of sepsis on wound healing. Author(s): Department of Surgery, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania 17033, USA. Source: Stamm, J Cooney, R N Maish, G O Shumate, M L Lang, C H Ehrlich, H P Vary, T C Wound-Repair-Regen. 2000 Mar-April; 8(2): 103-9 1067-1927
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Hydroxyethyl starch and modified fluid gelatin maintain plasma volume in a porcine model of septic shock with capillary leakage. Author(s): University Department of Anaesthesia, University of Liverpool, Liverpool L69 3GA, UK.
[email protected] Source: Marx, G Cobas Meyer, M Schuerholz, T Vangerow, B Gratz, K F Hecker, H Sumpelmann, R Rueckoldt, H Leuwer, M Intensive-Care-Med. 2002 May; 28(5): 629-35 0342-4642
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Images in infectious diseases in obstetrics and gynecology. Lethal sepsis due to traditional healing. Author(s): Department of Gynecology and Obstetrics, Katholieke Universiteit, Leuven, Belgium.
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Source: Donders, G G De Wet, H G De Jonghe, E Infect-Dis-Obstet-Gynecol. 2000; 8(2): 76 1064-7449 •
Impact of sepsis, lung injury, and the role of lipid infusion on circulating prostacyclin and thromboxane A(2). Author(s): Department of Anesthesiology, Ludwig-Maximilians-University, Munich, Germany.
[email protected] Source: Suchner, U Katz, P Furst, P Beck, K Felbinger, W Thiel, M Senftleben, U Goetz, E Peter, K Intensive-Care-Med. 2002 February; 28(2): 122-9 0342-4642
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Inhibiting early activation of tissue nuclear factor-kappa B and nuclear factor interleukin 6 with (1-->3)-beta-D-glucan increases long-term survival in polymicrobial sepsis. Author(s): Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City 37604-0575, USA. Source: Williams, D L Ha, T Li, C Kalbfleisch, J H Laffan, J J Ferguson, D A Surgery. 1999 July; 126(1): 54-65 0039-6060
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Levofloxacin in the empirical treatment of patients with suspected bacteraemia/sepsis: comparison with imipenem/cilastatin in an open, randomized trial. Author(s): Department of Infectious Diseases, University of Birmingham Medical School, Edgbaston, Birmingham, UK.
[email protected] Source: Geddes, A Thaler, M Schonwald, S Harkonen, M Jacobs, F Nowotny, I JAntimicrob-Chemother. 1999 December; 44(6): 799-810 0305-7453
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Lipopolyamines as a therapeutic strategy in experimental Gram-negative bacterial sepsis. Author(s): Brown University School of Medicine, Infectious Disease Division, Memorial Hospital of Rhode Island, Pawtucket, RI, USA.
[email protected] Source: Opal, S M Palardy, J E Parejo, N Morrison, D C J-Endotoxin-Res. 2001; 7(1): 35-8 0968-0519
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Low blood glucose levels and other complications during growth hormone supplementation in sepsis. Author(s): Nutrition Group, Department of Gastroenterology, Hospital das Clinicas, Sao Paulo, SP, Brazil. Source: Faintuch, J Leme, R B Cruz, M E Lima, A M Giannella Neto, D Gama Rodrigues, J J Rev-Hosp-Clin-Fac-Med-Sao-Paulo. 1999 Jul-August; 54(4): 135-8 0041-8781
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Malnutrition, infection, and sepsis in acute and chronic illness. Author(s): Women's Health Graduate Program, College of Nursing, University of Cincinnati, PO Box 210038, 3110 Vine Street, Cincinnati, OH 45221-0038, USA.
[email protected] Source: Felblinger, D M Crit-Care-Nurs-Clin-North-Am. 2003 March; 15(1): 71-8 08995885
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Nutritional support in sepsis. Source: Hasselgren, P.O. Fischer, J.E. Nutritional support in critical care / edited by Carol E. Lang. Rockville, Md. : Aspen Publishers, 1987. page 345-361. ill. ISBN: 0871896311
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Opening the microcirculation: can vasodilators be useful in sepsis? Author(s): Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
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Source: Buwalda, M Ince, C Intensive-Care-Med. 2002 September; 28(9): 1208-17 03424642 •
Organ dysfunction following hemorrhage and sepsis: mechanisms and therapeutic approaches (Review). Author(s): Center for Surgical Research and Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence, RI 02903, USA. Source: Jarrar, D Chaudry, I H Wang, P Int-J-Mol-Med. 1999 December; 4(6): 575-83 1107-3756
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Steroids in sepsis--more effective than activated protein C? Author(s): St. George's Hospital, London, UK. Source: Bradley, C Intensive-Crit-Care-Nurs. 2001 August; 17(4): 242-4 0964-3397
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The effects of prostaglandin E2 indomethacin & Ginkgo biloba extract on resistance to experimental sepsis. Author(s): Kocaeli University, Faculty of Medicine, Department of Surgery, Kocaeli, Turkey. Source: Canturk, N Z Utkan, N Z Canturk, Z Yenisey, C Yildirir, C Dulger, M Indian-JMed-Res. 1998 September; 10888-92 0971-5916
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The influence of nutrition and sepsis upon wound healing. Author(s): Department of Surgery, University of Manchester, Hope Hospital, Salford, UK. Source: Carlson, G L J-Wound-Care. 1999 October; 8(9): 471-4 0969-0700
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The International Sepsis Forum's controversies in sepsis: corticosteroids should be used to treat septic shock. Author(s): Department of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Center, The Hebrew University of Jerusalem, Israel. Source: Goodman, S Sprung, C L Crit-Care. 2002 October; 6(5): 381-3 1364-8535
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Why immunomodulatory therapies have not worked in sepsis. Author(s): Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
[email protected] Source: Abraham, E Intensive-Care-Med. 1999 June; 25(6): 556-66 0342-4642
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 sepsis; 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: •
Food and Diet Wound Healing Source: Healthnotes, Inc.; www.healthnotes.com
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CHAPTER 3. DISSERTATIONS ON SEPSIS Overview In this chapter, we will give you a bibliography on recent dissertations relating to sepsis. 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 “sepsis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on sepsis, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Sepsis 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 sepsis. 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: •
Alterations in Host Defence Mechanisms of Surgical Patients with Particular Reference to Polymorphonuclear Leckocyte Function and Predisposition to Major Sepsis and Mortality by Christou, Nicolas Velos; PhD from McGill University (Canada), 1979 http://wwwlib.umi.com/dissertations/fullcit/NK50417
Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 4. CLINICAL TRIALS AND SEPSIS Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning sepsis.
Recent Trials on Sepsis The following is a list of recent trials dedicated to sepsis.8 Further information on a trial is available at the Web site indicated. •
A Safety and Efficacy Study of Intravenous E5564 in Patients with Severe Sepsis Condition(s): Sepsis; Shock, Septic; Sepsis Syndrome; Septicemia; Infection Study Status: This study is currently recruiting patients. Sponsor(s): Eisai Medical Research Inc Purpose - Excerpt: Sepsis is a serious condition where there is inflammation and damage to body tissue, usually caused by an infection. This infection can lead to decreased function of vital body organs and in some cases may lead to permanent health problems or death. Much of the injury is due to endotoxin, a harmful substance produced by certain types of bacteria. An endotoxin antagonist is designed to block the effects of endotoxin. This study is designed to study the safety and efficacy when treating patients with severe sepsis. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00046072
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Assessment of Pleconaril for Treatment of Enteroviral Sepsis Syndrome in Neonates Condition(s): Sepsis Study Status: This study is currently recruiting patients.
8
These are listed at www.ClinicalTrials.gov.
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Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To determine if administration of pleconaril to critically ill neonates with enteroviral sepsis syndrome results in more rapid clearance of virus from various body sites and to determine the safety of administering pleconaril to critically ill neonates. To evaluate intersubject pharmacokinetic variability and the effect of pleconaril on clinical outcome. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00031512 •
Effects of Endotoxin in Normal Human Volunteers Condition(s): Healthy; Lung Disease; Sepsis; Septic Shock Study Status: This study is currently recruiting patients. Sponsor(s): Warren G Magnuson Clinical Center (CC) Purpose - Excerpt: Bacterial infections can progress to a life-threatening illness called septic shock, characterized by low blood pressure and vital organ damage. The syndrome is thought to be caused by parts of the bacteria and by the body's own immune response to the infection. A major bacterial product that interacts with the immune defenses is called endotoxin. This study will examine the body's response to endotoxin in the lungs or bloodstream. When endotoxin is given in small amounts to humans, even though it is not an infection, it triggers a set of responses that are typical of what one would see with a true bacterial infection. This allows us to study the earliest changes in molecules and cells that are involved in some bacterial infections. This type of model is safe and has been used in humans for many years to understand the body's responses during infections. Normal volunteers 18 to 45 years of age may be eligible for this study. Candidates will have a history and physical examination, blood and urine tests, electrocardiogram (EKG) and chest X-ray. In addition, volunteers 40 to 45 years old will have an exercise stress test to screen for asymptomatic coronary artery disease. Participants will undergo one or more of the following procedures: Bronchoscopy, Bronchoalveolar Lavage, Bronchial Brushings, and Endobronchial Mucosal Biopsies: These techniques for examining lung function are used routinely in patient care and clinical research. The mouth and nasal and lung airways are numbed with an anesthetic. A bronchoscope (pencil-thin flexible tube) is then passed through the nose into the large airways of the lung. Cells and secretions from the airways are rinsed with salt water (bronchoalveolar lavage) and a flexible brush the size of a pencil tip is passed through the bronchoscope to scrape cells lining the airways. Lastly, pieces of tissue (the size of the ball of a ballpoint pen) lining the airways are removed for examination under the microscope. Intravenous Endotoxin: A small dose of endotoxin is injected into a vein. Blood samples are drawn at regular intervals for 8 hours after the injection and again after 1, 2, 3, 7 and 14 days to analyze the body's immune response to the bacteria in the blood. Instilled Endotoxin in the Lungs: A small amount (2 teaspoons) of salt water is squirted through a bronchoscope into a lobe of one lung, and then salt water containing a small dose of endotoxin is squirted into the other lung. Bronchial lavage, brushing, and biopsy (see above) are then done to study the response of the lung to the endotoxin. In addition, air is withdrawn through the bronchoscope to study air components from the lung that was instilled with salt water or endotoxin. Nitric Oxide Therapy: Endotoxin is instilled in a lung (see above) and then nitric oxide-a colorless, odorless,
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tasteless gas-mixed with room air in a concentration of 40 parts per million, is given through a cushioned mask placed over the mouth and nose. (Some participants will be given the nitric oxide mixture and others will breathe only room air through the mask to test the effects of the nitric oxide on the lung inflammation.) The mask will be worn continuously for 6 hours and removed before repeat bronchoscopy with lavage, brushing and biopsy. Some of the above procedures require placement of a catheter (thin plastic tube) in a wrist artery to monitor blood pressure from heartbeat to heartbeat and to collect blood samples. First, the skin is numbed with an anesthetic (lidocaine). A needle is then inserted into the artery, the catheter is slipped over the needle into the vessel, and the needle is removed. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001303 •
Investigation of the Efficacy and Safety of Drotrecogin Alfa (Activated) in Pediatric Severe Sepsis. Condition(s): Sepsis Study Status: This study is currently recruiting patients. Sponsor(s): Eli Lilly and Company Purpose - Excerpt: The purposes of this study are to determine: 1. Whether drotrecogin alfa (activated) helps children with severe sepsis survive their condition more often or recover faster than children who do not receive drotrecogin alfa (activated). 2. Whether drotrecogin alfa (activated) minimizes long term disabilities associated with severe sepsis. 3. The side effects that might be associated with drotrecogin alfa (activated) administration to children with severe sepsis. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00049764
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Phase I Study of Vasoactive Intestinal Peptide in Patients with Acute Respiratory Distress Syndrome and Sepsis Condition(s): Sepsis; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Adult Study Status: This study is currently recruiting patients. Sponsor(s): FDA Office of Orphan Products Development; State University of New York Purpose - Excerpt: Objectives: I. Determine the maximum tolerated dose of vasoactive intestinal peptide in patients with acute respiratory distress syndrome. II. Evaluate the safety and pharmacodynamic activity of this peptide in these patients. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004494
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Prophylactic Heparin during Xigris [Drotrecogin Alfa (Activated)] Treatment of HighRisk Severe Sepsis Condition(s): Sepsis Study Status: This study is currently recruiting patients. Sponsor(s): Eli Lilly and Company Purpose - Excerpt: The purpose of this study is to evaluate the relative efficacy and safety of prophylactic heparin co-administration during Xigris infusion in the treatment of severe sepsis in the adult. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00049777
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Safety and Efficacy of PHP in the Treatment of Shock Associated with Systemic Inflammatory Response Syndrome (SIRS) Condition(s): Shock; Systemic Inflammatory Response Syndrome Study Status: This study is currently recruiting patients. Sponsor(s): Apex Bioscience Purpose - Excerpt: To determine the safety and effectiveness of pyridoxylated hemoglobin polyoxyethylene conjugate (PHP) administered by continuous intravenous (IV) infusion in systemic inflammatory response syndrome (SIRS) patients with shock. PHP is a human-derived chemically modified hemoglobin preparation. PHP selectively scavenges excess nitric oxide (NO) and does so in a catalytic, concentration-dependent reaction that results in the formation of the non-toxic NO metabolite, nitrate. PHP is postulated to reduce excess, toxic levels of NO while allowing critical beneficial levels of the molecule to persist. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00021502
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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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Teicoplanin in Treating Septicemia in Patients Who Are Receiving Chemotherapy Through a Central Venous Catheter Condition(s): Infection Study Status: This study is currently recruiting patients. Sponsor(s): United Kingdom Children's Cancer Study Group Purpose - Excerpt: RATIONALE: Giving the antibioticteicoplanin by infusion and allowing bacteria to be exposed to the antibiotic for a longer period of time may be effective in preventing or controlling septicemia. PURPOSE: Randomized clinical trial to compare two different methods of giving teicoplanin in treating septicemia in patients who are receiving chemotherapy through a central venous catheter. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00024453
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The Study of Drotrecogin Alfa (Activated) in a Subpopulation of Adult Patients with Severe Sepsis Condition(s): Sepsis Study Status: This study is no longer recruiting patients. Sponsor(s): Eli Lilly and Company Purpose - Excerpt: Severe sepsis is defined as a systemic inflammatory response syndrome that results from infection and is associated with acute organ dysfunction. It usually results from bacterial infections, but it may occur in response to other pathogens, such as fungi, viruses, and parasites. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00045760
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A Phase IIb Study to Determine the Efficacy and Safety of the Study Drug in Patients with Severe Sepsis Condition(s): Sepsis Study Status: This study is terminated. Sponsor(s): Eli Lilly and Company Purpose - Excerpt: The purpose of this study is to determine whether the administration of the study drug is effective in increasing the chance of survival in patients with severe sepsis. Patients entered into this study will be randomly assigned to one of two treatment groups. Patients in each treatment group will be given either the study drug or placebo as a continuous infusion directly into the bloodstream through a catheter placed in one of the patient's veins. The study drug is an investigational drug that is still in development. It has been studied in approximately 30 healthy subjects, approximately 30 patients with either kidney failure or arthritis, and approximately 600 patients with severe sepsis. Patient participation in this study will last for about one month. Phase(s): Phase I; Phase II
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Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00034476 •
A Prospective, Randomized, Phase III Trial of FLAC (5-Fluorouracil, Leucovorin, Adriamycin, Cytoxan) Chemotherapy with GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) Versus PIXY 321 in Advanced Breast Cancer Condition(s): Breast Neoplasms; Fever; Hematologic Diseases; Neutropenia; Sepsis Study Status: This study is completed. Sponsor(s): National Cancer Institute (NCI) Purpose - Excerpt: This is a prospective, randomized Phase III trial of FLAC chemotherapy with GM-CSF versus PIXY321 in advanced breast cancer. The primary endpoints of this study will be the duration of thrombocytopenia and the time to recovery of platelets to 50,000/microliters. Other clinical endpoints will include the depth and duration of leukopenia, neutropenia, and anemia, the platelet and RBC transfusion requirements, and the number of documented instances of sepsis and hospitalizations for fever and neutropenia. Laboratory correlates will include the detailed evaluation of the effects on circulating hematopoietic progenitor cells by GMCSF and PIXY321 and the potential effects these agents have on the bone marrow microenvironment. After 5 cycles of FLAC with GM-CSF versus PIXY321, patients will be treated with 5 cycles of 96 hour infusional taxol. The goal of this part of the study will be to assess the toxicity and feasibility of administering infusional taxol following doseintensive FLAC chemotherapy. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001338
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A Safety and Efficacy Study of Hospitalized Patients with Community-Acquired Pneumonia and Sepsis Condition(s): Pneumonia; Sepsis Study Status: This study is completed. Sponsor(s): ICOS Purpose - Excerpt: The objective of this study is to demonstrate the safety and efficacy of IC14 in the treatment of hospitalized patients with community-acquired pneumonia and sepsis. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00042588
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A Safety Evaluation of Xigris in Patients with Blood Cancer who Develop Severe Infection related to Bone Marrow Transplantation. Condition(s): Sepsis; Hematologic Transplantation; Infection
Neoplasms;
Hematopoietic
Stem
Cell
Study Status: This study is terminated. Sponsor(s): Eli Lilly and Company Purpose - Excerpt: The purpose of this study is to determine how Xigris(r) will affect leukemia, lymphoma and myeloma patients who develop severe sepsis within 60 days of starting chemotherapy in preparation for bone marrow transplant (BMT). This study will: ·Evaluate the safety of Xigris(r) by assessing the risk of serious bleeding events, including bleeding within the brain and serious bleeding leading to death. *Evaluate whether Xigris(r) can reduce death in BMT patients who develop severe sepsis. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00067730 •
Diagnostic Study of Adrenal Cortical Function in Children With Septic Shock Condition(s): Septic Shock Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); Children's Hospital Medical Center - Cincinnati Purpose - Excerpt: Objectives: I. Examine adrenal cortical function and the incidence of adrenal dysfunction in children with septic shock. II. Examine the mortality, length of stay in the PICU, and incidence of multiorgan failure in children with adrenal dysfunction and septic shock. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005890
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Glutamine Supplementation to Prevent Death or Infection in Extremely Premature Infants Condition(s): Sepsis; Infant, Premature, Diseases Study Status: This study is completed. Sponsor(s): National Institute of Child Health and Human Development (NICHD) Purpose - Excerpt: In this large multicenter trial, extremely premature newborns are randomized to early parenteral nutrition with or without glutamine to test whether glutamine will reduce the risk of death or infection. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005775
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Ibuprofen in Sepsis Study Condition(s): Acute Respiratory Distress Syndrome; Lung Diseases; Shock, Septic Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the effects of ibuprofen on mortality, development and reversal of shock, and adult respiratory distress syndrome, and on Lung Parenchymal Injury Score in adult patients with serious infection. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000574
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Safety and Efficacy of MBI 226 for the Prevention of Central Venous Catheter-related Bloodstream Infections Condition(s): Sepsis; Bacteremia; Fungemia Study Status: This study is completed. Sponsor(s): Micrologix Biotech Purpose - Excerpt: Central venous catheters (CVCs) are used in patient care for such purposes as the administration of medication, fluids, blood products and for functions such as hemodialysis and plasmapheresis. However, the use of CVCs can cause complications such as life-threatening bloodstream infections (BSI). BSIs are caused by organisms from the skin's surface tracking down the catheter's outer surface. The organisms grow on the catheter surface (catheter colonization) which is followed by seeding into the bloodstream. BSIs can be difficult to treat and the mortality rate is as high as 35% in Intensive Care patients with a catheter-related BSI. It is estimated that up to 70,000 patients in the US die each year from catheter-related BSI. MBI 226 is a new drug that, when applied to the skin surrounding the catheter insertion site, will prevent organisms on the skin from migrating down the catheter and entering the bloodstream and therefore decrease the incidence of catheter-related BSI in patients with CVCs. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00027248
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Safety and Efficacy of Recombinant Human Acetylhydrolase for the Treatment of Severe Sepsis
Platelet-Activating
Factor
Condition(s): Sepsis Study Status: This study is terminated. Sponsor(s): ICOS; Suntory Pharmaceutical Purpose - Excerpt: The objective of this study is to demonstrate that rPAF-AH is safe and reduces 28 day all cause mortality in patients with severe sepsis. Phase(s): Phase III Study Type: Interventional
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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00037687 •
Study of the Relationship Between Feeding and Late Onset Sepsis and/or Necrotizing Enterocolitis in Low Birth Weight Infants Condition(s): Necrotizing Enterocolitis; Sepsis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); Baylor College of Medicine Purpose - Excerpt: Objectives: I. Compare the incidence of late onset sepsis and/or necrotizing enterocolitis and duration of hospitalization in low birth weight infants fed with fortified mother's milk supplemented with either fortified pasteurized donor human milk or preterm formula, and with fortified mother's milk versus preterm formula. II. Determine the relationship between functional antibody titers in serial milk samples and the incidence of pathogen specific late onset sepsis (e.g., Staphylococcus epidermidis, Staphylococcus aureus) in these patients. III. Determine the long term sequelae (growth, body composition, health, and neurodevelopment) of human milk versus formula feeding in these patients. IV. Determine the relationship between stress and milk production in the mothers of these patients. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005888
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 “sepsis” (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 5. PATENTS ON SEPSIS 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 “sepsis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on sepsis, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Sepsis By performing a patent search focusing on sepsis, 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
9Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on sepsis: •
Acinetobacter outer membrane protein and gene sequence compositions and methods Inventor(s): Merchant; Juanita L. (Ann Arbor, MI) Assignee(s): The Regents of the University of Michigan (ann Arbor, Mi) Patent Number: 6,713,062 Date filed: May 17, 2000 Abstract: Disclosed are new outer membrane proteins and nucleic acids from Acinetobacter and related biological compositions and methods. The biological materials provided are useful in diagnostic, immunological and therapeutic applications, particularly those connected with peptic ulcers and cancers, respiratory diseases, sepsis and a variety of other conditions. Excerpt(s): The present invention relates generally to the field of genes and proteins derived from pathogenic bacteria. More particularly, the invention provides Acinetobacter outer membrane protein and gene compositions and methods for making and using a range of biological components related thereto. The invention thus provides nucleic acids, proteins, peptides and antibodies for use in various diagnostic and therapeutic applications, including those connected with peptic ulcers and cancers, respiratory diseases, sepsis and other conditions. Helicobacter pylori (H. pylori) causes chronic gastritis and is correlated with the development of peptic ulcer disease and gastric carcinoma (Marshall et al, 1994; Graham, 1998; Nomura et al., 1991). However, there is also a potential association between colonization of the stomach by nonHelicobacter organisms and gastric atrophy and gastritis (Elliott et al., 1998; Haruma et al., 1995; Saunders et al., 1998). Studies in the human and monkey have clearly shown that bacteria are important in triggering mucosal damage and inflammation in the stomach (Khanolkar-Gaitonde et al., 2000; Stockbruegger et al., 1984). It is not currently known whether colonization by non-Helicobacter organisms triggers perturbations in the neuroendocrine and epithelial cell populations. The implications being that the pathology observed may not be specific for H. pylori, but instead is the general response of the gastric mucosa to bacteria. Web site: http://www.delphion.com/details?pn=US06713062__
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Active immunization using a siderophore receptor protein Inventor(s): Carlson; Beth A. (Murdock, MN), Emery; Daryll A. (Willmar, MN), Huisinga; Richard (Willmar, MN), Straub; Darren E. (Willmar, MN) Assignee(s): Willmar Poultry Company, Inc. (willmar, Mn) Patent Number: 6,432,412 Date filed: July 26, 1999 Abstract: The invention provides a vaccine for immunizing poultry and other animals against infection by a gram-negative bacteria, and a method of immunizing an animal using the vaccine. The vaccine may contain purified siderophore receptor proteins derived from a single strain or species of gram-negative bacteria or other organism, which are cross-reactive with siderophores produced by two or more strains, species or genera of gram-negative bacteria. The invention further provides a process for isolating
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and purifying the siderophore receptor proteins, and for preparing a vaccine containing the proteins. Also provided is a method for diagnosing gram-negative sepsis. Excerpt(s): The economic impact of infectious diseases in the poultry industry is wellappreciated. Immunization of birds has helped reduce the cost of production by decreasing the incidence of-gastrointestinal, respiratory and systemic diseases. While vaccines provide adequate immunity for those pathogens against which a flock has been immunized, there are few vaccines which can provide broad-based cross-protection against unanticipated diseases or against those diseases for which an animal has not been specifically vaccinated. A number of important diseases of domestic poultry are caused by bacteria able to invade host tissues, such as Salmonella spp., Escherichia spp. and Pasteurella spp. While many vaccines are available for immunization against individual species and serotypes, none provide cross-protection or stimulate broadbased immunity against multiple serotypes, species or genera. One essential factor required for a bacteria to induce clinical disease is the ability to proliferate successfully in a host tissue. Iron is an essential nutrient for the growth of gram-negative bacteria in vivo, but is virtually unavailable in mammalian and/or avian tissues because the iron is either intracellular or extracellular, complexed with high affinity, iron-binding proteins, for example, transferring in blood and lymph fluids and lactoferrin in external secretions. In normal tissues, the concentration of iron is approximately 10.sup.-13 M, far below that required for bacterial growth. Web site: http://www.delphion.com/details?pn=US06432412__ •
Animal models for predicting sepsis mortality Inventor(s): Bellinger-Kawahara; Carole (Redwood City, CA), Contag; Pamela R (San Jose, CA), Hubbard; Alan (Berkeley, CA) Assignee(s): Xenogen Corporation (alameda, Ca) Patent Number: 6,610,503 Date filed: March 16, 2000 Abstract: Methods for selecting a candidate drug for treating sepsis are disclosed. The methods involve labeling a sepsis-causing pathogen with a reporter and monitoring the progress of infection by detecting levels of the reporter in animals treated with test compounds or drugs. The comparisons may be made between experimental and control animals, as well as within a single animal or group of animals. Also disclosed is a method for predicting an expected time of death of an experimental animal in a model system of sepsis using data generated in the initial part of the experiment. Excerpt(s): The present invention relates to animal models of sepsis and methods of use thereof. In particular, the invention relates to methods of predicting survival time of animals with sepsis, and methods of screening test compounds for effectiveness in treating sepsis. Sepsis, or illness caused by a severe infection, is the third leading cause of infectious death (Bone, et al., 1997). The majority of sepsis cases are caused by bacterial infections. Accordingly, a substantial amount of money and time has gone into the search for drugs effective to treat sepsis and/or eliminate the pathogens (e.g., bacteria) which cause sepsis. Current animal models of sepsis, used primarily to evaluate the efficacy of compounds in treating sepsis, are typically "death as an endpoint" models. In other words, the determination of whether an animal has succumbed to sepsis (or if a particular treatment was effective) is made by scoring whether the animal dies during the course of the experiment.
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Antagonism of immunostimulatory CpG-oligonucleotides by 4-aminoquinolines and other weak bases Inventor(s): Barlin; Gordon B. (Turner, AU), Ismail; Fyaz M. D. (Stockton on Tees, GB), Macfarlane; Donald E. (Iowa City, IA), Manzel; Lori (Cedar Rapids, IA), Strekowski; Lucjan (Stone Mountain, GA) Assignee(s): Georgia State University Research Foundation, Inc. (atlanta, Ga), The United States of America AS Represented by the Department of Veterans (washington, Dc), The University of Iowa Research Foundation (iowa City, Ia) Patent Number: 6,479,504 Date filed: June 16, 2000 Abstract: The present invention relates generally to the field of immunology. More particularly it concerns compositions and methods for inhibiting stimulation of the immune system. The compounds and methods comprise compounds that are analogs and derivatives of chloroquine, such as 4-aminoquinolines, and other weak bases. They can be used in preventative and therapeutic treatments of autoimmune diseases and phenomena, transplant rejection such as host-versus-graft disease, and sepsis. Excerpt(s): The present invention relates generally to the field of immunology. More particularly, it concerns preventative and therapeutic compositions and methods that inhibit stimulation of the immune system. While stimulation of the immune systems prevents and controls infection, it can have an adverse physiological effect, as is the case with autoimmune diseases and phenomena, with rejection of cells and tissues during adoptive immunotherapy and transplants, and with invasions by pathogens. Inhibition of this stimulation can have beneficial therapeutic results. However, new and more effective treatments to effect inhibition of immunostimulation are still needed. Autoimmunity is generally caused by aberrations in lymphocyte activities. While the precise cause of autoimmunity is not known, it most likely involves a mechanistic failure in at least one of the steps of maintaining self-tolerance to the body's own antigens. Several factors are thought to play a part in the development of autoimmunity, including the host's genetic makeup. Autoimmune diseases afflict approximately 1% to 2% of the human population. Autoimmune phenomena, are the result of a disease, for example myocardial infarcation, that may cause damage to tissue, which consequently effects the release of immunogenic tissue antigens; this condition, unlike autoimmune disease, is unrelated to the pathogenesis of the disease that caused it. Web site: http://www.delphion.com/details?pn=US06479504__
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Compositions and methods for the treatment of sepsis Inventor(s): Czermak; Boris (Frieburg, DE), Huber-Lang; Markus (South Lyon, MI), Sarma; Vidya (Ann Arbor, MI), Ward; Peter A. (Ann Arbor, MI) Assignee(s): The Regents of the University of Michigan (ann Arbor, Mi) Patent Number: 6,673,346 Date filed: August 31, 1999
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Abstract: The present invention relates to compositions and methods for the prevention and treatment of blood-borne and toxin mediated diseases, and in particular anti-C5a antibodies for the prevention and treatment of sepsis in humans as well as other animals. The present invention also relates to methods of generating anti-C5a antibodies employing C-terminal truncated C5a peptides. Excerpt(s): The present invention relates to compositions and methods for the prevention and treatment of blood-borne and toxin-mediated diseases, and in particular anti-C5a antibodies for the prevention and treatment of sepsis in humans as well as other animals. Sepsis is a systemic reaction characterized by arterial hypotension, metabolic acidosis, decreased systemic vascular resistance, tachypnea and organ dysfunction. Sepsis can result from septicemia (i.e., organisms, their metabolic endproducts or toxins in the blood stream), including bacteremia (i.e., bacteria in the blood), as well as toxemia (i.e., toxins in the blood), including endotoxemia (i.e., endotoxin in the blood). The term "bacteremia" includes occult bacteremia observed in young febrile children with no apparent foci of infection. The term "sepsis" also encompasses fungemia (i.e., fungi in the blood), viremia (i.e., viruses or virus particles in the blood), and parasitemia (i.e., helminthic or protozoan parasites in the blood). Thus, septicemia and septic shock (acute circulatory failure resulting from septicemia often associated with multiple organ failure and a high mortality rate) may be caused by a number of organisms. The systemic invasion of microorganisms presents two distinct problems. First, the growth of the microorganisms can directly damage tissues, organs, and vascular function. Second, toxic components of the microorganisms can lead to rapid systemic inflammatory responses that can quickly damage vital organs and lead to circulatory collapse (i.e., septic shock) and oftentimes, death. Web site: http://www.delphion.com/details?pn=US06673346__ •
Compounds having MIF antagonist activity Inventor(s): Al-Abed; Yousef (Locust Valley, NY), Bucala; Richard J. (Cos Cob, CT) Assignee(s): The Picower Institute of Medical Research (manhasset, Ny) Patent Number: 6,599,938 Date filed: October 27, 2000 Abstract: There is disclosed a genus of optionally substituted Schiff base condensation products (and the carba analogs thereof) comprising an amino acid component and a benzaldehyde component, that have MIF (macrophage migration inhibitory factor) antagonist activity. The compounds are useful for treating a variety of diseases involving inflammatory activity or pro-inflammatory cytokine responses, such as autoimmune diseases, asthma, arthritis, EAE, ARDS and various forms of sepsis and septic shock, and other conditions characterized by underlying MIF responses including, for instance, tumor growth and neovascularization. Excerpt(s): The present invention provides a genus of optionally substituted Schiff base condensation products (and the carba analogs thereof) comprising an amino acid component and a benzaldehyde component, that have MIF (macrophage migration inhibitory factor) antagonist activity. Specifically, the compounds are useful for treating a variety of diseases involving inflammatory activity or pro-inflammatory cytokine responses, such as autoimmune diseases, asthma, arthritis, EAE, ARDS and various forms of sepsis and septic shock, and other conditions characterized by underlying MIF responses including, for instance, tumor growth and neovascularization. Human MIF
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was first cloned in 1989 and its activity has been investigated in a number of studies. MIF was the first lymphokine to be discovered and was originally identified by its ability to prevent the migration of guinea pig macrophages in vitro (Bloom & Bennett, Science 153:80-82, 1966; David, Proc. Natl. Acad. Sci. USA 56:72-77, 1966). Given this activity, the role of MIF activity in inflammation and the immune system was investigated, however the precise role of MIF in either local or systemic inflammatory responses remained largely undefined in the course of this early work. Likewise the role of MIF in other physiological and pathophysiological is still being defined. Recombinant human MIF was originally cloned from a human T cell library (Weiser et al., Proc. Natl. Acad. Sci. USA 86: 7522-7526, 1989), and was shown to activate blood-derived macrophages to kill intracellular parasites and tumor cells in vitro, to stimulate IL1.beta. and TNF.alpha. expression, and to induce nitric oxide synthesis (Weiser et al., J. Immunol. 147:2006-2011, 1991; Pozzi et al., Cellular Immunol. 145:372-379, 1992; Weiser et al., Proc. Natl. Acad. Sci. USA 89:8049-8052, 1992; Cunha et al., J. Immunol. 150:19081912, 1993). While the conclusions available from several of these early reports are confounded by the presence of a bioactive mitogenic contaminant in the recombinant MIF preparations used, the potent pro-inflammatory activities of MIF have been confirmed in other studies that do not suffer from this complicating factor (reviewed in Bucala, The FASEB Journal 10:1607-1613, 1996). More recent MIF studies have capitalized on the production of recombinant MIF in purified form as well as the development of MIF-specific polyclonal and monoclonal antibodies to establish the biological role of MIF in a variety of normal homeostatic and pathophysiological settings (reviewed, for instance, in Rice et al., Annual Reports in Medicinal Chemistry 33:243-252, 1998). Among the most important insights of these later reports following the "re-discovery" of MIF has been the recognition that MIF not only is a cytokine product of the immune system, but also is a hormone-like product of the endocrine system, particularly the pituitary gland. Moreover, this recent work has underscored the potent activity of MIF as a counter-regulator of the anti-inflammatory effects of the glucocorticoids (both those endogenously released and those therapeutically administered), with the effect that the normal activities of glucocorticoids to limit and suppress the severity of inflammatory responses are inhibited by MIF, such that the endogenous MIF response is seen as a cause or an exacerbative factor in a variety of inflammatory diseases and conditions (reviewed in Donnelly and Bucala, Molecular Medicine Today 3:502-507, 1997). MIF has also been linked to tumor growth and neovascularization (angiogenesis), suggesting a further need for MIF antagonists in the area of oncology and cancer treatment (Chesney et al., Molecular Medicine 5:181-191, 1999). Web site: http://www.delphion.com/details?pn=US06599938__ •
Diagnostics for bacterial meningitus Inventor(s): Duff; Gordon W. (Sheffield, GB), Saverio di Giovine; Francesco (Sheffield, GB) Assignee(s): Interleukin Genetics, Inc. (waltham, Ma) Patent Number: 6,551,785 Date filed: May 10, 2001 Abstract: Methods and kits for detecting polymorphism that are predictive of a subject's susceptibility to developing sepsis are described.
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Excerpt(s): Clinical infection is the biological end result of a number of factors, including the nature of the invading organism, its intrinsic virulence, the microenvironment of the invaded tissue or organ, and the responsiveness of the host. Any means by which bacteria can be introduced into the tissues can result in an infection. However, the nature of the introduction can influence the severity of the infection and can alter the host's ability to respond. As injuries, a cutaneous laceration, for example, differs from an extensive surgical dissection, which in turn differs from a perforated gastrointestinal viscus. Similarly, a lung infection (a pneumonia) occurring in an area of atelectasis is different from a lung infection that takes place as a result of an aspiration event. Mere presence of pathogens in intact or injured areas does not comprise an infection. A certain critical mass of organisms is necessary in order to sufficiently overcome the host defenses and cause an invasive infection. This level of bacteria is usually stated to be 10.sup.5 organisms per gram of treatment. A variety of factors can influence the balance between microbial invader and host defenses sufficiently that infections develop at lower levels of bacterial exposure. Necrotic tissue or foreign bodies in a wound are termed adjuvant factors, understood to make infections likely to develop at lower concentrations. Local physiological factors such as impaired circulation also increase local susceptibility to infection. Systemic ailments like diabetes, uremia and AIDS are known to lower the host's resistance to infection, again making it easier for microbes to establish an infection in the tissues. The severity of an infection in part relates to the extent of the injury that accompanies or precedes it. More severe injury (e.g., an extensive accidental or surgical trauma) interferes with host integrity more substantially, permitting freer access to host tissues and compromising intrinsic host defenses. The severity of an infection depends upon the number and kind of microorganisms responsible for the infection. If a polymicrobial infection is diagnosed or suspected, early and aggressive antibiotic intervention is commonly warranted, often with broad-spectrum agents with activity against a number of possible invaders. Certain virulence factors have been associated with specific microorganisms, making invasion carried out by these cells more destructive. Virulence factors are of three general types: 1) biological products produced and secreted by the infecting agent that attack cells in the host or that affect host homeostatic mechanisms to produce clinical disease; 2) structural components of the normal bacterial cell which, when shed within the host's internal environment or when released following death and lysis of the bacterial cell, have toxic effects on the host; 3) responses of the microorganism to antibiotics that make them resistant to these chemotherapeutic agents. Particular microorganisms characteristically manifest specific virulence factors. For example, Staphylococcus aureus produces coagulase, which acts as a powerful virulence factor. Staph. and Streptococcal species also produce leukocidins. As a further example, strains of B. fragilis produce superoxide dismutase, which converts superoxide anions to hydrogen peroxide; strains of E. coli produce catalase, which reduces hydrogen peroxide to water, thereby rendering possible a synergism between these two organisms. A wide variety of other virulence factors have been identified. Web site: http://www.delphion.com/details?pn=US06551785__
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Inter-alpha-trypsin inhibitor as a marker for sepsis Inventor(s): Hixson; Douglas C. (Barrington, RI), Lim; Yow-Pin (East Providence, RI) Assignee(s): Rhode Island Hospital (providence, Ri) Patent Number: 6,660,482 Date filed: February 28, 2000 Abstract: The invention provides a method of diagnosing sepsis in a mammal by contacting a bodily fluid from the mammal with a ligand which binds to an inter-alpha trypsin inhibitor (ITI) polypeptide under conditions sufficient to form an ITI-ligand complex and detecting the complex. Excerpt(s): This invention relates to bacterial infections. The invention provides a method of diagnosing sepsis in a mammal. The methods are also useful as a prognostic tool in predicting the outcome of those diagnosed with sepsis and those undergoing therapy for sepsis. A method for diagnosis or prognosis sepsis in a mammal is carried out by contacting a bodily fluid, e.g., blood, plasma, or serum, from the mammal with a ligand which binds to an inter-alpha trypsin inhibitor (ITI) polypeptide under conditions sufficient to form an ITI-ligand complex and detecting the complex. The mammal is preferably a human patient; however, the assays are also applicable to veterinary use, e.g., to diagnose or prognose sepsis in animals such as dogs, cats, horses, cows and the like. Preferably, the ligand binds to an epitope of human ITI light chain. ITI is used as a marker for diagnosis or prognosis of sepsis in infants such as neonates as well as adult mammals. Web site: http://www.delphion.com/details?pn=US06660482__
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Isolated asgal lipopolysaccharides and use of same to inhibit innate immune response Inventor(s): Pardy; Rosevelt L. (Lincoln, NE) Assignee(s): Board of Regents of University of Nebraska (lincoln, Ne) Patent Number: 6,444,654 Date filed: October 31, 2000 Abstract: The isolation and purification of lipopolysaccharides from several related strains of eukaryotic algae is disclosed. These lipopolysaccharides have been shown to be structurally and functionally similar to the lipopolysaccharides of gram negative bacteria, or endotoxins, which have been shown to be a cause of sepsis or septic shock. The present invention also relates to the use of these algal lipopolysaccharides to inhibit the release of TNF-a from macrophages, which has been associated with the initiation and escalation of sepsis as a result of bacterial endotoxins. The present invention further relates to the use of these algal lipopolysaccharides to inhibit the innate immune system of insects and mammals. Excerpt(s): The present invention relates to the isolation and use of lipopolysaccharides from eukaryotic algae. More particularly, the present invention relates to the isolation of algal lipopolysaccharides and their use to inhibit the release of TNF-alpha from macrophages and, thus, inhibit endotoxin-initiated sepsis or septic shock. Further, the present invention relates to the use of algal lipopolysaccharides to inhibit the innate immune system of insects and mammals. Lipopolysaccharides are high molecular weight amphipathic molecules typically associated with the cell walls of gram negative
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enteric bacteria. The lipopolysaccharides of gram negative bacteria are known as endotoxins and have been found to be responsible for the pathogenicity of the bacteria. The primary pathogenicity of gram negative bacteria is its physiological interaction with a host to initiate sepsis or septic shock. When a gram negative bacterium enters a host it begins to reproduce. As the bacteria reproduces, a number of the lipopolysaccharide molecules from the cell walls of the bacteria are shed from the organisms and are released into the circulatory system of the host. The discarded lipopolysaccharide molecules then interact with the host's immune system and begin a cascade of immunorelated physiological reactions. The lipopolysaccharides interact with the host macrophages. The interaction of lipopolysaccharides with the macrophages stimulates these white cells to release the cellular hormone TNF-alpha ("TNF-a"). This TNF-a hormone negatively impacts the host and produces a series of stereotypical responses including elevated temperature, blood coagulation, changes in white blood cell morphology and increased activity of the immune response. These responses become increasingly severe and ultimately manifest clinically as sepsis or septic shock. Web site: http://www.delphion.com/details?pn=US06444654__ •
Isoxazole derivatives to be used as phosphodiesterase VII inhibitors Inventor(s): Eggenweiler; Hans-Michael (Weiterstadt, DE), Gassen; Michael (Griesheim, DE), Jonas; Rochus (Darmstadt, DE), Welge; Thomas (Alsbach, DE), Wolf; Michael (Darmstadt, DE) Assignee(s): Merck Patentgesellschaft (darmstadt, De) Patent Number: 6,531,498 Date filed: May 3, 2002 Abstract: The invention relates to compounds of formula I and to their physiologically acceptable salts and solvates which act as phosphodiesterse VII inhibitors and are thus useful for the treatment of allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases, rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumor growth, tumor metastases, sepsis, memory disturbances, atherosclerosis and AIDS. Excerpt(s): and their physiologically acceptable salts and/or solvates as phosphodiesterase VII inhibitors. The invention further relates to the use of the compounds of the formula I for producing a pharmaceutical for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as, for example, rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastases, sepsis, memory disturbances, atherosclerosis and AIDS. Compounds of the formula I are described by Bionet. Web site: http://www.delphion.com/details?pn=US06531498__
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Lipopolysaccharide-binding and neutralizing peptides Inventor(s): Hoess; Adolf (Warngau, DE), Liddington; Robert C. (Boston, MA), Siber; George R. (Irvington, NY) Assignee(s): Dana-farber Cancer Institute, Inc. (boston, Ma) Patent Number: 6,384,188 Date filed: June 7, 1995 Abstract: Substance which bind with high affinity to endotoxin (lipopolysaccharide [LPS]), and which are useful for the prevention or treatment of, for example, Gramnegative and Gram-positive bacterial sepsis, and for the treatment of bacterial and fungal infections as well as for neutralizing effects associated with heparin. The substances are LPS-binding peptides comprising an LPS-binding domain. DNA sequences encoding peptides, recombinant microorganisms containing the DNA, pharmaceutical compositions containing the peptides of the invention, and diagnostic kits. Methods for the detection and removal of bacterial LPS from solutions. Excerpt(s): The present invention relates to substances which bind with high affinity to endotoxin (lipopolysaccharide [LPS]), and which are useful for the prevention or treatment of a variety of conditions and diseases, such as of Gram-negative and Grampositive bacterial sepsis, or bacterial or fungal infections. Furthermore, said substances may be used for neutralizing effects associated with heparin. The substances are LPSbinding peptides comprising an LPS-binding domain. The invention also encompasses methods for the detection and removal of bacteria LPS from solutions. In humans, LPS released during infection by Gram-negative bacteria can cause the severe pathological changes associated with septic shock (Duma, Am. J. Med. 78 (1985) 154-163; Glauser et al., Lancet 338 (1991), 732-736). In the United States, septic shock is responsible for between 100,000 and 300,000 deaths annually (Ziegler et al., N. Eng. J. Med. 324 (1991), 429-436) and in Germany for between 70,000 and 100,000. Although a variety of agents have been evaluated for neutralizing LPS or enhancing its clearance in vivo, there remains no specific treatment for Gram-negative bacterial sepsis. Septic shock is complex condition which arises from a cascade of molecular and cellular events following infection by microorganisms, predominant among which are Gram-negative bacteria. The onset of shock arises from the interaction of LPS or lipid A with membrane-bound receptors on macrophages and blood monocytes (Couturier et al., J. Immun. 147 (1991), 1899-1904) or various serum proteins, such as the septins (Wright et al., J. Exp. Med. 176 (1992), 719-727). These interactions lead to an increase in the levels of pro-inflammatory mediators such as tumor necrosis factor, IL-1, IL-6, and interferonc. Endothelial cells are also stimulated to produce factors which attract neutrophils. Release of enzymes and other factors by activated neutrophils causes damage to local vasculature which can lead rapidly to death. Web site: http://www.delphion.com/details?pn=US06384188__
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Method for therapeutic immunmodulation of plasma Inventor(s): Altrichter; Jens (Kavelstorf, DE), Freytag; Jens (Rostock, DE), Mitzner; Steffen (Rostock, DE), Stange; Jan (Rostock, DE) Assignee(s): Teraklin Aktiengessellschaft (de) Patent Number: 6,509,147 Date filed: July 14, 1999
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Abstract: A process and set-up of therapeutic immunomodulation is provided for medicine. Many illnesses (i.e. Sepsis) are, among other things, characterized by a disruption of the immune system. In spite of previous therapies using antibiotics, the mortality rate is still very high. The administration of individual cytokins has not yet resulted in any convincing results. The use of cells in an extra-corporal circulation that can adsorb or self-release immunomodulatory effect substances is a completely new type of complex therapeutic approach to such illnesses, which leads to an improvement in the health of the affected patients. Excerpt(s): The current knowledge regarding the course and the pathogenesis of a sepsis comes in large part from studies on the interaction between gram-negative bacteria and the human organism (Chest 1992; 101; 1644-1655). The primary agents for introducing a sepsis cascade accordingly produce bacterial endotoxins, a group of lipopolysaccharides from the cell wall of gram-negative bacteria. (Reviews Infect. Dis. 1983; 5; 733-747). Endotoxins, possibly the most potent fever-producing substances of all (pyrogens), activate above all monocytes and endothelial cells. The immune system is activated through the release of mediators or, as the case may be, the development of adhesive molecules, preparing a leukocytic suppression. This leads to a migration of the leukocytes into tissues with high chemotoxin content (site of local inflammation). If the local cause can be eliminated, then the inflammation process is impeded. If over a longer time period, either intermittently or continuously, this leads to an excessive influx of bacteria, endotoxins or other antigen-like acting cell products into the blood, then the useful defense reaction by monocytes and endothelial cells changes into an autoaggressive process with severe circulation dysfunction, secondary organ failures, coagulation disruptions (DIC), etc.; a sepsis (with positive proof of causative agent) or, as the case may be, a systemic inflammatory response syndrome (SIRS, no provable cause) develop and cause death in up to 30% of the cases where a simple sepsis is involved and up to 90% in patients where septic shock is involved. (Sepsis. An interdisciplinary challenge. Berlin, Heidelberg, New York: Springer Verlag, 1989). Gram-positive causes of the genesis of sepsis have in recent years increasingly become an object of research study. Countless studies deal with the increased incidence of grampositive sepsis in the last decade. Statistics show that now already 30 to 40% of all cases of sepsis can be traced back to gram-positive causes (Am J. Med. 1991; 91 (suppl. 3B): 7289). The treatment of bacterial sepsis in intensive-care medical centers is made additionally difficult because of increasing resistance to antibiotics. Web site: http://www.delphion.com/details?pn=US06509147__ •
Method for treatment and prevention of physiological shock Inventor(s): Hugli; Tony (San Diego, CA), Mitsuoka; Hiroshi (Hamamatsu, JP), SchmidSchoenbein; Geert (Del Mar, CA) Assignee(s): The Regents of the University of California (oakland, Ca), The Scripps Institute (la Jolla, Ca) Patent Number: 6,534,283 Date filed: November 22, 2000 Abstract: Shock is a life threatening complication in situations associated with trauma including burns, surgery, ischemia, sepsis, and other critical care applications. Shock is induced by pancreatic proteases when they are released into the small intestine when the tissue is compromised due to trauma. Administration of protease inhibitors into the small intestine, either orally, intraveneously, or by direct lavage, was demonstrated to
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prevent shock in rats as determined by both survival time and molecular and histological analysis. Excerpt(s): The present invention is a method for the prevention and treatment physiologic shock involving the inhibition or removal of proteases in the small intestine and in circulation to prevent the generation of the mediators of shock. It is also a method for the identification of the proteases involved in shock to allow for the development of protease inhibitors for use in the treatment of shock. Shock is a life-threatening complication in situations associated with trauma including burns, surgery, ischemia, sepsis, and other critical care applications. Shock is a broad term that describes a group of circulatory syndromes, all of which result in general cellular hypoxia. This leads to a depletion of the adenosine triphosphate (ATP), the failure of the sodium-potassium pump, mitochondrial dysfunction, and ultimately the release of a variety of toxic substances, including superoxides. Superoxides are toxic to essentially all tissues. They react with proteins and cause unfolding and are able to induce DNA damage. Additionally, cellular activation in the circulation can be detected by leukocytes or endothelial cells resulting in superoxide production, pseudopod projections, enzyme release, cytokine release, and expression of membrane adhesion molecules. Cell activation fundamentally alters the biomechanics of microvascular blood flow by a shift in rheological, adhesive, and cytotoxic cell properties. Eventually these stress responses give rise to irreversible cardiovascular collapse because of their combined effects on the microcirculation. The interaction between activated leukocytes, both neutrophils and monocytes, and endothelial cells leads to accumulation of leukocytes in various organs, leading to cytotoxicity and cell death. Although such processes are mediated by humoral activators in the plasma of systemic circulation, an inflammation in organs throughout the body may eventually lead to multi-organ failure. When leukocytes are activated, neutrophil pseudopod formation is upregulated and several membrane adhesion molecules are expressed. This process lowers cell deformability and leads to accumulation of neutrophils in microcirculation. Not only may leukocytes start inflammation, but the abnormal cellular entrapment in the microcirculation also leads to immune suppression because of the reduced numbers of circulating cells. Web site: http://www.delphion.com/details?pn=US06534283__ •
Method of reducing mortality in severe sepsis Inventor(s): Grinnell; Brian William (Indianapolis, IN), Hartman; Daniel Lawrence (Indianapolis, IN), Yan; Sau-Chi Betty (Indianapolis, IN) Assignee(s): Eli Lilly and Company (indianapolis, In) Patent Number: 6,489,296 Date filed: May 10, 2000 Abstract: A method of treatment for human patients with an acquired hypercoagulable state or acquired protein C deficiency associated with sepsis, purpura fulminans, meningococcal sepsis, bone marrow and other transplantations, severe burns, pregnancy, major surgery, severe trauma, or ARDS, which comprises administering activated protein C providing a highly selective therapeutic agent with a low potential for causing bleeding complications. Excerpt(s): This invention relates to medical science particularly the treatment of hypercoagulable states or acquired protein C deficiency with activated protein C. Protein C is a serine protease and naturally occurring anticoagulant that plays a role in
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the regulation of hemostasis through its ability to block the generation of thrombin production by inactivating Factors Va and VIIIa in the coagulation cascade. Human protein C is made in vivo primarily in the liver as a single polypeptide of 461 amino acids. This precursor molecule undergoes multiple post-translational modifications including 1) cleavage of a 42 amino acid signal sequence; 2) proteolytic removal from the one chain zymogen of the lysine residue at position 155 and the arginine residue at position 156 to make the 2-chain form of the molecule, (i.e., a light chain of 155 amino acid residues attached through a disulfide bridge to the serine protease-containing heavy chain of 262 amino acid residues); 3) vitamin K-dependent carboxylation of nine glutamic acid residues clustered in the first 42 amino acids of the light chain, resulting in 9 gamma-carboxyglutamic acid residues; and 4) carbohydrate attachment at four sites (one in the light chain and three in the heavy chain). The heavy chain contains the well established serine protease triad of Asp 257, His 211 and Ser 360. Finally, the circulating 2-chain zymogen is activated in vivo by thrombin at a phospholipid surface in the presence of calcium ion. Activation results from removal of a dodecapeptide at the Nterminus of the heavy chain, producing activated protein C (aPC) possessing enzymatic activity. In conjunction with other proteins, aPC functions as perhaps the most important down-regulator of blood coagulation resulting in protection against thrombosis. In addition to its anti-coagulation functions, aPC has anti-inflammatory effects through its inhibition of cytokine generation (e.g. TNF and IL-1) and also exerts profibrinolytic properties that facilitate clot lysis. Thus, the protein C enzyme system represents a major physiological mechanism of anti-coagulation, anti-inflammation, and fibrinolysis. Web site: http://www.delphion.com/details?pn=US06489296__ •
Method of treating sepsis and ARDS with chemokine.beta.-4 Inventor(s): Pelus; Louis Martin (Richboro, PA), White; John Richard (Coatesville, PA) Assignee(s): Human Genome Sciences, Inc. (rockville, Md) Patent Number: 6,406,688 Date filed: February 1, 2000 Abstract: The invention relates to the method of preventing and treating sepsis and ARDS using chemokine.beta.-4 or a biologically active fragment thereof, alone or in conjunction with an anti-infective agent. Excerpt(s): This invention relates to the method of preventing and treating sepsis and adult respiratory distress syndrome using certain chemokines or biologically active fragments thereof alone or in conjunction with an anti-infective agent or hematopoietic maturing agent. (1) temperature >38.degree. C. or <36.degree. C.; (2) heart rate >90 beats per minute; (3) respiratory rate >20 breaths per minute or PaCO.sub.2 <32 mm Hg; (4) white blood cell count >12,000/cu mm, <4,000/cu mm, or >10% immature (band) forms; (5) organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to lactic acidosis, oliguria, or an acute alteration in mental states. (Chest 1992; 101: 1644-1566). Sepsis can occur in hospitalized patients having underlying diseases or conditions that render them susceptible to bloodstream invasion or in burn, trama or surgical patents. In many cases of sepsis, the predominant pathogen is Escherichia coli, followed by other Gram-negative bacteria such as the Klebsiella-Enterobacter-Serratia group and then Pseudomonas. Although comprising a somewhat smaller percentage of infection, Gram-positive microbes such as Staphylococcus and systemic viral and fungal infections are included by the term sepsis
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as used herein. The genitourinary tract is the most common site of infection, the gastrointestinal tract and respiratory tract being the next most frequent sources of sepsis. Other common foci are wound, burn, and pelvic infections and infected intravenous catheters. Web site: http://www.delphion.com/details?pn=US06406688__ •
Methods and compositions for ameliorating the symptoms of sepsis Inventor(s): Mathison; John C. (San Diego, CA), Tobias; Peter (Encinitas, CA), Ulevitch; Richard (Del Mar, CA), Wright; Samuel D. (New York, NY) Assignee(s): The Rockefeller University (new York, Ny), The Sripps Research Institute (la Jolla, Ca) Patent Number: 6,495,332 Date filed: October 2, 2001 Abstract: The present invention concerns a method of treating sepsis comprising administering a therapeutically effective amount of anti-CD14 antibody molecules. A therapeutic composition comprising anti-CD14 antibody molecules in a pharmaceutically acceptable excipient is also contemplated. Excerpt(s): The present invention relates to methods and compositions for preventing or treating sepsis. More particularly, the present invention relates to molecules that bind the CD14 monocyte differentiation antigen or LPS-LBP complexes, thereby inhibiting the binding of LPS-LBP complexes by CD14-expressing cells. Sepsis is a morbid condition induced by a toxin, the introduction or accumulation of which is most commonly caused by infection or trauma. The initial symptoms of sepsis typically include chills, profuse sweat, irregularly remittent fever, prostration and the like, followed by persistent fever, hypotension leading to shock, neutropenia, leukopenia, disseminated intravascular coagulation, adult respiratory distress syndrome and multiple organ failure. Sepsis-inducing toxins have been found associated with pathogenic bacteria, viruses, plants and venoms. Among the well described bacterial toxins are the endotoxins or lipopolysaccharides(LPS) of the gram-negative bacteria. These molecules are glycolipids that are ubiquitous in the outer membrane of all gramnegative bacteria. While chemical structure of most of the LPS molecule is complex and diverse, a common feature is the lipid A region of LPS [Rietschel, E. Th. et al., in Handbook of Endotoxins, 1:187-214 eds. R. A. Proctor and E. Th. Rietschel, Elsevier, Amsterdam (1984)]; recognition of lipid A in biologic systems initiates many, if not all, of the pathophysiologic changes of sepsis. Because lipid A structure is highly conserved among all types of gram-negative organisms, common pathophysiologic changes characterize gram-negative sepsis. Web site: http://www.delphion.com/details?pn=US06495332__
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Methods for the prophylactic and therapeutic treatment of cardiac tissue damage Inventor(s): Li; Chuanfu (Johnson City, TN), Williams; David L. (Johnson City, TN) Assignee(s): East Tennessee State University (johnson City, Tn) Patent Number: 6,713,459 Date filed: April 28, 2000
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Abstract: The invention provides a method for treating tissue damage caused by ischemia/reperfusion, microbial infection, or sepsis using (1.fwdarw.3)-.beta.-D-glucans to modulate immune response mediators and their effects. Excerpt(s): The present invention relates to methods for preventing and treating tissue injury. More specifically, the invention relates to methods for treating major organ (especially cardiac) tissue damage, particularly when associated with ischemia/reperfusion injury, sepsis, or microbial infection. Worldwide, the World Health Organization estimates that by 2020 up to 40 percent of all deaths will be related to cardiovascular disease. In 1995, cardiovascular disease accounted for almost 15 million deaths. Since 1900, cardiovascular disease has been the number one killer in the United States in every year except 1918 (the year of the influenza pandemic), and medical costs directly related to heart disease are estimated at 30 billion dollars annually. The American Heart Association estimates that approximately 59.7 million Americans have one or more types of cardiovascular disease. Ischemic heart disease and related cardiac myopathies are the major causes of cardiac dysfunction, with ischemic heart disease causing approximately 90% of cardiac mortalities. Myocyte loss, presumably due to apoptosis, is a feature of every known type of cardiomyopathy. Treatments for ischemic disease include aspirin, adrenoceptor blocking agents, nitrates, and angiotensin converting enzyme (ACE) inhibitors. Heparin has been administered (either intravenously or subcutaneously) in conjunction with a nonspecific fibrinolytic agent such as streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC), or urokinase. Web site: http://www.delphion.com/details?pn=US06713459__ •
Non-cognate hybridization system (NCHS) Inventor(s): Hibbs; Jonathan (116 Pinehurst Ave., Albany, NY 12203), Schrenzel; Jacques (1 chemin des Tulipiers, CH-1208 Geneva, CH) Assignee(s): None Reported Patent Number: 6,544,777 Date filed: June 2, 2000 Abstract: The present invention comprises a non-cognate hybridization system (NCHS). The NCHS generally includes a hybridization technology that is simply and economically used to probe for non-cognate nucleic acid sequences, i.e., for nucleic acid strands without known target sequences. NCHS causes nucleic acids, bound to a probe surface, to create a hybridization pattern that provides information about the presence and/or quantity of the nucleic acid sequences in a sample. The NCHS results normally orient the examiner towards a small number of specific diagnoses across a wide variety of diagnostic categories (including but not limited to infections, neoplasms and autoimmune diseases). The test will also identify final-common-pathway syndromes such as sepsis, anaphylaxis and tumor necrosis. While the test utilizes genetic information, it does not depend on prior knowledge of the genes involved in a particular disease or syndrome. Excerpt(s): Rapid, accurate diagnosis of acutely ill patients is critical for their survival. Typically, thousands of dollars in diagnostic tests are performed within 24 hours of a patient's admission to hospital. Accurate diagnosis of a treatable condition allows appropriate therapy to be started and unnecessary, potentially harmful medications to be stopped. On the other hand, some diagnostic tests require days to complete, some are
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invasive or even dangerous to perform, and all contribute to the upward spiral of medical costs. Selection and interpretation of appropriate tests in the appropriate order is therefore a highly valued skill, necessary to the physical health of the patient and the financial health of the care provider. Requiring fast, accurate responses for an everexpanding list of diagnostic questions, clinical laboratories turn more and more frequently to answers from molecular genetics. This rapidly evolving discipline comprises the study of gene structure and function at the molecular level. The most straightforward diagnostic application of this approach is to search clinical specimens for the presence of a particular gene or a particular allele (one variety of a particular gene). It is possible to use this direct approach to diagnose genetically transmitted diseases such as Huntington's chorea (by detecting the disease-causing allele), or to diagnose occult infections with agents such as Bartonella henselae, the agent of catscratch disease (by detecting genes specific for that organism). Gene detection tests such as these have already found a welcome place for themselves within the vast arsenal of tests offered by reference laboratories. In some cases (notably the detection of herpes simplex virus in cerebrospinal fluid or Chlamydia trachomatis in genital specimens) amplification and detection of genes have become the front-line standard diagnostic tests for conditions difficult to diagnose by other means. These tests require <24 hours from specimen to final result, and replace less sensitive methods with a turnaround time of several days or even weeks. Gene detection tests of this kind remain expensive, however, and have to be tailor-made for one or two organisms at a time. They are not useful for diagnosing disease caused by certain organisms such as bacteria of the genus Staphylococcus, which is normally present on the skin but which can also cause lifethreatening disease. A less obvious application of molecular genetics to clinical diagnosis requires analysis of gene transcription rather than the presence or absence of a particular gene. Disease-associated genes are present in all living things, including human hosts and parasites of all kinds (worms, protozoa, fungi, bacteria and viruses). In some cases, the mere presence of genetic material in a human specimen is enough to signify disease--the presence of genes specific for human immunodeficiency virus, for example, or trisomy 21 for a diagnosis of Down's syndrome. In other cases, however, a "pathological" gene may be present, but clinically silent for a variety of reasons. Examples include the defective hemoglobin gene which causes sickle cell anemia when two copies are present, but minimal disease when one copy is transcribed along with the normal hemoglobin allele, and no disease at all when the sickle cell allele is present but not transcribed. Moreover, genes for certain components of the immune system are present in every cell, but are only transcribed --that is, copied from DNA into RNA-when the host organism is diseased. The presence of these genes is universal, but transcription of them usually indicates a disease state. Web site: http://www.delphion.com/details?pn=US06544777__ •
Nutritional compositions which contain slightly negatively charged, non-digestible polysaccharides and use thereof for reducing transport through tight junctions Inventor(s): Bijlsma; Pieter Brandt (Amsterdam, NL), Groot; Jacques Alphons (Heiloo, NL), Kiliaan; Amanda Johanna (Wageningen, NL), Timmermans; Johannes Wilhelmus (Ede, NL), Van Der Meulen; Jan (Dronten, NL) Assignee(s): N.v. Nutricia (zoetermeer, Nl) Patent Number: 6,686,341 Date filed: January 2, 2002
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Abstract: A nutritional composition which contains slightly negatively charged nondigestible polysaccharides having a molecular weight of 8 kD to 40,000 kD, characterized in that the rise in the viscosity of the composition caused by the polysaccharides is less than 20 mpa.multidot.s. This nutritional composition is used to reduce the uptake of high molecular weight substances, allergens and microorganisms through the intestinal wall, more particularly to reduce transport of high molecular weight substances, allergens and microorganisms through the intestinal wall, ore particularly to reduce transport of high molecular weight substances, allergens and microorganisms through the tight junctions in the intestines. The nutritional compositions can be used to prevent or to treat allergies, allergic reactions, sepsis and inflammatory processes, such as those which can arise under emotional and physical stress, ischaemia, reperfusion damage during and after operations, following radiation treatment and/or chemotherapy of cancer patients and in the case of inflammatory intestinal diseases, diarrhoea and allergies. Excerpt(s): The present invention relates to nutritional compositions which contain certain classes of non-digestible polysaccharides. These compositions reduce the uptake of high molecular weight substances, allergens and microorganisms through the intestinal wall. In particular the present invention relates to reduction of the free transport of such substances through the tight junctions (TJs) of the intestines, without the transport of low molecular weight substances, such as nutrients, via the intestinal epithelium being impeded. The compositions can be used to prevent the increased permeability of the intestinal wall, due to various causes, and the penetration, resulting therefrom, of toxins, antigens and pathogenic microorganisms present in the lumen. The structure and fraction of tight junctions is described, inter alia, in Ann. Rev. Physiol. 60, 121-160 (1998) and in Ballard T. S. et al., Annu.Rev.Nutr., 1995, 15:35-55. Tight junctions do not form a rigid barrier but play an important role in diffusion through the intestinal epithelium from lumen to bloodstream and vice versa. Web site: http://www.delphion.com/details?pn=US06686341__ •
Nutritional preparation comprising ribose and medical use thereof Inventor(s): Hageman; Robert Johan Joseph (Waddinxveen, NL), Smeets; Rudolf Leonardus Lodewijk (Venlo, NL), Verlaan; George (Wageningen, NL) Assignee(s): N.v. Nutricia (zoetermeer, Nl) Patent Number: 6,420,342 Date filed: May 8, 2000 Abstract: Trauma, surgery, inflammation, subfertility, lactation problems, gut disorders, infant nutrition, cancer, arthritis and other joints problems, vascular problems and cardio- or cerebro vascular problems, ischaemia, aging, impaired immune function, burns, sepsis, malnutrition, problems with liver or kidneys, malaria, cystic fibrosis, migraine, neurological problems, respiratory infections, improvement of sports results, muscle soreness, drug intoxication and pain can be treated with a nutritional composition containing effective amounts of ribose and folic acid, optionally combined with other components such as niacin, histidine, glutamine, orotate, vitamin B6 and other components. Excerpt(s): The invention is related to nutritional, pharmaceutical or dietetic preparations that comprise ribose or folic acid or functional analogs thereof and the use of these compositions in the prevention or treatment of specific diseases that are related
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to disorders or insufficiencies of total nucleotide metabolism. Nucleotides are heterocyclic compounds that occur in all mammals. Nucleotides consist of a purine or pyrimidine base, a sugar unit and one to three phosphate groups. The major purine bases that occur in the human body are adenine (6-aminopurine), guanine (2-amino-6hydroxypurine), hypoxanthine (6-hydroxypurine) and xanthine (2,6-dihydroxypurine); the major pyrimidines are uracil (2,4-dihydroxypyrimidine), cytosine (2,4-dihydroxy-5methylpyrimidine) and thymine (4-amino-2-hydroxypyrimidine). The sugar moiety can be ribose (in ribonucleosides) or 2-deoxyribose. The sugar moiety is connected to the base through a.beta.-N-glycosidic bond at N9 of the base; the phosphate groups are connected to the sugar moiety through the 3' or 5' position. When the phosphate groups are split from nucleotides compounds called nucleosides are formed. For the purpose of this document, total nucleotide netabolism (TNM), is defined as the combination of all biochemical pathways in which nucleotides, their precursors and metabolites are directly involved as main ingredients and that occur in the body of mammals. The pathways include the synthetic routes for purines and pyrimidines, both de novo and salvage pathways, starting from carbamoyl phosphate and 5-phosphoribosyl-1pyrophosphate (PRPP), respectively. They also include the interconversions of the various nucleotides into each other, the phosphorylation and dephosphorylation reactions of respectively nucleosides and nucleotides and the catabolic pathways of nucleotides to the compounds that are cleared from the body. They do not include the further reactions of phosphoric groups thus split off from the phosphorylated nucleotides. Web site: http://www.delphion.com/details?pn=US06420342__ •
Polynucleotides encoding chemokine alpha-3 Inventor(s): Li; Haodong (Gaithersburg, MD), Ni; Jian (Rockville, MD), Su; Jeffrey (Gaithersburg, MD) Assignee(s): Human Genome Sciences, Inc. (rockville, Md) Patent Number: 6,410,268 Date filed: March 18, 1997 Abstract: Human chemokine Alpha-3 polypeptides and DNA (RNA) encoding such chemotactic cytokines and a procedure for producing such polypeptides by recombinant techniques is disclosed. Also disclosed are methods for utilizing such chemotactic cytokines for the treatment of leukemia, tumors, chronic infections, auto-immune disease, fibrotic disorders, sepsis, wound healing and psoriasis and to stimulate stem cell mobilization. Antagonists against such chemotactic cytokines and their use as a therapeutic to treat rheumatoid arthritis, auto-immune and chronic and acute inflammatory and infective diseases, allergic reactions, prostaglandin-independent fever, ARDS and bone marrow failure are also disclosed. Also disclosed are diagnostic assays for detecting diseases related to mutations in the nucleic acid sequences and altered concentrations of the polypeptides. Also disclosed are diagnostic assays for detecting mutations in the polynucleotides encoding the chemotactic cytokines and for detecting altered levels of the polypeptide in a host. Excerpt(s): This invention relates, in part, to newly identified polynucleotides and polypeptides; variants and derivatives of the polynucleotides and polypeptides; processes for making the polynucleotides and the polypeptides, and their variants and derivatives; agonists and antagonists of the polypeptides; and uses of the polynucleotides, polypeptides, variants, derivatives, agonists and antagonists. In
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particular, in these and in other regards, the invention relates to polynucleotides and polypeptides of human chemokine alpha-3, hereinafter referred to as "Ck.alpha.-3. The ability to control the migration and "trafficking" of various cell types is controlled by a subset of factors, or proteins, among which chemokines are an example. Chemokines, also referred to as intercrine cytokines, are a subfamily of structurally and functionally related chemotactic cytokines. These molecules are 8-10 kd in size. In general, chemokines exhibit 20% to 75% homology at the amino acid level and are characterized by four conserved cysteine residues that form two disulfide bonds. Based on the arrangement of the first two cysteine residues, chemokines have been classified into two subfamilies, alpha and beta. In the alpha subfamily, the first two cysteines are separated by one amino acid and hence are referred to as the "C-X-C" subfamily. In the beta subfamily, the two cysteines are in an adjacent position and are, therefore, referred to as the "C-C" subfamily. to as the "C-C" subfamily. Thus far, at least eight different members of this family have been identified in humans. Web site: http://www.delphion.com/details?pn=US06410268__ •
Process for purifying apolipoprotein A or apolipoprotein E Inventor(s): Wiklund; Sara (Skarpnack, SE), Winge; Stefan (Stockholm, SE) Assignee(s): Esperion Therapeutics, Inc. (ann Arbor, Mi) Patent Number: 6,423,830 Date filed: July 17, 2000 Abstract: The present invention relates to a process for purifying apolipoprotein A (ApoA) or apolipoprotein E (ApoE) from human plasma, by obtaining a fraction of human plasma containing said ApoA or ApoE, prepurifying said fraction in at least one step, binding said ApoA or ApoE to an anion-exchange chromatography gel, and thereafter eluting said ApoA or ApoE from said anion-exchange chromatography gel. The thus produced ApoA or ApoE can be used for the manufacture of a medicament in the treatment of atherosclerosis and cardiovascular diseases, or peripheral atherosclerosis and sepsis as well as in a method for treatment of atherosclerosis and cardiovascular diseases, or peripheral atherosclerosis and sepsis when administered in a therapeutically effective amount. Excerpt(s): The present invention relates to a process for purifying apolipoprotein A (ApoA) or apolipoprotein E (ApoE), which are important components of the high density and low density lipoproteins in plasma. More particularly, this invention relates to a process for obtaining ApoA or ApoE from human plasma, by prepurifying said ApoA or ApoE in at least one step, binding said ApoA or ApoE to an anion-exchange chromatography gel, and thereafter eluting said ApoA or ApoE from said anionexchange chromatography gel. The main function of lipoproteins in plasma is to transport lipids, such as cholesterol and triglycerides. For transport in plasma, cholesterol, normally as cholesteryl esters, and the triglycerides are included into lipoprotein particles in which they form a hydrophobic core. The core is surrounded by a surface coat containing phospholipids, unesterified cholesterol and proteins called apolipoproteins. The latter are responsible for the lipid transport, and in addition, some may interact with many of the enzymes involved in lipid metabolism. To date, at least nine apolipoproteins have been identified: A-I, A-II, A-IV, B, C-I, C-II, C-III, D and E. There are four major classes of lipoproteins: chylomicrons (CM), very low density (VLDL), low density (LDL) and high density (HDL) lipoproteins. Of these, HDL is directly involved in the removal of cholesterol from peripheral tissues, carrying it back
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either to the liver or to other lipoproteins, by a mechanism known as "reverse cholesterol transport" (RCT). Web site: http://www.delphion.com/details?pn=US06423830__ •
Substituted quinoxaline derivatives as interleukin-8 receptor antagonists Inventor(s): Carson; Kenneth G. (Needham, MA), Connor; David Thomas (Ann Arbor, MI), Li; Jie Jack (Ann Arbor, MI), Low; Joseph Edwin (Brighton, MI), Luly; Jay R. (Wellesley, MA), Miller; Steven Robert (Ann Arbor, MI), Roth; Bruce David (Plymouth, MI), Trivedi; Bharat Kalidas (Farmington Hills, MI) Assignee(s): Millennium Pharmaceuticals, Inc. (cambridge, Ma) Patent Number: 6,548,499 Date filed: October 20, 2000 Abstract: Quinoxaline compounds are described as well as methods for the preparation and pharmaceutical compositions of same, which are useful as interleukin-8 (IL-8) receptor antagonists and can be used in the treatment of a chemokine-mediated disease wherein the chemokine binds to an IL-8a (CXCR1) or b (CXCR2) receptor such as a chemokine-mediated disease selected from psoriasis, or atopic distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, or thrombosis, Alzheimer's disease, graft versus host reaction, allograft rejections, or allergic diseases. Excerpt(s): The present invention relates to novel quinoxaline compounds useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutical carrier, and to pharmaceutical methods of treatment. The compounds of the present invention are Interleukin-8 (IL-8) receptor antagonists. More particularly, the compounds of the present invention are useful in the treatment of a chemokine-mediated disease wherein the chemokine binds to an IL-8a (CXCR1) or b (CXCR2) receptor such as, for example, a chemokine-mediated disease selected from psoriasis, or atopic dermatitis, tumor growth and angiogenesis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, or thrombosis, Alzheimer's disease, graft versus host reaction, allograft rejections, or allergic diseases. We have identified a series of quinoxalines that are IL-8 receptor antagonists and which can additionally be used in psoriasis, or atopic dermatitis, disease associated with pathological angiogenesis (i.e. cancer), asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulonephritis, or thrombosis, Alzheimer's disease, graft versus host reaction, allograft rejections, or allergic diseases. or a pharmaceutically acceptable salt thereof. Web site: http://www.delphion.com/details?pn=US06548499__
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Synthetic peptides with antimicrobial and endotoxin neutralizing properties for management of the sepsis syndrome Inventor(s): Abraham; Philip Richard (Duivendrecht, NL), Appelmelk; Bernard Jan (Amsterdam, NL), Van Deventer; Sander Jan Hendrik (Haarlem, NL) Assignee(s): Academisch Ziekenhuis Bij DE Universiteit Van Amsterdam Academisch Medisch (amsterdam-zuidoost, Nl) Patent Number: 6,624,140 Date filed: January 28, 2000 Abstract: A peptide with an amino acid composition such that the peptide is amphipathic, cationic and forms a stable.alpha.-helix and has the following structure comprising at least 12 amino acidsR.sub.1 -R.sub.2 -A.sub.1 -B.sub.1 -(A.sub.2 -B.sub.2 C.sub.1 -A.sub.3).sub.m -(C.sub.2).sub.n -R.sub.3, whereinA=an amino acid selected from the basic amino acids Lys,Arg or HisB=an amino acid selected from the aromatic amino acids Phe, Trp or TyrC=an amino acid selected from the group comprising the hydrophobic amino acids Leu, Ile, Val or Ala, andsaid peptide has either the orientation according to the formula or the retro orientation thereof, wherein at least 0-m of the repetitive sequence motifs (A.sub.2 -B.sub.2 -C.sub.1 -A.sub.3) have the retro orientation and the remaining repetitive motifs (A.sub.2 -B.sub.2 -C.sub.1 -A.sub.3) have the orientation as presented in the formula and wherein,R.sub.1 -R.sub.2 - and R.sub.3 are a number of amino acids, and whereinm=1-10, preferably 2-8, more preferably 2-5 andn=1-3, a pharmaceutical composition comprising such a peptide application thereof in treatment or diagnosis related to i.a. parasite infection topical and systemic tumors and septic shock. Excerpt(s): Bacterial infections as a complication of surgery, prolonged hospitalization, accidents and other traumatic events, may lead to serious clinical symptoms such as sepsis, septic shock, inadequate organ perfusion, multiple organ failure and acute respiratory distress syndrome (ARDS). Despite advances in medicine over the past decade, an increase in the incidence of sepsis is evident with a mortality rate of 20 to 80%. The sepsis syndrome is initiated when micro-organisms bypass the natural defensive barriers of the body, such as skin and mucous membranes. If the immune system is unable to arrest the infection locally, the organism or its toxins may invade the circulation, where specific bacterial products elicit an inflammatory response that leads to the activation of an array of plasma proteins and cellular defense systems. Although mobilisation of the defence systems of the host is of paramount importance in combatting invading organisms, a cascade of events may simultaneously be triggered that can lead to irreversible tissue injury and organ dysfunction. Uncontrolled infections with Gram-negative bacteria such as Escherichia coli, Klebsiella spp., Neisseria spp., Pseudomonas aeruginosa, Salmonella spp, or Bordella spp. or the Gram-positive bacteria Staphylococcus aureus, Enterococcus spp., Streptococcus spp., Micrococcus luteus or Listeria monocytogenes give rise to a variety of clinical symptoms collectively referred to as the sepsis syndrome. The component of Gram-negative bacteria responsible for the initiation of the host response is termed endotoxin or lipopolysaccharide (LPS), a major glycolipid constituent of the outer membrane. In the circulation, LPS stimulates specific blood cells to produce endogenous mediators of inflammation termed cytokines such as tumor necrosis factor alpha (TNF-.alpha.), interleukin-6 (IL-6) and interleukin-8 (IL-8) which have profound physiological effects on the organs and blood vessels of the body. Persistent stimulation of the cellular defence system by excessive LPS leads to overproduction of cytokines which activate a cascade of secondary inflammatory mediators eventually leading to blood vessel
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damage, circulatory and metabolic disturbances. The toxic component of the LPS molecule is the highly conserved Lipid A moiety which is sufficient to induce the pathophysiological changes characteristic of sepsis. The prognosis of patients with endotoxemia would be considerably improved if the onset of sepsis could be detected at a sufficiently early stage in the disease process to enable effective treatment. Direct measurement of circulating endotoxins is of importance for the prediction of important clinical events such as bacteremia, septic shock and death. Clinically significant endotoxemia may go undetected by the currently available endotoxin assay, the Limulus amoebocyte lysate assay or LAL test, which has been shown to have serious limitations relating to sensitivity as well as to interference by plasma factors. Current therapeutic options for Gram-negative bacterial sepsis are limited to anti microbial agents, hemodynamic support and management of sepsis-induced organ dysfunction. Although conventional antibiotic therapy is effective in halting the proliferation of susceptible micro-organisms, the massive release of LPS into the circulation by damaged bacteria may aggravate a septic episode. The relative importance of endotoxin release (endotoxemia) versus bacterial proliferation (bacteremia) during Gram-negative septic shock, however, has not fully been defined. Extensive clinical use of conventional antibiotics such as penicillins, cephalosporins and the like, in the treatment of bacterial infections during the past three decades, has resulted in a dramatic reduction in the efficacy of antibiotic therapy due to an alarming increase in the number of multi-drugresistant bacteria. Web site: http://www.delphion.com/details?pn=US06624140__
Patent Applications on Sepsis 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 sepsis: •
5-Thia-omega-(substituted phenyl)-prostaglandin e alcohols, process for preparing the alcohols and pharmaceutical preparations containing the same as the active ingredient Inventor(s): Kobayashi, Kaoru; (Osaka, JP), Maruyama, Toru; (Osaka, JP) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, N.W.; Washington; DC; 20037; US Patent Application Number: 20030097023 Date filed: July 3, 2002 Abstract: A 5-thia-.omega.-substituted phenyl-prostaglandin E alcohol of the formula (I) 1(wherein, all the symbols are the same meanings as defined in the specification), a process for producing it and a pharmaceutical composition comprising it as an active ingredient.The compounds of the formula (I) may be converted into carboxylic acids in the living body which can bind on PGE.sub.2 receptors (especially, subtype EP.sub.4) strongly, so the compounds of the formula (I) are expected to be useful for prevention and/or treatment of immunological diseases, asthma, abnormal bone formation, neuronal cell death, lung failure, liver damage, acute hepatitis, nephritis, renal
10
This has been a common practice outside the United States prior to December 2000.
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insufficiency, hypertension, myocardiac ischemia, systemic inflammatory response syndrome, sepsis, hemophagous syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure, shock, sleeping disorder and blood platelet aggregation. Excerpt(s): The present invention relates to a 5-thia-.omega.-substituted phenylprostaglandin E alcohol. (wherein, all the symbols are the same meaning as defined hereinafter), a process for producing it and a pharmaceutical composition it as an active ingredient. Prostaglandin E.sub.2 (abbreviated as PGE.sub.2) has been known as a metabolite in the arachidonate cascade. It has been known that PGE.sub.2 possesses cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a suppressive effect on gastric acid secretion, hypotensive activity and diuretic activity etc. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Administration of an anti-endotoxin drug by bolus or intermittent intravenous infusion Inventor(s): DiLea, Clifford; (Spring Lake, NJ), Lynn, Melvyn; (East Brunswick, NJ), Rossignol, Daniel P.; (Mahwah, NJ) Correspondence: Clark & Elbing Llp; 101 Federal Street; Boston; MA; 02110; US Patent Application Number: 20030105033 Date filed: June 13, 2002 Abstract: The invention provides methods for administering an anti-endotoxin drug, E5564, by bolus or intermittent intravenous infusion. The methods can be used for treating conditions such as endotoxemia, sepsis, and septic shock. Excerpt(s): This application claims priority from U.S. Ser. No. 09/879,718, filed Jun. 11, 2001, which claims priority from U.S. Serial No. 60/210,638, filed Jun. 9, 2000, now abandoned. This invention relates to a regimen of administration of an anti-endotoxin drug. Since the 1930's, the increasing use of immunosuppressive therapy and invasive devices, as well as the increased incidence of antibiotic resistance in bacteria, have led to a gradual rise in the occurrence of sepsis and septic shock. Currently, the estimated incidences in the U.S. of sepsis and septic shock are greater than 400,000 and greater than 200,000 patients/year, respectively. This results in about 100,000 fatalities/year, making septic shock the most common non-coronary cause of death in the hospital Intensive Care Unit (ICU). Currently, ICU therapy for septic shock is limited to antibiotic therapy, cardiovascular resuscitation, Vasopressor/ionotrope therapy, and ventilatory support. This ICU care can cost up to $1,500/day and average a total of $13,000 to $30,000 per patient. Recently, Drotrecogin (Xigris.TM.) has been approved for the treatment of severe sepsis. Clearly, any therapy that can further reduce the morbidity and mortality, and therefore the cost of care, relating to sepsis/septic shock will be of great value. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Allenic aryl sulfonamide hydroxamic acids as matrix metalloproteinase and tace inhibitors Inventor(s): Delos Santos, Efren Guillermo; (Nanuet, NY), Sandanayaka, Vincent Premaratna; (Northboro, MA) Correspondence: Daniel B. Moran; Five Giralda Farms; Madison; NJ; 07940; US Patent Application Number: 20030130238 Date filed: November 1, 2002 Abstract: Compounds of the formula 1are useful in treating disease conditions mediated by TNF-.alpha., such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease, degenerative cartilage loss, graft rejection, cachexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease and HIV. Excerpt(s): This invention relates to allenic aryl sulfonamide hydroxamic acids which act as inhibitors of TNF-.alpha. converting enzyme (TACE) and matrix metalloproteinase (MMP). The compounds of the present invention are useful in disease conditions mediated by MMP and TACE, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease, degenerative cartilage loss, graft rejection, cachexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease and HIV. TNF-.alpha. converting enzyme (TACE) catalyzes the formation of TNF-.alpha. from membrane bound TNF-.alpha. precursor protein. TNF-.alpha. is a proinflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W. Exp. Opin. Ther. Patents 1998, 8(5), 531; Grossman, J. M.; Brahn, E. J. Women's Health 1997, 6(6), 627; Isomaki, P.; Punnonen, J. Ann. Med. 1997, 29, 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5), 613.] septic shock [Mathison, et. al. J. Clin. Invest. 1988, 81, 1925; Miethke, et. al. J. Exp. Med. 1992, 175, 91.], graft rejection [Piguet, P. F.; Grau, G. E.; et. al. J. Exp. Med. 1987, 166, 1280.], cachexia [Beutler, B.; Cerami, A. Ann. Rev. Biochem. 1988, 57, 505.], anorexia, inflammation [Ksontini, R,; MacKay, S. L. D.; Moldawer, L. L. Arch. Surg. 1998, 133, 558.], congestive heart failure [Packer, M. Circulation, 1995, 92(6), 1379; Ferrari, R.; Bachetti, T.; et. al. Circulation, 1995, 92(6), 1479.], post-ischaemic reperfusion injury, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance [Hotamisligil, G. S.; Shargill, N. S.; Spiegelman, B. M.; et. al. Science, 1993, 259, 87.] and HIV infection [Peterson, P. K.; Gekker, G.; et. al. J. Clin. Invest. 1992, 89, 574; Pallares-Trujillo, J.; Lopez-Soriano, F. J. Argiles, J. M. Med. Res. Reviews, 1995, 15(6), 533.]], in addition to its well-documented antitumor properties [Old, L. Science, 1985, 230, 630.]. For example, research with antiTNF-.alpha. antibodies and transgenic animals has demonstrated that blocking the formation of TNF-.alpha. inhibits the progression of arthritis [Rankin, E. C.; Choy, E. H.; Kassimos, D.; Kingsley, G. H.; Sopwith, A. M.; Isenberg, D. A.; Panayi, G. S. Br. J. Rheumatol. 1995, 34, 334; Pharmaprojects, 1996, Therapeutic Updates 17 (Oct.), au197M2Z.]. This observation has recently been extended to humans as well as described in "TNF-.alpha. in Human Diseases", Current Pharmaceutical Design, 1996, 2, 662. Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors. It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can
Patents 157
degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neo-vascularization and corneal graft rejection. For recent reviews, see: (1) Recent Advances in Matrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H. Davidson, A. H. Drummond, P. Huxley and M. Whittaker, Research Focus, Vol. 1,16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16, (3) Curr. Medicinal Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther. Patents (1995) 5(2): 1087-110, (5) Exp. Opin. Ther. Patents (1995) 5(12): 1287-1196: (6) Exp. Opin. Ther. Patents (1998) 8(3): 281-259. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Animal models and methods for sepsis Inventor(s): Bellinger-Kawahara, Carole; (Redwood City, CA), Contag, Pamela R.; (San Jose, CA), Hubbard, Alan; (Berkeley, CA) Correspondence: Cooley Godward, Llp; 3000 EL Camino Real; 5 Palo Alto Square; Palo Alto; CA; 94306; US Patent Application Number: 20030203418 Date filed: May 15, 2003 Abstract: Methods for selecting a candidate drug for treating sepsis are disclosed. The methods involve labeling a sepsis-causing pathogen with a reporter and monitoring the progress of infection by detecting levels of the reporter in animals treated with test compounds or drugs. The comparisons may be made between experimental and control animals, as well as within a single animal or group of animals. Also disclosed is a method for predicting an expected time of death of an experimental animal in a model system of sepsis using data generated in the initial part of the experiment. Excerpt(s): This application is related to U.S. Provisional Patent Application Serial No. 60/124,725 filed Mar. 17, 1999, from which priority is claimed under 35 USC.sctn.119(e)(1), and which application is incorporated herein by reference in its entirety. The present invention relates to animal models of sepsis and methods of use thereof. In particular, the invention relates to methods of predicting survival time of animals with sepsis, and methods of screening test compounds for effectiveness in treating sepsis. Sepsis, or illness caused by a severe infection, is the third leading cause of infectious death (Bone, et al., 1997). The majority of sepsis cases are caused by bacterial infections. Accordingly, a substantial amount of money and time has gone into the search for drugs effective to treat sepsis and/or eliminate the pathogens (e.g., bacteria) which cause sepsis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Antagonists of HMG1 for treating inflammatory conditions Inventor(s): Tracey, Kevin J.; (Old Greenwich, CT), Wang, Haichao; (Avenel, NJ) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20030113323 Date filed: September 11, 2002 Abstract: There is disclosed a pharmaceutical composition and method for treating sepsis, including septic shock and ARDS (acute respiratory distress syndrome), comprising administering an effective amount of a HMG1 antagonist. There is further disclosed a diagnostic method for monitoring the severity or potential lethality of sepsis or septic shock, comprising measuring the serum concentration of HMG1 in a patient exhibiting or at risk or exhibit sepsis or septic shock symptoms. Lastly, there is disclosed a pharmaceutical composition and method for effecting weight loss or treating obesity, comprising administering an effective amount of HMG1 or a therapeutically active HMG1 fragment. Excerpt(s): The present invention provides a pharmaceutical composition and method for treating diseases characterized by activation of an inflammatory cytokine cascade, particularly sepsis, including septic shock and ARDS (acute respiratory distress syndrome), comprising administering an effective amount of an antagonist to the high mobility group 1 protein (HMG1). The present invention further provides a diagnostic method for monitoring the severity of sepsis and related conditions, comprising measuring the serum concentration of HMG1 in a patient exhibiting symptoms of a disease characterized by activation of inflammatory cytokine cascade. Lastly, the present invention provides a pharmaceutical composition and method for effecting weight loss or treating obesity, comprising administering an effective amount of an HMG1 protein or a therapeutically active fragment of the gene product of an HMG1 gene. Sepsis is an often fatal clinical syndrome that develops after infection or injury. Sepsis is the most frequent cause of mortality in hospitalized patients. Experimental models of gram negative sepsis based on administration of bacterial endotoxin (lipopolysaccharide, LPS) have led to an improved understanding of the pathogenic mechanisms of lethal sepsis and conditions related to sepsis by virtue of the activation of a common underlying inflammatory cytokine cascade. This cascade of host-response mediators includes TNF, IL-1, PAF and other macrophage-derived factors that have been widely studied as acute, early mediators of eventual lethality in severe endotoxemia (Zhang and Trace), In The Cytokine Handbook, 3rd ed. Ed. Thompson (Academic Press Limited, USA). 515-547, 1998). Unfortunately therapeutic approaches based on inhibiting these individual "early" mediators of endotoxemia have met with only limited success in large prospective clinical trials against sepsis in human patients. It is possible to infer from these disappointing results that later-appealing factors in the host response might critically determine pathogenesis and/or lethality, in sepsis and related disorders. Accordingly, there is a need to discover such putative "late" mediators necessary and/or sufficient for part or all of the extensive multisystem pathogenesis, or for the lethality, of severe endotoxemia, particularly as endotoxemia is representative of clinical sepsis and related clinical disorders. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Anti-sepsis conjugate vaccine Inventor(s): DeBorde, Dan C.; (Missoula, MT), Gustafson, Gary L.; (Missoula, MT) Correspondence: Schwegman, Lundberg, Woessner & Kluth, P.A.; P.O. Box 2938; Minneapolis; MN; 55402; US Patent Application Number: 20030138448 Date filed: October 15, 2002 Abstract: The present invention provides an immunogenic conjugate comprising biologically deacylated gram-negative bacterial moieties linked to D. discoideum proteinase 1, as well as novel subunits thereof, and methods of making and using the conjugates in vaccines to treat sepsis and other infectious complications. Excerpt(s): In spite of significant improvements in antibiotic therapy and in intensive care, sepsis, and its sequelae, sepsis syndrome or septic shock (collectively, "sepsis"), remain a leading cause of morbidity and mortality among hospitalized patients. Sepsis is triggered by gram-negative and gram-positive bacteria, fungi, and other pathogenic microorganisms. These organisms release toxins at the nidus of injury or infection, that in turn trigger the release of cytokines and other mediators. If infection is not controlled, endotoxin and/or other mediators of inflammation may enter the circulation, initiating sepsis and the cascade of events that leads to endothelial damage, hypotension and multi-organ failure. Gram-negative bacteria are responsible for a large number of such episodes, which are associated with a high mortality rate. See, e.g., Centers for Disease Control, "Increase in national hospital discharge survey rates for septicemia B United States, 1979-1987," Morbid. Mortal. Weekly Reports, 39, 31 (1990). In patients who develop septic shock caused by gram-negative bacteria, the fatality rate may reach 50% or more. See, R. C. Bone et al., N. Eng. J. Med., 317, 653 (1987). Escherichia coli remains the leading causative organism, accounting for 40 to 52% of gram-negative blood isolates (S. Chamberland et al., Clin. Infect. Dis., 15, 615 (1992); B. E. Kreger et al., Am. J. Med., 68, 332 (1980)). One of the most promising approaches for the immunotherapy of sepsis is passive immunization with antibodies that are directed against the conserved regions of LPS, i.e., lipid A and the core region. Such antibodies are expected to be crossreactive with different gram-negative pathogens and might therefore be crossprotective. Passive immunization with polyclonal or monoclonal antibodies (Mabs) against bacterial LPS has shown protective effects in animal models of sepsis. It was shown that partially detoxified LPS from E. coli J5 could elicit polyclonal antibodies in rabbits that provided passive protection against Pseudomonas aeruginosa infections in rats (A. K. Bhattacharjee et al., J. Infect. Dis., 170, 622 (1994)). Similarly, it has been shown that monoclonal antibodies against E. coli J5 could provide passive immune protection against heterologous bacteria challenges in mice (M. P. Schutze et al., J. Immunol., 142, 2635 (1989)). See also, F. E. DiPadova et al., Infect. Immun., 61, 3869 (1993); J. D. Baumgartner et al., Immunobiology, 187, 464 (1993). However, protection generally requires that the antibodies (Ab) be administered before sepsis pathology begins. This indicates that passive immunization has the potential to provide prophylactic protection but not therapeutic efficacy. Prophylactic protection is best provided by active immunization, or vaccination, rather than by passive immunization. The induction of protective antibodies could potentially be achieved by immunization with LPS presented in an appropriately modified form or via mutant bacteria defective in LPS biosynthesis (rough mutants) (C. Galanos et al., Eur. J. Biochem., 31, 230 (1972); S. C. Bruins et al., Infect. Immun., 17, 16 (1977)). Escherichia coli J-5, a rough mutant of E. coli O111:B4, has been used in the majority of immunological studies for more than three decades in an attempt to induce broadly cross-reactive and cross-protective
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antibodies directed against LPS. In fact, immunization of mice with heat-killed E. coli J5 cells can elicit active immune protection against a challenge of the mice with Haemophilus influenzae type b (M. I. Marks et al., J. Clin. Invest, 69, 742 (1982)). See also, J. B. Baumgartner et al., J. Infect. Dis., 163, 769 (1991). Multiple injections of purified, detoxified E. coli J5 LPS can also function as an antigen to elicit cross-protective anti-LPS Abs. A. K. Bhattacharjee et al., J. Infect. Dis., 173, 1157 (1996) prepared a noncovalent vaccine using partially detoxified J5 LPS and the outer membrane protein of N. meningitidis Group B. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Crystal form of N-(4-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamid- e Inventor(s): Faasch, Holger; (Hochheim, DE), Hedtmann, Udo; (Frankfurt, DE), Paulus, Erich; (Eppstein, DE), Westenfelder, Uwe; (Frankfurt, DE) Correspondence: Finnegan, Henderson, Farabow, Garrett & Dunner; Llp; 1300 I Street, NW; Washington; DC; 20005; US Patent Application Number: 20030166945 Date filed: November 25, 2002 Abstract: The invention relates to a crystal modification of the compound of the formula I 1and the processes for the preparation of and use that crystal modifications 1. The invention is used for treating acute immunological episodes, such as sepsis, allergies, graft-versus-host and host-versus-graft-reactions, autoimmune diseases, in particular rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, atopic dermatitis, asthma, urticaria, rhinitis, uveitis, type II diabetes, liver fibrosis, cystic fibrosis, colitis, cancers, such as lung cancer, leukemia, ovarian cancer, sarcomas, Kaposi's sarcoma, meningioma, intestinal cancer, lymphatic cancer, brain tumors, breast cancer, pancreatic cancer, prostate cancer, or skin cancer. Excerpt(s): This case claims benefit under 35 U.S.C.sctn.119 of German priority document 19734438.0 filed on Aug. 8, 1997. This document, as well as German priority document 19756093.8, filed Dec. 17, 1997, are hereby incorporated by reference. The compound of formula I crystallizes in the first crystal modification in the space group P2.sub.1/c with 8 molecules in the unit cell. Molecules of the compound of formula I are present as dimers which originate from the individual molecules by formation of a -C.dbd.O. HN hydrogen bridge bond (2.938.ANG.), the two molecular levels being virtually perpendicular to one another (91.2.degree.). The two molecules have very different conformations. The angles made by the five- and six-membered rings with the central carbonyl group are 5.4.degree. and 2.1.degree. and 23.4.degree. and 23.1.degree., respectively. The latter twist creates the steric preconditions permitting the hydrogen bridge bond between the two molecules. Lines of strong intensity: 16.70; 18.90; 23.00; 23.65; and 29.05 degrees. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Early detection of sepsis Inventor(s): Anderson, Stephen J.; (The Woodlands, TX), Haney, Douglas J.; (Santa Clara, CA), Waters, Cory A.; (Pleasanton, CA) Correspondence: Becton, Dickinson And Company; 1 Becton Drive; Franklin Lakes; NJ; 07417-1880; US Patent Application Number: 20030194752 Date filed: March 26, 2003 Abstract: Diagnostic methods, systems, and kits for identifying patients with systemic inflammatory response syndrome who are likely to progress to sepsis. Excerpt(s): This application claims priority under 35 U.S.C.sctn. 119(e) of provisional application Serial No. 60/370,115, filed Apr. 2, 2002, which is incorporated herein by reference. The present invention relates to methods and reagents for identifying patients at risk for developing a systemic inflammatory condition, such as sepsis. Early detection of the presence of disease conditions in patients typically allows more effective therapeutic treatments and results in more favorable clinical outcomes than occur when disease conditions are not recognized until an advanced stage. Unfortunately, the early detection of disease symptoms in many instances is problematic, and a disease may be relatively advanced before clinical suspicion of the disease occurs. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Effectors of innate immunity determination Inventor(s): Bowdish, Dawn; (Vancouver, CA), Finlay, B. Brett; (Richmond, CA), Gough Scott, Monisha; (Vancouver, CA), Hancock, Robert E.W.; (Vancouver, CA), Rosenberger, Carrie Melissa; (Vancouver, CA), Steven Powers, Jon-Paul; (Vancouver, CA) Correspondence: Morgan & Finnegan, L.L.P.; 345 Park Avenue; New York; NY; 10154; US Patent Application Number: 20040001803 Date filed: December 2, 2002 Abstract: A method of identifying a polynucleotide or pattern of polynucleotides regulated by one or more sepsis or inflammatory inducing agents and inhibited by a peptide is described. A method of identifying a pattern of polynucleotide expression for inhibition of an inflammatory or septic response. The method includes contacting cells with LPS, LTA, CpG DNA and/or intact microbe or microbial components in the presence or absence of a cationic peptide; detecting a pattern of polynucleotide expression for the cells in the presence and absence of the peptide, wherein the pattern in the presence of the peptide represents inhibition of an inflammatory or septic response. Also included are compounds and agents identified by the methods of the invention. In another aspect, the invention provides methods and compounds for enhancing innate immunity in a subject. Excerpt(s): This application claims priority under 35 USC 119(e) to U.S. patent application Ser. No. 60/336,632, filed Dec. 3, 2001, herein incorporated by reference in its entirety. The present invention relates generally to peptides and specifically to peptides effective as therapeutics and for drug discovery related to pathologies resulting from microbial infections and for modulating innate immunity or anti-inflammatory activity. Infectious diseases are the leading cause of death worldwide. According to a 1999 World
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Health Organization study, over 13 million people die from infectious diseases each year. Infectious diseases are the third leading cause of death in North America, accounting for 20% of deaths annually and increasing by 50% since 1980. The success of many medical and surgical treatments also hinges on the control of infectious diseases. The discovery and use of antibiotics has been one of the great achievements of modem medicine. Without antibiotics, physicians would be unable to perform complex surgery, chemotherapy or most medical interventions such as catheterization. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Immune enhancing composition containing lactoferrin Inventor(s): Castro, Gilbert A.; (Houston, TX), Kruzel, Marian L.; (Houston, TX) Correspondence: Kurt S. Myers; 7634 Braesdale; Houston; TX; 77071; US Patent Application Number: 20030203839 Date filed: June 6, 2003 Abstract: The composition of the present invention provides a novel use of the iron binding protein lactoferrin as a medicament to prevent the progression of systemic inflammatory response syndrome (SIRS) into sepsis, severe sepsis, septic shock and multiple organ failure in mammals. More particularly, the present invention is the use of lactoferrin for the manufacture of a medicament for the treatment of the metabolic imbalance in ICU patient. Excerpt(s): This application is a continuation-in-part application of Ser. No. 09/430,484, filed Oct. 29, 1999--which is based on PCT application PCT/US98/09053, filed Apr. 30, 1998, entitled "Method for Treating Aseptic SIRS in Humans and other Animals", which in turn is based on provisional application Ser. No. 60/045,521 filed May 3, 1997 entitled "Use of Lactoferrin for Prophylaxis and Therapy of the Systemic Inflammatory Response System in Animals and Humans", both of which are incorporated herein by reference. This application also relates to U.S. Pat. No. 6,066,469, based on Ser. No. 08/724,586, filed Sep. 30, 1996, entitled "Cloning, Expression and Uses of Human Lactoferrin", which in turn is a continuation of U.S. Ser. No. 08/238,445, filed May 5, 1994, which in turn is a CIP of U.S. Ser. No. 08/132,218, filed Oct. 6, 1993, which in turn is a continuation of U.S. Ser. No. 07/489,186, filed Mar. 8, 1990, all of which are incorporated herein by reference. The present invention relates generally to the iron binding protein lactoferrin administered either systemically or orally to prevent the progression of systemic inflammations into sepsis in humans and animals. More specifically, it relates to lactoferrin as an adjunctive medicament (formula) aimed to increase the medical benefits of desired therapy in human and non-human animals. The immune system plays in mammals a central role in protection against microbial infections, neoplasia, as well as many age-related disorders. The mucosal surface of the gastrointestinal tract is one of the first important interfaces between the pathogens or various dietary antigens and the host. Thus, the intestine is the site of intense immunologic activities and the challenge is to maintain a disease-free state in the face of chronic antigen exposure. Normal immune homeostasis depends on coordinated interactions among the various lymphoid, phagocytic and somatic cells which comprise the immune system. In general, these interactions are tightly regulated to obtain a balance between the need to eliminate harmful insults and the need to avoid damaging autoimmune response. The maintenance of homeostasis is essential for cellular integrity and depends on the ability of our body to induce proper inflammatory responses. The ultimate goal of inflammation is to dispose of both the initial cause of injury and its consequence. In the
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intestine of a normal healthy individual however, inflammation has its own "physiologically justified" chronic character. Again, this is a reflection of continuous exposure of epithelium to myriads of dietary antigens and pathogens. In fact, this constitutes oral tolerance which is defined as the immunologic mechanism by which the mucosal immune system maintains unresponsiveness to many antigens. Homeostasis is a state of equilibrium in the internal environment. The integrity of such system is continuously disturbed by stimuli that tend to create an internal imbalance. In response to prolonged stimuli, the compensatory mechanisms often do not restore the balance. This may, consequently lead to the activation of self-perpetuating, autodestructive mechanisms promoting systemic inflammation and its sequels, including death. Regardless the insult cause the internal environment responds to those insults by activating thermoregulatory mechanisms that coincide with the production and release of many immunomodulatory substances. Cytokines, prostaglandins, and different growth factors and hormones are released from specific cells to restore the internal metabolic balance. In the normal controlled inflammatory response mediators are released timely in conjunction with specific inhibitors to contain the response. If these responses are activated in an uncontrolled fashion with dissemination via the circulation, over the period of time, organs distant from the initial insult can be affected to produce multiple organ failure. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Inhibition therapy for septic shock with mutant CD14 Inventor(s): Kirkland, Theo N.; (La Jolla, CA), Viriyakosol, Suganya; (San Diego, CA) Correspondence: Brown, Martin, Haller & Mcclain Llp; 1660 Union Street; San Diego; CA; 92101-2926; US Patent Application Number: 20030114377 Date filed: September 20, 2002 Abstract: Described are methods and novel therapeutics for treating CD14-mediated diseases, especially sepsis and septic shock. The methods and compounds are founded on principles of structural mimicry of the innate compound. Changes to the innate compound are described that result in unexpected properties useful for blocking or ameliorating the harmful effects of systemic infection by microbes. Diagnostic applications and product-by-process claims are also contemplated based on the same underlying principle and observation. Excerpt(s): This application claims priority to U.S. Provisional Application Ser. No. 60/109,227 filed Nov. 18, 1998, which is herein incorporated by reference in its entirety including drawings. The field of invention relates to protein and genetic engineering with the objective of achieving new, pharmacologically active compounds and therapeutic methodologies based on structural mimicry of the naturally occurring biological compound, CD14. U.S. alone, with a mortality rate approaching 50% (1,2). Septic shock remains the most common cause of death in intensive care units (1,2). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Interferon-gamma-binding molecules for treating septic shock, cachexia, immune diseases and skin disorders Inventor(s): Buyse, Marie-Ange; (Merelbeke, BE), Sablon, Erwin; (Merchtem, BE) Correspondence: Patricia A. Kammerer; Howrey Simon Arnold & White, Llp; 750 Bering Drive; Houston; TX; 77057-2198; US Patent Application Number: 20030099648 Date filed: February 7, 2002 Excerpt(s): This application is a section 371 national stage filing of PCT/EP98/05165, Filed Aug. 14, 1998 (published in English on Feb. 25, 1999 As WO 99/09055) and claiming priority to EP 97870122.5 filed Aug. 18, 1997; and EP 98870139.7 filed Jun. 18, 1998. The present invention concerns molecules which bind and neutralize the cytokine interferon-gamma. More specifically, the present invention relates to sheep-derived antibodies and engineered antibody constructs, such as humanized single-chain Fv fragments, chimeric antibodies, diabodies, triabodies, tetravalent antibodies and peptabodies which can be used to treat diseases wherein interferon-gamma activity is pathogenic. Examples of such diseases are: septic shock, cachexia, multiple sclerosis and psoriasis. Interferon-gamma (IFN.gamma.) is a member of the interferon family of immunomodulatory proteins and is produced by activated T helper type-1 cells (Th1 cells) and natural killer cells (NK cells). Apart from its potent antiviral activity, IFN.gamma. is known to be involved in a variety of immune functions (for a review, see Billiau, 1996) and inflammatory responses. Indeed, IFN.gamma. is the primary inducer of the expression of the major histocompatibility complex (MHC) class-II molecules (Steinman et al., 1980) by macrophages and other cell types and stimulates the production of inflammatory mediators such as tumor necrosis factor-alpha (TNF.alpha.), interleukin-1 (IL-1) and nitric oxide (NO) (Lorsbach et al., 1993). In this respect, IFN.gamma. is shown to be important in the macrophage-mediated defence to various bacterial pathogens. Furthermore, IFN.gamma. is also shown to be a potent inducer of the expression of adhesion molecules, such as the intercellular adhesion molecule-1 (ICAM-1, Dustin et al., 1988), and of important costimulators such as the B7 molecules on professional antigen presenting cells (Freedman et al., 1991). Moreover, IFN.gamma. induces macrophages to become tumoricidal (Pace et al., 1983) and provokes Ig isotype switching (Snapper and Paul, 1987). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Measurement of analytes Inventor(s): Romaschin, Alexander D.; (Etobicoke, CA), Walker, Paul M.; (Toronto, CA) Correspondence: Klauber & Jackson; 411 Hackensack Avenue; Hackensack; NJ; 07601 Patent Application Number: 20040053342 Date filed: July 7, 2003 Abstract: The invention relates to a method for measuring the level of a preselected analyte in a sample such as of blood of a human or animal patient by incubating the test sample with an antibody specific to the analyte to form an immunocomplex, which then interacts with the white blood cells present in or added to the sample and result in the production of oxidants. Oxidants are detected using chemiluminescent reagents. The assay is performed on the sample and in addition may include a measurement of the oxidant production resulting from a maximal stimulatory dose of immunocomplexes,
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providing a ratio to indicate the level of analyte in the sample. The white blood cell oxidant response may be enhanced by the inclusion of certain agents such as zymosan or complement. This method may be used to determine levels of analytes in a sample of a patient's blood including endotoxin and other analytes related to sepsis, in order to select the proper therapeutic course, or may be used to measure other analytes such as inflammatory mediators, hormones, acute phase proteins, toxins, drugs of abuse, markers of cardiac muscle damage, therapeutic drugs, cytokines, and chemokines. Excerpt(s): ii) U.S. patent application Ser. No. 09/961,889, which is a continuation-inpart of application Ser. No. 08/552,145, filed Nov. 2, 1995, now U.S. Pat. No. 5,804,370, which is a continuation-in-part of application Ser. No. 08/516,204, filed Aug. 17, 1995, abandoned, which is a continuation of application Ser. No. 08/257,627, filed Jun. 8, 1994, abandoned. All of the foregoing applications are incorporated herein by reference in their entireties. Rapid quantitation of specific analytes that may be present in a bodily fluid such as whole blood is critically important for the diagnosis of disease and its severity, often under emergency conditions, in the monitoring of the progression of pathological conditions and following the recovery process brought about by surgical and drug therapies. It is often important to know not only whether a specific analyte is present, but also its level, in order to determine the present stage of a particular condition or disease and in order to prescribe the most effective remedy at that particular stage. In the treatment of many diseases, a particular therapy may be ineffective or toxic if given at the wrong stage of the condition. For example, the levels of specific markers of cardiac muscle damage and the relationship among them may indicate that a patient has had or may be having a heart attack. The level of a therapeutic drug in the circulation may indicate whether the patient is being dosed optimally, and whether presumptive side effects are possibly due to excess levels of the drug. In infection and sepsis, the circulating levels of infectious microorganism-derived toxins and inflammatory mediators produced by the patient's white blood cells in response to these toxins may indicate the severity and level or stage of sepsis and help identify the most efficacious course of therapy. Quantitation of analytes under emergency conditions and using the information to prescribe a particular therapy may mean the difference between saving a patient's life and contributing to the patient's death. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method and pharmaceutical composition for preventing and/or treating systemic inflammatory response syndrome Inventor(s): Jacquemin, Marc G.; (Sart-Bernard, BE), Saint-Remy, Jean-Marie R.; (GrezDoiceau, BE) Correspondence: Lee, Mann, Smith, Mcwilliams, Sweeney, & Ohlson; P.O. Box 2786; Chicago; IL; 60690-2786; US Patent Application Number: 20030175268 Date filed: January 11, 2002 Abstract: A partial inhibitor of factor VIII such as a monoclonal antibody is useful for preventing and/or treating a disease selected from the group consisting of systemic inflammatory response syndrome, sepsis, septic shock, thrombus formation in the micro-vasculature and disseminated intravascular coagulation in a mammal by partially inhibiting thrombin formation.
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Excerpt(s): The present application claims benefit from U.S. application Ser. No. (not yet assigned) filed Dec. 31, 2001, which is the U.S. National Phase application of PCT/EP00/06677 claiming benefit from U.S. Provisional Application Serial No. 60/143,891, and U.S. Provisional Application Serial No. 60/261,405 filed on Jan. 11, 2001, the disclosures of which are incorporated herein in their entirety. Reference is made to the attached sequence listing (pages 1-15) as referred to herein. The present invention relates to the prevention and/or treatment of systemic inflammatory response syndrome in mammals. The invention further relates to pharmaceutical compositions for the therapeutic treatment of sepsis and/or septic shock, as well as thrombus formation in the microvasculature and/or disseminated intravascular coagulation in mammals. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method for assessing capillary permeability Inventor(s): Uzgiris, Egidijus E.; (Niskayuna, NY) Correspondence: Raymond E. Farrell, ESQ.; Carter, Deluca, Farrell & Schmidt, Llp; 445 Broad Hollow Road - Suite 225; Melville; NY; 11747; US Patent Application Number: 20040024317 Date filed: July 31, 2002 Abstract: Polymeric contrast agents are used to test for blood vessel permeability, such as, for example, to diagnose sepsis. The agent is injected and images are obtained at various time intervals after injection. For increased accuracy, the blood circulation levels of the agents may optionally be monitored. Excerpt(s): This disclosure relates to methods for assessing capillary permeability using contrast agents and imaging techniques, such as, for example, magnetic resonance imaging (MRI). Sepsis is a major cause of morbidity and mortality in humans and other animals. Sepsis has become the leading cause of death in intensive care units among patients with non-traumatic illnesses. It is also the leading cause of death in young livestock (e.g., neonatal calves), and is a common medical problem in neonatal foals. Sepsis can result from septicemia (i.e., organisms, their metabolic end-products or toxins in the blood stream), including bacteremia (i.e., bacteria in the blood), as well as toxemia (i.e., toxins in the blood), including endotoxemia (i.e., endotoxin in the blood). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method for continuous monitoring of patients to detect the potential onset of sepsis Inventor(s): Ebner, Dennis M.; (Sisters, OR), McKenzie, Jack E.; (Bend, OR) Correspondence: Smith-hill And Bedell; 12670 N W Barnes Road; Suite 104; Portland; OR; 97229 Patent Application Number: 20030181815 Date filed: March 19, 2003 Abstract: A method of screening for possible onset of sepsis in a patient includes providing the patient with a transducer that automatically and periodically measures a first physiological parameter of the patient and transmits a first signal that is encoded with the measured parameter value, and receiving the first signal and automatically
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comparing the measured parameter value with at least one alarm limit. The first physiological parameter is body temperature, heart rate, respiration rate or a clinical indicator of sepsis. A conditional warning signal is asserted in the event that the measured parameter value bears a predetermined relationship to said alarm limit and an alarm signal is issued in the event that a physiological condition other than the condition that gave rise to the conditional warning signal is indicative of onset of sepsis. Excerpt(s): This application claims benefit of U.S. Provisional Application No. 60/367,076 filed Mar. 22, 2002 and U.S. Provisional Application No. 60/394,340 filed Jul. 3, 2002, the entire disclosure of each of which is hereby incorporated by reference herein for all purposes. This invention relates to a method for continuous monitoring of patients to detect the potential onset of sepsis. Sepsis is a medical condition in which bacteria invade the body causing a serious infection. Large and increasing numbers of microorganisms overwhelm the body's defense systems and actively multiply in the bloodstream. Sepsis is associated with a large stress on the body, such as trauma. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method for detecting conditions indicative of sepsis Inventor(s): Heinecke, Jay W.; (Seattle, WA) Correspondence: Pharmacia Corporation; Global Patent Department; Post Office Box 1027; ST. Louis; MO; 63006; US Patent Application Number: 20030100122 Date filed: August 22, 2002 Abstract: The disclosure describes a method for detecting conditions indicative of sepsis. In one embodiment of the invention, an increase in the level of 3-chlorotyrosine or 3-bromotyrosine from the normal level in a sample of body fluid or tissue is indicative of early sepsis or infection. In another embodiment of the invention, the level of 3-chlorotyrosine or 3-bromotyrosine is measured or monitored to determine the response to therapeutic treatment of the infective condition in which a reduction in the level that existed prior to the treatment is an early sign or indication that the treatment is working in vivo. In a preferred embodiment, the method of the invention is illustrated in a clinically relevant mouse model of sepsis. Excerpt(s): This application claims the benefit of Application Ser. No. 60/323,532, filed Sep. 19, 2001. The present invention relates to the field of detecting conditions indicative of sepsis. Sepsis is a toxic condition resulting from the spread of bacteria or their products from a focus of infection, especially septicemia. According to the Centers for Disease Control (CDC), septicemia is a leading cause of death in the United States, especially among the elderly. Death can occur in 40% to 60% of the patients with septicemia. It has been estimated that some five hundred thousand cases of sepsis occur annually in the United States. Accordingly, methods for detecting conditions indicative of sepsis would have significant use in medical practice. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method for the early diagnosis of subacute, potentially catastrophic illness Inventor(s): Griffin, M. Pamela; (Charlottesville, VA), Moorman, J. Randall; (Charlottesville, VA) Correspondence: University OF Virginia Patent Foundation; 1224 West Main Street, Suite 1-110; Charlottesville; VA; 22903; US Patent Application Number: 20030100841 Date filed: January 29, 2001 Abstract: In one aspect of the invention, there is provided a method and apparatus for early detection of subacute, potentially catastrophic infectious illness in a premature newborn infant. The method comprises: (a) continuously monitoring heart rate variability in the premature newborn infant; and (b) identifying at least one characteristic abnormality in the heart rate variability that is associated with the illness. This method can be use to diagnose illnesses such as, but not limited to, sepsis, necrotizing enterocolitis, pneumonia and meningitis. In another aspect of the present invention, there is provided a method and apparatus for early detection of subacute, potentially catastrophic infectious illness in a patient. The method comprises: (a) continuously monitoring the patient's RR intervals; (b) generating a normalized data set of the RR intervals; (c) calculating one or more of (i) moments of the data set selected from the third and higher moments and (ii) percentile values of the data set; and (d) identifying an abnormal heart rate variability associated with the illness based on one or more of the moments and the percentile values. Excerpt(s): This application claims priority from U.S. Provisional Application No. 60/078,319 filed on Mar. 17, 1998 and entitled "Device to Make the Early Diagnosis of Subacute, Potentially Catastrophic Illness," the disclosure of which is hereby incorporated by reference in its entirety. The present invention relates to the indication of early phases of potentially catastrophic illnesses and relates to heart rate variability monitoring in patients. Approximately 40,000 very low birth weight ("VLBW") infants (less than 1,500 gm) are born in the United States each year. Ventura et al., "Advance report of final natality statistics, 1994." Monthly Vital Statistics Report 1996; 44:1-88. Survival of this group has improved with advances in neonatal intensive care, but lateonset sepsis and necrotizing enterocolitis ("NEC") continue to be major causes of morbidity and mortality. Stoll B J, Gordon T, Korones S B, Shankaran S, Tyson J E, Bauer C R, "Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network." Journal of Pediatrics 1996; 129:63-71. Gray J E, Richardson D K, McCormick M C, Goldmann D A, "Coagulase-negative staphylococcal bacteremia among very low birth weight infants: relation to admission illness severity, resource use, and outcome." Pediatrics 1995; 95:225-230. Unfortunately these illnesses are common in neonates, and infected infants have a significant increase in the number of days spent on the ventilator and an average increase in duration of hospital stay of 25 days. See Stoll et al. above. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method for treating septic shock Inventor(s): Oldner, Anders; (Sollentuna, SE), Rudehill, Anders; (Bromma, SE), Wanecek, Michael; (Lidingo, SE), Weitzberg, Eddie; (Stockholm, SE) Correspondence: Finnegan, Henderson, Farabow, Garrett & Dunner; Llp; 1300 I Street, NW; Washington; DC; 20005; US Patent Application Number: 20030158201 Date filed: March 24, 2003 Abstract: Levosimendan, or (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, which has been previously suggested for the treatment of congestive heart failure is useful in the treatment of septic shock. Excerpt(s): The present invention relates to a method for the treatment of septic shock by administering levosimendan, or (-)-[[4-(1,4,5,6-tetrahydr- o-4-methyl-6-oxo-3pyridazinyl)phenyl]hydrazono]propanedinitrile (I), or pharmaceutically acceptable salts thereof, to a patient in need of such treatment. The hemodynamic effects of levosimendan in man are described in Sundberg, S. et al., Am. J. Cardiol., 1995; 75: 10611066 and in Lilleberg, J. et al., J. Cardiovasc. Pharmacol., 26(Suppl.1), S63-S69, 1995. Pharmacokinetics of levosimendan in man after i.v. and oral dosing is described in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol., 26(Suppl.1), S57-S62, 1995. The use of levosimendan in the treatment of myocardial ischemia is described in WO 93/21921. The use of levosimendan in the treatment of pulmonary hypertension is described in WO 99/66912. Clinical studies have confirmed the beneficial effects of levosimendan in heart failure patients. Septic shock (also known as sepsis) is the leading cause of morbidity and mortality in the intensive care units. Despite increased knowledge about the pathophysiology underlying the clinical symptoms mortality remains high and has not decreased substantially over the last decades. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method for treatment of sepsis Inventor(s): Araki, Seiichi; (Tuchiura-shi, JP), Kato, Akira; (Kakamigahara, JP), Onai, Katsumi; (Haguri-gun, JP) Correspondence: Choate, Hall & Stewart; Exchange Place; 53 State Street; Boston; MA; 02109; US Patent Application Number: 20030143265 Date filed: December 19, 2001 Abstract: It has unexpectedly been found that the administration of high doses of riboflavin or derivatives thereof (including, but not limited to salts and prodrugs), results in an effective treatment for sepsis. Thus, the present invention provides methods for treating sepsis by administering to a subject in need thereof a high dose of a composition comprising riboflavin or derivatives thereof. Excerpt(s): Sepsis, a major cause of morbidity and mortality in humans and other animals, results from an out-of-control host response to invading microbes. Specifically, sepsis can be triggered by the invasion of these organisms (e.g., bacteria) in the blood, by the toxins produced by these invading organisms, or a combination thereof. Sepsis is most commonly caused by invasion by bacteria, but can also be caused by the invasion of fungi or viruses or virus particles or parasites. This out-of-control host response
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results from a dramatic rise in the levels cytokines (often in response to the toxins produced by the organisms) and results in an escalation of the clotting cascade throughout the body. Clearly, the systemic invasion of these microorganisms incurs direct damage to tissues, organs and vascular function, and additionally, the toxic components of the microorganisms can lead to rapid systemic inflammatory responses that can quickly damage vital organs and lead to circulatory collapse (septic shock) and oftentimes, death. Specifically, gram negative sepsis is the most common and has a case fatality rate of about 35%. The majority of these infections are caused by Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Gram-positive pathogens such as the staphylococci and streptococci are the second major cause of sepsis. The third major group includes the fungi, with fungal infections causing a relatively small percentage of sepsis cases, but with a high mortality rate. It has previously been established that, for infections caused by gram-negative bacteria, sepsis is related to the toxic components of the bacteria. Specifically, among the well-described bacterial toxins are the endotoxins or lipopolysaccharides (LPS), a cell-wall structure of the gram-negative bacteria. These molecules are glycolipids that are ubiquitous in the outer membrane of all gramnegative bacteria. While the chemical structure of most of the LPS molecule is complex and diverse, a common feature is the lipid A region of LPS (Rietschel, et al., in the Handbook of Endotoxins, 1: 187-214 eds. R. A. Proctor and E. Th. Rietschel, Elsevier, Amsterdam (1984)); recognition of lipid A in biologic systems initiates many, if not all, of the pathophysiologic changes of sepsis. Because lipid A structure is highly conserved among all types of gram-negative organisms, common pathophysiologic changes characterize gram-negative sepsis. It is also generally thought that the distinct cell wall substances of gram-positive bacteria and fungi trigger a similar cascade of events, although the structures involved are not as well studied as gram-negative endotoxin. Regardless of the etiologic agent, many patients with septicemia or suspected septicemia exhibit a rapid decline over a 24-48 hour period. Thus, rapid methods of diagnosis and treatment delivery are essential for effective patient care. Unfortunately, a confirmed diagnosis as to the type of infection traditionally requires microbiological analysis involving inoculation of blood cultures, incubation for 18-24 hours, plating the causative organism on solid media, another incubation period, and final identification 12 days later. Therefore, therapy must be initiated without any knowledge of the type and species of the pathogen, and with no means of knowing the extent of the infection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method for using lipoprotein associated coagulation inhibitor to treat sepsis Inventor(s): Broze, George J.; (Landue, MO), Creasey, Abla A.; (Piedmont, CA) Correspondence: Banner & Witcoff; 1001 G Street N W; Suite 1100; Washington; DC; 20001; US Patent Application Number: 20030171292 Date filed: February 19, 2003 Abstract: A method for prophylactically or therapeutically treating sepsis or septic shock is described, wherein an inhibitor to tissue factor is administered to septic patients. Additionally, a method for treating inflammation is described wherein the inhibitor is administered to pateints. This inhibitor is termed lipoprotein associated coagulation inhibitor, or commonly LACI. It is 38 kD and has 276 amino acids. LACI has now been shown to be useful for the treatment of sepsis, septic shock and inflammation.
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Excerpt(s): This is a continuation-in-part of U.S. Ser. No. 08/224,118 filed Mar. 29, 1994, which is a continuation of Ser. No. 08/020,427, filed Feb. 22, 1993 (abandoned), which is a continuation-in-part of Ser. No. 07/897,135, filed Jun. 11, 1992 (abandoned). It is also a continuation-in-part of Ser. No. 08/253,427, filed Jun. 2, 1994, which is a continuation of Ser. No. 08/004,505 filed Jan. 13, 1993, (abandoned), which is a continuation-in-part of Ser. No. 07/891,947, filed Jun. 1, 1992 (abandoned). It is also a continuation-in-part of Ser. No. 08/270,455 filed Jul. 5, 1994, which is a continaution of Ser. No. 07/891,947, filed Jun. 1, 1992 (abandoned). The present invention is a method for prophylactically and therapeutically treating acute and chronic inflammation, sepsis and septic shock. More specifically, it comprises administering a therapeutically effective amount of a specific protein to attenuate physiological pathways associated with septic shock. Lipoproteinassociated coagulation inhibitor (LACI) is a protein inhibitor present in mammalian blood plasma. LACI is also known as tissue factor (TF) inhibitor, tissue thromboplastin (Factor III) inhibitor, extrinsic pathway inhibitor (EPI) and tissue factor pathway inhibitor (TFPI). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods Inventor(s): Anand, Rakesh; (Macclesfield, GB), Morten, John E.N.; (Macclesfield, GB), Smith, John C.; (Macclesfield, GB) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20030190607 Date filed: January 18, 2001 Excerpt(s): This invention relates to polymorphisms in the human pyruvate dehydrogenase E1.beta. (PDH E1.beta.) gene. The invention also relates to methods and materials for analysing allelic variation in the PDH E1.beta. gene, and to the use of PDH E1.beta. polymorphism in the diagnosis and treatment of diseases in which modulation of pyruvate dehydrogenase activity could be of therapeutic benefit, such as diabetes, asthma, obesity, sepsis and peripheral vascular disease. The production of energy for biosynthesis of complex molecules and for muscle contraction is mediated by the hydrolysis of high energy phosphate bonds within adenosine triphosphate (ATP). In oxidative metabolism ATP is generated from acetyl coenzyme A (acetyl CoA), which itself is produced by the beta-oxidation of fatty acids, or as a result of the metabolism of glucose via the glycolytic pathway. The key regulatory enzyme which controls the rate of acetyl CoA formation from glucose is pyruvate dehydrogenase (PDH), which catalyses the oxidation of pyruvate to acetyl CoA and carbon dioxide with concomitant reduction of NAD to NADH. PDH is a multienzyme complex located in the mitochondrial matrix, containing multiple copies of three enzyme components required to complete the conversion of pyruvate to acetyl CoA (Patel and Roche 1990; FASEB J., 4: 3224-3233). E1 (pyruvate decarboxylase, E.C. 1.2.4.1) catalyses the non-reversible removal of carbon dioxide from pyruvate; E2 (dihydrolipoamide acetyltransferase, E.C. 2.3.1.12) catalyses the formation of acetyl CoA; and E3 (dihydrolipoamide dehydrogenase, E.C. 1.8.1.4) reduces NAD to NADH. The E1 enzyme is a heterotetramer composed of two a and two.beta. subunits. Decarboxylation of pyruvate, catalysed by E1 is the rate limiting step in the overall activity of the PDH complex. This step is also the target for a cycle of phosphorylation and dephosphorylation which forms one of the main mechanisms for regulating PDH activity. Two additional enzyme activities are also associated with the PDH complex: a specific kinase (PDK) which is capable of
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phosphorylating E1.alpha. at three serine residues, and a loosely-associated specific phosphatase which reverses the phosphorylation. Phosphorylation of only one of the three serine residues on E1.alpha. renders E1 inactive. Removal of the phosphate groups by the specific phosphatase restores activity. Thus, the proportion of PDH in its active (dephosphorylated) state is determined by a balance between the activity of the kinase and phosphatase. The activity of the kinase may be regulated in vivo by the relative concentrations of metabolic substrates such as NAD/NADH, CoA/acetylCoA and ADP/ATP as well as by the availability of pyruvate itself, therefore providing highly regulated, responsive control of PDH activity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods of treating sepsis Inventor(s): Guh, Jih-Hwa; (Taipei, TW), Kuo, Sheng-Chu; (Taichung, TW), Lee, FangYu; (Tachia Taichung, TW), Pan, Shiow-Lin; (Taipei, TW), Teng, Che-Ming; (Taipei, TW) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20030181502 Date filed: January 24, 2003 Abstract: The present invention features a method for treating sepsis. The method includes administrating to a subject in need thereof an effective amount of a fused pyrazolyl compound of formula (I): 1A is H, C.sub.1.about.C.sub.6 alkyl, or (CH.sub.2).sub.n-- 2in which n is 0, 1, 2, or 3; each of Ar.sub.1, Ar.sub.2, and Ar.sub.3, independently, is phenyl, pyridinyl, thienyl, furyl, or pyrrolyl; and each of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6, independently, is XYZ; or R.sub.1 and R.sub.2 together, R.sub.3 and R.sub.4 together, or R.sub.5 and R.sub.6 together are O(CH.sub.2).sub.1-6O; in which X is a bond or C.sub.1.about.C.sub.6 alkylene, Y is a bond, O, S, OC(O), OC(O)(CH.sub.2).sub.1-6C(O)O, C(O)O, C(O)S, C(O)NH, C(O)NC.sub.1.about.C.sub.6 alkyl, NH, or NC.sub.1.about.C.sub.6 alkyl, and Z is H, halogen, CN, NO.sub.2, or C.sub.1.about.C.sub.6 alkyl; and provided that one of R.sub.3 and R.sub.4 is not H. Excerpt(s): This application claims priority to U.S. provisional application No. 60/351,788, filed on Jan. 25, 2002, the contents of which are incorporated herein by reference. Sepsis ranges from systemic inflammatory response to organ dysfunction to multiple organ failure, and ultimately death. See, e.g., Stone (1994) Science 264: 365-367; Stone (1994) Science 264: 365-367; Karima et al. (1999) Mol. Med. Today 5: 123-132; and Parrillo et al. (1990) Ann Int Med. 113: 227-242). To prevent sepsis, studies have been conducted on compounds including antioxidants, anti-inflammation agents, and inhibitors of lipopolysaccharide (LPS)-induced nitric oxide (NO) synthesis. See, e.g., Ortolani et al. (2000) Am J Respir Crit Care Med. 161: 1907-1911; Kox et al. (2000) Intensive Care Med. 26: S124-128; and Boyle et al. (2000) Circ Res 87: E18-24). The results of these studies are not satisfactory (Glauser (2000) Crit Care Med. 28: S4-8). Some data indicated that large quantities of NO contribute to the pathogenesis of vascular failure in sepsis (Rees (1995) Biochem Soc Trans. 23: 1025-1029). In vivo, large quantities of NO result from: (i) exaggerated synthesis of NO in endothelium after severe attacks such as sepsis, see, e.g., Ochoa et al. (1991) Ann Surg 214: 621-626; Nakatsu & Diamond (1989) Can J Physiol Pharmacol. 67: 251-262; and Guh et al. (1998) Mol. Pharmacol. 53: 467-474; and (ii) up-regulation of the inducible NO synthase (iNOS) as cells respond to bacterial products (e.g., LPS) or inflammatory cytokines (e.g., interleukin-1.beta. and tumor necrosis factor-.alpha.), see, e.g., Curran et al. (1989) J Exp Med. 170: 1769-1774; and
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Nakayama et al. (1992) Am J Respir Cell Mol Biol. 7: 471-476. NO can react with a superoxide to produce peroxynitrite, which accounts for oxidative injury (Szabo (1996) Shock. 6: 79-88). Peroxynitrite has also been reported to be involved in vascular cell apoptosis (Cuzzocrea et al. (1998) Br J Pharmacol. 123: 525-537). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Novel synthetic peptides with antimicrobial and endotoxin neutralizing properties for management of the sepsis syndrome Inventor(s): Abraham, Philip Richard; (Duivendrecht, NL), Appelmelk, Bernard Jan; (Amsterdam, NL), Van Deventer, Sander Jan Hendrik; (Haarlem, NL) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, N.W.; Washington; DC; 20037; US Patent Application Number: 20040049011 Date filed: July 1, 2003 Abstract: A peptide with an amino acid composition such that the peptide is amphipathic, cationic and forms a stable.alpha.-helix and has the following structure comprising at least 12 amino acidsR.sub.1-R.sub.2-A.sub.1-B.sub.1-(A.sub.2-B.sub.2C.sub.1-A.sub.3).sub.m-(C-.sub.2).sub.n-R.sub.3, whereinA=an amino acid selected from the basic amino acids Lys,Arg or HisB=an amino acid selected from the aromatic amino acids Phe, Trp or TyrC=an amino acid selected from the group comprising the hydrophobic amino acids Leu, Ile,Val or Ala, andsaid peptide has either the orientation according to the formula or the retro orientation thereof, wherein at least 0-n of the repetitive sequence motifs (A.sub.2-B.sub.2-C.sub.1-A.sub.3) have the retro orientation and the remaining repetitive motifs (A.sub.2-B.sub.2-C.sub.1-- A.sub.3) have the orientation as presented in the formula and wherein,R.sub.1-R.sub.2- and R.sub.3 are a number of amino acids, and whereinm=1-10, preferably 2-8, more preferably 2-5 andn=1-3, a pharmaceutical composition comprising such a peptide application thereof in treatment or diagnosis related to i.a. parasite infection topical and systemic tumors and septic shock. Excerpt(s): Bacterial infections as a complication of surgery, prolonged hospitalization, accidents and other traumatic events, may lead to serious clinical symptoms such as sepsis, septic shock, inadequate organ perfusion, multiple organ failure and acute respiratory distress syndrome (ARDS). Despite advances in medicine over the past decade, an increase in the incidence of sepsis is evident with a mortality rate of 20 to 80%. The sepsis syndrome is initiated when micro-organisms bypass the natural defensive barriers of the body, such as skin and mucous membranes. If the immune system is unable to arrest the infection locally, the organism or its toxins may invade the circulation, where specific bacterial products elicit an inflammatory response that leads to the activation of an array of plasma proteins and cellular defense systems. Although mobilisation of the defence systems of the host is of paramount importance in combatting invading organisms, a cascade of events may simultaneously be triggered that can lead to irreversible tissue injury and organ dysfunction. Uncontrolled infections with Gram-negative bacteria such as Escherichia coli, Klebsiella spp., Neisseria spp., Pseudomonas aeruginosa, Salmonella spp, or Bordella spp. or the Gram-positive bacteria Staphylococcus aureus, Enterococcus spp., Streptococcus spp., Micrococcus luteus or Listeria monocytogenes give rise to a variety of clinical symptoms collectively referred to as the sepsis syndrome. The component of Gram-negative bacteria responsible for the initiation of the host response is termed endotoxin or
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lipopolysaccharide (LPS), a major glycolipid constituent of the outer membrane. In the circulation, LPS stimulates specific blood cells to produce endogenous mediators of inflammation termed cytokines such as tumor necrosis factor alpha (TNF-.alpha.), interleukin-6 (IL-6) and interleukin-8 (IL-8) which have profound physiological effects on the organs and blood vessels of the body. Persistent stimulation of the cellular defence system by excessive LPS leads to overproduction of cytokines which activate a cascade of secondary inflammatory mediators eventually leading to blood vessel damage, circulatory and metabolic disturbances. The toxic component of the LPS molecule is the highly conserved Lipid A moiety which is sufficient to induce the pathophysiological changes characteristic of sepsis. The prognosis of patients with endotoxemia would be considerably improved if the onset of sepsis could be detected at a sufficiently early stage in the disease process to enable effective treatment. Direct measurement of circulating endotoxins is of importance for the prediction of important clinical events such as bacteremia, septic shock and death. Clinically significant endotoxemia may go undetected by the currently available endotoxin assay, the Limulus amoebocyte lysate assay or LAL test, which has been shown to have serious limitations relating to sensitivity as well as to interference by plasma factors. Current therapeutic options for Gram-negative bacterial sepsis are limited to anti microbial agents, hemodynamic support and management of sepsis-induced organ dysfunction. Although conventional antibiotic therapy is effective in halting the proliferation of susceptible micro-organisms, the massive release of LPS into the circulation by damaged bacteria may aggravate a septic episode. The relative importance of endotoxin release (endotoxemia) versus bacterial proliferation (bacteremia) during Gram-negative septic shock, however, has not fully been defined. Extensive clinical use of conventional antibiotics such as penicillins, cephalosporins and the like, in the treatment of bacterial infections during the past three decades, has resulted in a dramatic reduction in the efficacy of antibiotic therapy due to an alarming increase in the number of multi-drugresistant bacteria. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Novel transcription factor regulating TNF-alpha Inventor(s): Amar, Salomon; (Brookline, MA) Correspondence: Kevin M. Farrell; Pierce Atwood; Suite 350; One New Hampshire Avenue; Portsmouth; NH; 03801; US Patent Application Number: 20030166159 Date filed: April 2, 2003 Abstract: Disclosed herein is an isolated polypeptide which binds to the DNA binding domain located from -550 to -487 in the promoter of the human TNF-.alpha. gene. This isolated polypeptide is referred to herein as the LITAF protein. Polypeptides of human origin are specifically provided. Also disclosed is a nucleic acid sequence which encodes the LITAF protein. Such nucleic acids may be incorporated into an expression vector, which may be inserted into a cell. LITAF dependent induction of TNF-.alpha. gene expression in a cell can be inhibited by delivering an inhibitor of expression of the LITAF gene to the cell. Such an inhibitor is for example an antisense construct which encodes an antisense RNA molecule which is complementary to a portion of the LITAF mRNA which is greater than 200 nucleotides in length. Preferably, the antisense RNA molecule is complementary to the start site of translation, upstream adjacent 5' untranslated sequence, and downstream adjacent coding sequence of the LITAF mRNA.
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Optimal lengths and specific nucleotides for complementary are discussed. Inhibition of LITAF dependent induction of TNF-.alpha. gene expression in a cell can also be achieved by contacting an inhibitor of LITAF protein function to the LITAF protein within a cell. Such an inhibitor may be an antibody which binds the LITAF protein, or alternatively a small molecule which inhibits the function of the LITAF protein. One example of such an inhibitor is a recombinant mutant LITAF protein. Administration of a LITAF inhibitor can be performed as a therapeutic method for treating a patient with a disease associated with chronic inflammation. Such diseases include rheumatoid arthritis, gum disease Crohn's disease, and graft-versus-host disease. Therapeutic methods for treating a patient with a disease in which TNF-.alpha. plays a role in pathology are also provided. Examples of such diseases are diabetes mellitus, cancer, cachexia, breast cancer, HIV, sepsis, malaria, trypanomiasis and asthma. Other methods provided include a method for identifying genes which are regulated by the LITAF protein, a method for identifying a molecule which inhibits LITAF binding to the TNF.alpha. promoter, and a method for identifying molecules which bind LITAF from a protein array. Excerpt(s): The innate host response to bacterial pathogens is characterized by an immediate release of biologically active compounds, including monokines and cytokines. These proinflammatory molecules, which are intended to enable the host to eliminate the pathogen, may also adversely affect the host. In acute situations, the pathogen is often eliminated, with resolution of inflammation and minimal tissue damage. However, failure to control the pathogen often leads to a state of metabolic anarchy in which the inflammatory response is not controlled and significant tissue damage results. Endotoxins, produced from the outer membrane of Gram-negative bacteria, and exotoxins, released from the cell wall of Gram-positive bacteria, are known to be potent inducers of the inflammatory response. Lipopolysaccharide (LPS), extracted from the outer membrane of Gram-negative bacteria, has been identified as a principal endotoxic component. Although the inflammatory response is mediated by a variety of secreted factors, the cytotoxic effects of LPS have been ascribed to TNF-.alpha. activity (Beutler et al., Science 229: 869-871 (1985); Tracey et al., Science 234: 470-474 (1986); Miethke et al., J. Exp. Med. 175: 91-98 (1992)). TNF-.alpha. is a pleiotropic cytokine which serves to either benefit the host or in some situations exert detrimental effects on the host (Beutler and Cerami, Nature 320: 584-588 (1986); Beutler et al., Science 232: 977980 (1986); Beutler and Cerami, N. Engl. J. Med. 316: 379-385 (1987)). TNF-.alpha. benefits the host by helping to prevent cancer, protecting against infection, promoting tissue remodeling, and activating inflammatory responses. Conversely, in host responses which have gone awry, TNF-.alpha. mediates septic shock in chronic infections, is responsible for cachexia in cancer patients, causes inflammation in rheumatoid arthritis patients, and activates the human immunodeficiency virus. The pleiotropic effects of TNF-.alpha. are dose-dependent. Hence, the perceived need to control TNF-.alpha. production has raised interest into the understanding of the mechanisms that modulate TNF-.alpha. gene expression. It is well known that gene transcription is controlled by DNA-binding proteins. Recently, several groups have examined the transcriptional regulation of TNF-.alpha. by various inducers, such as virus, LPS, and PMA. The human TNF-.alpha. promoter contains motifs that resemble nuclear factor kappa B (NF-.kappa.B) binding sites; however, controversy exists as to the involvement of NF-.kappa.B in TNF-.alpha. gene regulation. The nature of the nuclear factor(s) involved in the regulation of LPS-induced TNF-.alpha. gene expression in humans remains unknown. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Opiate, cannabinoid, and estrogen receptors Inventor(s): Fimiani, Caterina; (Roma, IT), Stefano, George B.; (Melville, NY) Correspondence: Fish & Richardson P.C.; 3300 Dain Rauscher Plaza; 60 South Sixth Street; Minneapolis; MN; 55402; US Patent Application Number: 20030175822 Date filed: January 8, 2003 Abstract: The present invention relates generally to mu3 opiate receptors, cannabinoid receptors, and estrogen surface receptors (ESRs). Specifically, the invention provides methods and materials for identifying mu3 opiate receptor agonists and antagonists, cannabinoid receptor agonists and antagonists, and ESR agonists and antagonists. In addition, the invention provides an isolated nucleic acid molecule that encodes a mu3 opioid receptor, a host cell containing an isolated nucleic acid molecule that encodes a mu3 opioid receptor, and an isolated mu3 opioid receptor polypeptide. Further, the invention provides methods and materials for treating cancers, inflammatory conditions, sepsis conditions, viral infections, and cardiovascular diseases. Excerpt(s): The invention relates to methods and materials involved in the activation and inhibition of opiate, cannabinoid, and estrogen receptors. Specifically, the invention relates to mu3 opiate receptors, cannabinoid receptors, and estrogen surface receptors, and the biological responses induced by such receptors. Three general classes of cell surface opioid receptors (kappa, delta, and mu) have been described based on ligand specificity. Opioid receptors exhibiting high binding specificity for morphine have been designated mu opioid receptors. Detailed analysis of mu opioid receptors from various tissue has revealed the existence of multiple mu opioid receptor subtypes. In fact, the cDNA encoding the mu1 opioid receptor subtype has been identified. Oligonucleotides complementary to some, but not all, exons of the mu1 opioid receptor can block the effects mediated by the mu1 and mu2 receptor subtypes. Thus, the mu1 and mu2 opioid receptor subtypes appear to share exon sequences, as would be expected of splice variants. Supporting the idea of alternative splicing is the finding of a single mu gene in mouse chromosomal DNA. In addition, a novel rat brain mu opioid receptor subtype, designated rMOR1B, has been identified. This receptor is identical to the rat mu1 opioid receptor at its N-terminus but differs in its length and sequence at the C-terminus. Further, affinity studies demonstrated that the substrate specificity of rMOR1B is similar to that of the rat mu1 opioid receptor, but rMOR1B is more resistant to agonist-induced desensitization and has a different expression pattern in brain. The presence of another opiate receptor, designated mu3 opiate receptor, has been demonstrated pharmacologically. This mu3 opiate receptor is opioid peptide insensitive and opiate alkaloid selective. In addition, detailed binding analysis indicates that the mu3 opiate receptor is expressed by immune tissues (e.g., human monocytes and granulocytes). Cannabinoids induce physiological activities similar to those induced by morphine. Cannabinoids, however, induce these activities by interacting with specific cannabinoid receptors that are structurally distinct from opioid receptors. To date, two subtypes of G-protein-coupled cannabinoid receptors have been identified: CB1 and CB2. These two cannabinoid receptor subtypes are expressed by different tissues and have different pharmacological properties. For example, the CB1 receptor is expressed in brain and endothelial tissue while the CB2 receptor is expressed in the immune system. In addition, SR 141716A is a CB1 receptor antagonist while SR 144528 is a CB2 receptor antagonist. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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PON3 and uses thereof Inventor(s): Draganov, Dragomir I.; (Ann Arbor, MI), La Du, Bert N.; (Ann Arbor, MI), Stetson, Phillip L.; (Ann Arbor, MI), Watson, Catherine E.; (Ann Arbor, MI) Correspondence: Medlen & Carroll, Llp; Suite 350; 101 Howard Street; San Francisco; CA; 94105; US Patent Application Number: 20030144228 Date filed: June 27, 2002 Abstract: The present invention relates to paraoxonase genes, in particular PON3. The present invention provides isolated nucleotide sequence encoding PON3, wild type and mutant PON3 peptides. The present invention also provides methods for using PON3 to screen compounds for the ability to alter PON3 associated activities, methods for generating antibodies useful in the detection of PON3, and methods of treating and preventing oxidative damage, sepsis, chemical toxicity, and other conditions. Excerpt(s): The present invention relates to compositions comprising paroxonase 3 genes and polypeptides, in particular to compositions comprising rabbit PON3 genes and polypeptides. The present invention also provides methods for using PON3 genes and peptides in the treatment of endotoxemia, oxidative damage, chemical toxicity, and other conditions. Endotoxic shock is a condition, often fatal, provoked by the release of lipopolysaccharide (LPS) from the outer membrane of most gram negative bacteria (e.g., Escherichia coli; Salmonella tymphimurium). One example of a condition involving Endotoxic shock is sepsis. Sepsis is a major cause of morbidity and mortality in humans and other animals. It is estimated that 400,000-500,000 episodes of sepsis resulted in 100,000-175,000 human deaths in the U.S. alone in 1991. Sepsis has become the leading cause of death in intensive care units among patients with non-traumatic illnesses (Machiedo et al., Surg. Gyn. & Obstet., 152:757-759 [1981]). It is also the leading cause of death in young livestock, affecting 7.5-29% of neonatal calves (Morris et al., Am. J. Vet. Res., 47:2554-2565 [1986]), and is a common medical problem in neonatal foals (Hoffman et al., J. Vet. Int. Med., 6:89-95 [1992]). Despite the major advances of the past several decades in the treatment of serious infections, the incidence and mortality due to sepsis continues to rise (Wolff, New Eng. J. Med., 324:486-488 [1991]). Sepsis is a systemic reaction characterized by arterial hypotension, metabolic acidosis, decreased systemic vascular resistance, tachypnea and organ dysfunction. Sepsis can result from septicemia (i.e., organisms, their metabolic end-products or toxins in the blood stream), including bacteremia (i.e., bacteria in the blood), as well as toxemia (i.e., toxins in the blood), including endotoxemia (i.e., endotoxin in the blood). The term "bacteremia" includes occult bacteremia observed in young febrile children with no apparent foci of infection. The term "sepsis" also encompasses fungemia (i.e., fungi in the blood), viremia (i.e., viruses or virus particles in the blood), and parasitemia (i.e., helminthic or protozoan parasites in the blood). Thus, septicemia and septic shock (acute circulatory failure resulting from septicemia often associated with multiple organ failure and a high mortality rate) may be caused by a number of organisms. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Pyrimidine compounds Inventor(s): Kostik, Elena; (Arlington, MA), Ono, Mitsunori; (Lexington, MA), Sun, Lijun; (Harvard, MA), Wada, Yumiko; (Waltham, MA) Correspondence: Y. Rocky Tsao; Fish & Richardson P.C.; 225 Franklin Street; Boston; MA; 02110-2804; US Patent Application Number: 20040024206 Date filed: November 26, 2002 Abstract: This invention features pyrimidine compounds of formula (I): 1R.sub.1 is 2, in which one of R.sup.a and R.sup.b is H or alkyl, and the other is aryl or heteroaryl optionally substituted with R.sup.d and R.sup.e.sub.m; each of R.sub.2 and R.sub.4 is H; R.sub.3 is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; R.sub.5 is H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; X is NR.sup.c; Y is covalent bond, CH.sub.2, C(O), C.dbd.N--R.sup.c, C.dbd.N--OR.sup.c, C.dbd.N--SR.sup.c, O, S, S(O), S(O.sub.2), or NR.sup.c; Z is N or CH; one of U and V is N, and the other is CR.sup.c; and W is O, S, S(O), S(O.sub.2), NR.sup.c, or NC(O)R.sup.c; in which R.sup.c is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; R.sup.d is halogen, CN, alkyl alkyloxy, alkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, alkylamino, or alkylaminocarbonyl; R.sup.e is halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; and m is 0, 1, 2, 3, or 4. The pyrimidine compounds can be used to treat an IL-12 overproduction-related disorder (e.g., rheumatoid arthritis, sepsis, Crohn's disease, multiple sclerosis, psoriasis, or insulin-dependent diabetes mellitus). Excerpt(s): This is a continuation-in-part of U.S. application Ser. No. 10/000,742, filed on Nov. 30, 2001, the contents of which are incorporated herein by reference. Interleukin-12 (IL-12) is a heterodimeric cytokine (p70) composed of two subunits (p35 and p40), and plays key roles in immune responses by bridging innate resistance and antigen-specific adaptive immunity. Trinchieri (1993) Immunol Today 14: 335. For example, it promotes type 1 T helper cell (Th1) responses and, hence, cell-mediated immunity. Chan et al. (1991) J Exp Med 173: 869; Seder et al. (1993) Proc Natl Acad Sci USA 90:10188; Manetti et al. (1993) J Exp Med 177:1199; and Hsieh et al. (1993) Science 260: 547. Overproduction of IL-12 causes excessive Th1 responses, and may result in inflammatory disorders, such as insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, or sepsis. See, for example, Gately et al. (1998) Annu Rev Immunol. 16: 495; and Abbas et al. (1996) Nature 383: 787. Thus, inhibiting IL-12 overproduction is an approach to treat the just-mentioned diseases. Trembleau et al. (1995) Immmunol. Today 16: 383; and Adorini et al. (1997) Chem. Immunol. 68: 175. For example, overproduction of IL-12 and the resultant excessive Th1 type responses can be suppressed by modulating IL-12 production. A compound that down-regulates IL-12 production can be used for treating inflammatory diseases. Ma et al. (1998) Eur Cytokine Netw 9: 54. ,in which one of R.sup.1 and R.sup.b is H or alkyl, and the other is aryl or heteroaryl optionally substituted with R.sup.d and R.sup.e.sub.m; each of R.sub.2 and R.sub.4 is H; R.sub.3 is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; R.sub.5 is H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; X is NR.sup.c; Y is covalent bond, CH.sub.2, C(O), C.dbd.N--R.sup.c, C.dbd.N--OR.sup.c, C.dbd.N--SR.sup.c, O, S, S(O), S(O.sub.2), or NR.sup.c; Z is N or CH; one of U and V is N, and the other is CR.sup.c; and W is O, S, S(O), S(O.sub.2), NR.sup.c, or NC(O)R.sup.c; in which R.sup.c is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; R.sup.d is halogen, CN, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, alkylamino, or alkylaminocarbonyl; R.sup.e is halogen, CN, hydroxyl,
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alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; and m is 0, 1, 2, 3, or 4. Note that the left atom shown in any substituted group described above is closest to the pyrimidine ring. Also note that when there are more than one R.sup.c-containing substituted groups in a pyrimidine compound, the R.sup.c moieties can be the same or different. The same rules apply to other similar situations. Further note that R.sup.c can be a monovalent or bivalent substitutent. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory heptitis Inventor(s): von Borstel, Reid W.; (Potomac, MD), Bamat, Michael K.; (Potomac, MD), Hiltbrand, Bradley M.; (Columbia, MD) Correspondence: Nixon & Vanderhye, PC; 1100 N Glebe Road; 8th Floor; Arlington; VA; 22201-4714; US Patent Application Number: 20030212036 Date filed: April 24, 2003 Abstract: Pyrimidine nucleotide precursors including acyl derivatives of cytidine, uridine, and orotate, and uridine phosphorylase inhibitors, and their use in enhancing resistance to sepsis or systemic inflammation are disclosed. Excerpt(s): This application is a continuation-in-part application of copending U.S. application Ser. No. 158,799, filed Dec. 1, 1993, which in turn is a continuation-in-part application of copending U.S. application Ser. No. 987,730, filed Dec. 8, 1992, which in turn is a continuation-in-part application of U.S. application Ser. No. 438,493, filed Jun. 26, 1990, which in turn is a continuation-in-part application of U.S. application Ser. No. 115,929 filed Oct. 28, 1987. All of these applications are hereby incorporated by reference. This invention relates generally to pyrimidine nucleotide precursors including acyl derivatives of cytidine, uridine and orotate, and to the prophylactic and therapeutic uses of these compounds. The invention also relates to the administration of these compounds, alone or in combinations, with or without other agents, to animals. These compounds are capable of enhancing resistance of an animal to bacterial endotoxin and other inflammatory stimuli, and inflammatory mediators. Sepsis, also referred to as sepsis syndrome, is a consequence of serious infection by bacteria, fungi, or viruses. Sepsis accounts for tens of thousands of deaths in the United States every year; it is a leading cause of death of patients in surgical intensive care units. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Substituted heterocyclic compounds and methods of use Inventor(s): Dominguez, Celia; (Thousand Oaks, CA), Zhang, Dawei; (Thousand Oaks, CA) Correspondence: Amgen Incorporated; Mail Stop 27-4-a; One Amgen Center Drive; Thousand Oaks; CA; 91320-1799; US Patent Application Number: 20040058918 Date filed: September 8, 2003
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Abstract: The present invention relates to compounds having the general formula 1or a pharmaceutically acceptable salt thereof. Also included is a method of prophylaxis or treatment of inflammation, rheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic.beta. cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft vs. host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster infection in a mammal comprising administering an effective amount a compound as described above. Excerpt(s): The present invention comprises a new class of compounds useful in treating diseases, such as TNF-.alpha., IL-1.beta., IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. This invention also relates to intermediates and processes useful in the preparation of such compounds. Interleukin-1 (IL-1) and Tumor Necrosis Factor.alpha. (TNF-.alpha.) are proinflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli (e.g., lipopolysaccharide--LPS) or external cellular stress (e.g., osmotic shock and peroxide). Elevated levels of TNF-.alpha.and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; Pagets disease; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic 13 cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpes zoster are also exacerbated by TNF-.alpha. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Substituted liposaccharides useful in the treatment and prevention of endotoxemia Inventor(s): Christ, William J.; (Andover, MA), Rossignol, Daniel P.; (Andover, MA) Correspondence: Clark & Elbing Llp; 101 Federal Street; Boston; MA; 02110; US Patent Application Number: 20030144503 Date filed: May 13, 2002 Abstract: Novel substituted liposaccharides useful as in the prophylactic and affirmative treatment of endotoxemia including sepsis, septicemia and various forms of septic shock and methods of using these agents are provided. Also provided are methods of preparing these agents and intermediates useful therein.
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Excerpt(s): This application is a continuation-in-part of Ser. No. 08/461,675, filed Jun. 5, 1995. This invention relates to compounds which are useful as in the prophylactic and affirmative treatment of endotoxin exposure including sepsis, septicemia, endotoxemia and various forms of septic shock. The invention relates to analogs of Lipid A which are useful as inhibitors of endotoxemia. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Tethered receptor-ligand reagent and assay Inventor(s): Zweig, Stephen Eliot; (Los Gatos, CA) Correspondence: Stephen E. Zweig; 224 Vista DE Sierra; Los Gatos; CA; 95030; US Patent Application Number: 20030108972 Date filed: December 3, 2002 Abstract: A tethered reagent and assay is disclosed consisting of protein receptors tethered to ligands. The protein receptors can be antibodies, enzymes, hormone receptors, integral membrane proteins, and other proteins. Ligands can be antigens, enzymatic inhibitors, hormone agonists, drugs, and other protein binding ligands. The protein receptors and ligands will each be labeled with moieties capable of detecting changes in the average distance between the protein receptors and the ligand, using detection methods in which there is a sharp fall-off in signal as a function of distance. As a result, a change in the average distance between the two label moieties, such as that caused by protein-ligand binding and dissociation, produces a change in a detectable signal produced by the reagent. Tethering means may consist of flexible polymers, typically composed of a material that is chemically distinct from either the receptor or the ligand, so that the receptors and ligands may freely associate and dissociate via their specific binding sites, but not totally diffuse away from each other. When bound to solid phase surfaces, such reagents are particularly well suited for proteomic microarrays and flow cells. Such reagents may have utility for immunoassays, enzyme assays, ligand binding assays, sepsis assays, drug screening assays, and drug ADMET assays. Excerpt(s): The invention generally concerns reagents and methods useful for enzymatic, immunochemical, and protein-ligand binding assays. This application claims the priority benefit of provisional patent applications Ser. No. 60/339,916, and 60/389,679; both entitled "Tethered receptor-ligand reagent and assay", filed Dec. 6, 2001 and Jun. 17, 2002. Biological systems consist of complex networks of thousands of interacting enzymes, enzyme regulators, enzyme substrates, soluble receptors, membrane receptors, biological response modifiers, and genes all acting in concert to conduct thousands of different biological processes. Although traditionally, such biological components have been studied and analyzed on a one-at-a-time basis, recent advances in biotechnology have made it clear that more global methods of study and analysis are highly desirable. For example, cancer researchers have found that cellular proliferation, cellular death, and angiogenesis, intimately involved in many aspects of cancer, are each regulated by complex networks of tens to hundreds of different cell surface receptors, enzymes and regulatory factors. A change in any one of these factors may give information relevant to the prognosis or therapy of a particular disease. Analytical methods that can globally survey these networks are thus of great medical utility for cancer research. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Treatment of diseases associated with cytokine production with inhibitors of the tec family of protein tyrosine kinases Inventor(s): Foxwell, Brian Maurice John; (Hammersmith, GB) Correspondence: Nixon & Vanderhye, PC; 1100 N Glebe Road; 8th Floor; Arlington; VA; 22201-4714; US Patent Application Number: 20030125235 Date filed: November 14, 2002 Abstract: The present invention relates to a method of treating a condition comprising administering a pharmaceutically effective amount of an inhibitor of the Tec family of protein tyrosine kinases (PTKs). The condition is typically associated with cytokine production. Conditions addressed by the invention include sepsis, septic shock, inflammation, rheumatoid arthritis and Crohn's disease. In one embodiment, the condition is induced by zymosan. The invention also provides the use of an inhibitor of a member or members of the Tec family of PTKs in the manufacture of a medicament for use in the treatment of a condition associated with cytokine production and methods for identifying an inhibitor of a member or members of the Tec family of PTKs which is also suitable for use in the treatment of a condition associated with stimulus-induced cytokine production. Excerpt(s): The invention relates to the use of inhibitors of the Tec family of protein tyrosine kinases to treat a condition. Typically the condition is associated with cytokine production, particularly TNF and IL-1.beta. production. The condition may be sepsis, septic shock and/or inflammation. Toll-like receptors (TLRs) are a group of germlineencoded receptors known in the art (Rock et al (1998) PNAS 95, 588-593). 9 TLRs are currently known (Du et al (2000) Eur Cytokine Netw 11, 362-371) and many more expected to exist. Although the extracellular portions of Toll-related receptors (TRRs), including TLRs, IL-1R and IL-18R, are relatively divergent, the cytoplasmic portions are more conserved. They contain a well-defined region known as the toll domain, which is also found in the cytoplasmic portion of proteins comprising the IL-1 receptor, the IL-18 receptor and other receptors broadly termed the IL-1 receptor family. In addition, soluble cytoplasmic proteins such as MyD88 can have Toll domains. TLRs and IL-1 receptor use an analogous framework of signalling; upon ligand binding, they recruit the adaptor molecule MyD88 through homotypic interactions with a toll domain that MyD88 contains in its C-terminus. MyD88, in turn, recruits IRAK, TRAF-6 and TollIP to activate NF-.kappa.B and mitogen-activated protein kinases (O'Neill & Dinarello (2000) Immunol Today 21, 206-209; Burns et al (2000) Nature cell Biol. 2, 346-351). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Treatment of sepsis by low dose administration of tissue factor pathway inhibitor (TFPI) Inventor(s): Creasey, Abla; (Piedmont, CA) Correspondence: Chiron Corporation; Intellectual Property - R440; P.O. Box 8097; Emeryville; CA; 94662-8097; US Patent Application Number: 20030139340 Date filed: February 4, 2003
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Abstract: Methods for prophylactically or therapeutically treating sepsis or septic shock involve administration of tissue factor pathway inhibitor (TFPI) or a TFPI analog to patients suffering from sepsis or other inflammatory conditions. The methods involve the use of continuous intravenous infusion of TFPI or a TFPI analog at low doses to avoid adverse side effects. Excerpt(s): This application claims priority to provisional application Serial No. 60/328,806 filed Oct. 15, 2001, hereby incorporated by reference in its entirety. The present invention is a method for prophylactically and therapeutically treating sepsis, septic shock, and acute or chronic inflammation while minimizing adverse side effects. More specifically, it comprises administering low doses of a tissue factor pathway inhibitor protein to attenuate amplified or activated physiological pathways associated with sepsis and septic shock. Sepsis and its sequela septic shock remain among the most dreaded complications after surgery and in critically ill patients. The Center for Disease Control has ranked septicemia as the 13th leading cause of death in the United States (MMWR, 1987, 39:31 and US Dept. of Health and Human Services, 37:7, 1989), and the 10th leading cause of death among elderly Americans (see MMWR, 1987, 32:777). The incidence of these disorders is increasing, and mortality remains high. Caring for patients with septicemia was estimated to cost billions of dollars annually (MMWR, 1987, 39:31). Death can occur in 28% to 60% of the patients, and this percentage has not seen any sizeable improvement for more than 20 years. Grampositive and gram-negative bacterial infections are equally likely to lead to sepsis and septic shock. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Treatment of sepsis with TAFI Inventor(s): Bajzar, Laszlo; (Stoney Creek, CA), Taylor, Fletcher B. JR.; (Oklahoma City, OK) Correspondence: Patrea L. Pabst; Holland & Knight Llp; Suite 2000, One Atlantic Center; 1201 West Peachtree Street, N.E.; Atlanta; GA; 30309-3400; US Patent Application Number: 20030114359 Date filed: September 18, 2002 Abstract: A method for inhibiting and for reversing the dysfunctional response of vascular endothelial cells to an inflammatory stimulus in a subject in need of such therapy has been developed in which an effective amount of a pharmaceutical composition comprising thrombin-activatable fibrinolysis inhibitor (TAFI) combined with a pharmaceutically acceptable carrier and optionally other treatments is administered to the subject. Excerpt(s): This application claims priority to U.S. Ser. No. 6,323,219 filed Sep. 19, 2002. The present invention is in the general field of treatments of sepsis and other disorders characterized by endothelial cell dysfunction, specifically using thrombin-activable fibrinolysis inhibitor (TAFI) and analogues thereof administered in a therapeutically acceptable amount, alone or in combination with other active compounds such as activated protein C. Vascular endothelium is comprised of the epithelial cells that form the lining of blood vessels. While vascular endothelium once was thought to be a passive barrier that simply channeled the blood, it now is known that endothelial cells are actively involved in the regulation of intravascular coagulation mechanisms and in the movement of fluid between the parenchyma and the intravascular space. The
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endothelium of the microvasculature further normally functions as a dynamic semipermeable membrane. Intracellular mechanisms selectively control the porosity of the cell to various blood components. Normally, the membrane of endothelial cells is permeable to certain small physiologic molecules, such as water and nutrients, and to larger molecules under selected conditions, allowing them to pass as needed to and from the adjacent tissues. However, the endothelium normally is impermeable to larger molecules, such as plasma proteins that must remain in the blood to function. Although the endothelial mechanisms for regulating permeability and preventing thrombosis ordinarily are remarkably efficient, these mechanisms may be disrupted by an inflammatory stimulus which elicits the release of inflammatory mediators, and in particular the monokines tumor necrosis factor (TNF) and interleukin 1 (IL-1). In most cases, the release of these mediators is accompanied by activation of the plasma complement system. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Treatment of shock using adrenomedullin and adrenomedullin binding protein-1 Inventor(s): Wang, Ping; (Roslyn, NY) Correspondence: Elie H. Gendlof; Amster, Rothstein & Ebenstein; 90 Park Avenue; New York; NY; 10016; US Patent Application Number: 20030216291 Date filed: May 16, 2003 Abstract: The present invention provides methods of preventing organ destruction and shut-down due to shock in a patient suffering from sepsis or at risk for sepsis, comprising administering adrenomedullin and adrenomedullin binding protein-1 to the patient. Also provided are compositions containing adrenomedullin and adrenomedullin binding protein-1 or precursors, in a pharmaceutically acceptable carrier. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/380,838, filed May 17, 2002, incorporated by reference in its entirety. This invention relates to treatment of shock to prevent organ shut-down during the hypodynamic phase. The invention described herein involves administration of adrenomedullin in conjunction with administration of adrenomedullin binding protein-1. Elsasser T H, Kahl S, Martinez A, Montuenga L M, Pio R, Cuttitta F: Adrenomedullin binding protein in the plasma of multiple species: characterization by radioligand blotting. Endocrinol 140:4908-4911, 1999. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Use of antibodies to block the effects of Gram-positive bacteria and mycobacteria Inventor(s): Pugin, Jerome; (Puplinge, CH), Tobias, Peter S.; (San Diego, CA), Ulevitch, Richard J.; (Del Mar, CA) Correspondence: Gary Cary Ware & Friendenrich Llp; 4365 Executive Drive; Suite 1600; San Diego; CA; 92121-2189; US Patent Application Number: 20030103969 Date filed: July 25, 2002
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Abstract: The present invention concerns a method of treating bacteremia, sepsis and other forms of toxemia caused by Gram-positive bacteria and mycobacteria comprising administering a therapeutically effective amount of anti-CD14 antibody molecules. A therapeutic composition comprising anti-CD14 antibody molecules in a pharmaceutically acceptable excipient is also contemplated. Excerpt(s): The present invention relates to methods and compositions for preventing or treating disease states caused by bacteria. More particularly, the present invention relates to antibodies and molecules that mediate cellular activation in response to Grampositive bacteria and mycobacteria. Septic shock is a tragic complication of bacterial infections, characterized by refractory hypotension, leading to inadequate organ perfusion, multiple organ failure and frequently death (Glauser, et al., Lancet, 338:732736, 1991; Bone, Chest, 100:802-808, 1991). The lipopolysaccharide (endotoxin, LPS) of Gram-negative bacteria triggers cellular and physiological responses such as those observed during Gram-negative sepsis (Glauser, et al., supra; Ulevitch and Tobias, Curr. Opin. Immunol. 6:125-130, 1994). Cells of the immune/inflammatory systems respond to LPS by a pathway involving both plasma and membrane proteins (Ulevitch and Tobias, supra, 1994; Tobias, et al., Am. J. Respir. Cell Mol. Biol., 7:239-245, 1992). Included in this group of proteins are lipopolysaccharide-binding protein (LBP), a soluble serum protein which binds LPS and subsequently enables the binding of LPS to a second molecule, CD14. The LBP/CD14-dependent pathway is operative under physiological conditions and controls cell activation when nanomolar concentrations of LPS are used (Schumann, et al., Science, 249:1429-1433,1990; Wright, et al., Science, 249:1431-1433, 1990). CD14 is found as a glycosylphosphatidylinositol-anchored membrane protein (mCD14) of myeloid cells, or in plasma/serum as a soluble protein (sCD14) (Ulevitch and Tobias, supra, 1994; Tobias, et al., supra, 1992; Pugin, et al., Proc. Natl. Acad. Sci. USA, 90:27442748, 1993a). Binding of LPS to mCD14 leads to cellular activation and generation of various proinflammatory molecules (Ulevitch and Tobias, supra, 1994). Other cell types such as endothelial, epithelial, vascular smooth muscle cells, and astrocytes do not bear CD14 but respond to soluble CD14-LPS complexes (Pugin, et al., supra, 1993a; Frey, et al., J. Exp. Med., 176:1665-1671, 1992). A CD14-and LBP-independent pathway of LPS stimulation is observed only when high LPS concentrations are used. In recent multicenter trials on sepsis, Gram-positive bacteria were found responsible for half of the cases of bacterial sepsis (Bone, Arch. Intern. Med., 154:26-34, 1994). The prevalence of sepsis due to Gram-positive bacteria has risen markedly over the past two decades, and those microorganisms may well predominate as the cause of sepsis within the next few years (Bone, supra, 1994; Schaberg, et al., Am. J. Med., 91 :72S-75S, 1991). In contrast to what has been learned about how LPS stimulates cells much less is known about the molecular mechanisms of cellular activation by Gram-positive bacteria. Products of Gram-positive bacteria that can activate host cells include soluble exotoxins and cell wall components (Bone, supra, 1994). It is known that cell walls isolated from different Gram-positive strains, as well as purified cell wall components such as peptidoglycan or lipoteichoic acid activate cells of myeloid origin and induce cell responses very similar to that of LPS (Chin and Kostura, J. Immunol., 151:5574-5585, 1993; Mattson, et al, FEMS Immun. Med. Microbiol., 7:281-288, 1993; Rotta, Z. Immunol. -Forsch, Bd, 149-230-244, 1975). However, few studies have addressed the mechanisms of receptor-dependent recognition of Gram-positive cell wall components by mammalian cells. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Use of glutamate and/or a glutamate precursor for the preparation of a nutritional or pharmaceutical preparation for the treatment or prevention of hyperpermeability or undesired permeability of the intestinal wall Inventor(s): Glas, Cornelis; (Tietjerk, NL), Houdijk, Alexander Petrus Johannes; (Amstelveen, NL), Van Leeuwen, Paulus Aluisius Marie; (Amstelveen, NL) Correspondence: Fitch Even Tabin And Flannery; 120 South LA Salle Street; Suite 1600; Chicago; IL; 60603-3406; US Patent Application Number: 20030138476 Date filed: November 20, 2002 Abstract: The present invention relates to the use of glutamic acid for the preparation of a nutritional preparation that is intended for use for the treatment or prevention of excess or undesired permeability of the intestinal wall. In particular, according to the invention the glutamic acid is used in a nutritional preparation, such as a baby food or an enteral food. Examples of conditions where glutamic acid is used are: food allergy, internal drug allergy, sepsis, low blood flow through the intestines, ICU patients, surgical interventions, malnutrition or intestinal maturation of newborn babies. Excerpt(s): The invention relates to the preparation of a nutritional preparation that is suitable for use in the case of conditions associated with an increased permeability of the intestinal wall. The intestinal epithelium acts as a selective barrier which allows the absorption of nutrients but restricts the passage of microorganisms and undesired macromolecules. Maintaining this barrier is considered to be important in order to protect the host against the migration of pathogenic microorganisms from the intestines to the bloodstream. It is assumed that the increase in the permeability of the intestines is associated with damage to the paracellular transport system of the intestinal mucosa, as a result of which translocation of endotoxins and (pathogenic) bacteria can occur. As a result of the damage to the intestinal mucosa it is also possible for absorption of macromolecules to occur, which are then able to initiate allergic reactions. An increase in the permeability of the intestinal wall has been detected in clinical conditions associated with damage to the intestinal mucosa barrier, such as endotoxaemia, sepsis, multiple trauma, malnutrition, major surgical interventions, parenteral nutrition and burns. An increase in the permeability to larger molecules, such as proteins, has been found in the newborn, but also occurs in healthy people if they are allergic to food products. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Xanthine oxidase inhibition as a strategy to alleviate oxidative impairment of vascular function Inventor(s): Aslan, Mutay; (Antalya, TR), Freeman, Bruce A.; (Birmingham, AL), Ryan, Tom; (Birmingham, AL), Tarpey, Margaret; (Birmingham, AL), Townes, Tim; (Birmingham, AL) Correspondence: Bradley Arant Rose & White, Llp; Intellectual Property Departmentnwj; 1819 Fifth Avenue North; Birmingham; AL; 35203-2104; US Patent Application Number: 20030158213 Date filed: November 18, 2002 Abstract: Disclosed is a method for alleviating the oxidative impairment of vascular function by inhibiting the activity of xanthine oxidase, or active forms thereof. Xanthine
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oxidase levels have been shown to be increased by a variety of conditions, including sickle cell disease. In the present disclosure, allopurinol is used to inhibit xanthine oxidase activity. As a result of the inhibition of xanthine oxidase,.NO levels in a subject can be maintained. In addition to sickle cell disease, allopurinol inhibition of xanthine oxidase may be used to treat other conditions, including, but not limited to, respiratory distress, kidney disease, liver disease, ischemia-reperfusion injury, organ transplant, sepsis, burns, viral infections and hemorrhagic shock. Excerpt(s): This disclosure claims the benefit of U.S. Provisional Patent Application No. 60/333,268, filed on Nov. 16, 2001. The present disclosure is directed to a method of using compounds which inhibit the activity of xanthine oxidase in order to alleviate the inhibition of vascular function caused by oxidative events and/or inflammatory conditions. The production of oxygen radical species, such as O.sub.2. and H.sub.2O.sub.2, have been know to cause tissue injury in living organisms and contribute to a wide variety of disease processes. Multiple features of sickle cell disease (SCD) reveal that inflammatory-derived oxidative reactions lead to impaired nitric oxide (.NO)-dependent vascular function. Nitric oxide is a free radical mediator of neurotransmitter, cell-mediated immunity and tissue redox reactions. In regulating endothelial-dependent vascular relaxation,.NO diffuses to target cells to stimulate cGMP production by guanylate cyclase and activate a chain of events in the vasculature including smooth muscle cell relaxation, inhibition of platelet aggregation and neutrophil margination and regulation of gene expression. In SCD, the production of.NO appears to be chronically activated to maintain vasodilation, as indicated by low baseline blood pressure, decreased pressor responses to angiotensin II, renal hyperfiltration and a tendency for priapism. Plasma arginine levels drop precipitously during pain crises, indicating a possible demand for, or insufficient synthesis of,.NO. The mechanisms underlying blood flow deprivation, the associated pain and consequent tissue injury in SCD remain poorly understood. If the tissue ischemia that is a hallmark of SCD resulted solely from polymerized, sickled red cells, occlusion of predominantly small blood vessels would occur. In contrast, stroke in SCD results from occlusion of large and medium-sized arteries (internal carotid and middle cerebral arteries). Importantly, levels of sickled erythrocytes or dense cells do not correlate with painful episodes and other manifestations of vascular occlusion, inferring that morbidity is due to vascular functional defects that occur in response to sickling, rather than mechanical effects of sickling. Increased oxidant production in the vasculature of SCD patients has been recognized for almost two decades. However, this disclosure reveals that the endogenous rate of production of superoxide (O.sub.2.--) and hydrogen peroxide (H.sub.2O.sub.2) by human sickle red cells is not significantly increased. In contrast, elevated plasma and vessel wall xanthine oxidase (XO) and myeloperoxidase activity in SCD patients and SCD mice, and increased vessel wall O.sub.2.-- and H.sub.2O.sub.2 generation in SCD mice is observed. This is ascribed to the a) vessel wall binding of liver-derived circulating XO, released following repeated hepatic hypoxiareoxygenation events, b) release and vessel wall binding of of neutrophil myeloperoxidase, and c) possible increased vessel wall expression of XO or other oxidases. This vascular inflammatory condition in SCD can induce O.sub.2.-- and H.sub.2O.sub.2 dependent inhibition of the salutary actions of.NO, while concomitantly yielding the potent and versatile reaction products, peroxynitrite (ONOO--) and nitrogen dioxide, oxidizing and nitrating species capable of further impairing vascular function. Thus, it is viewed that XO-derived reactive species impair nitric oxidedependent systemic vascular function in SCD patients and contribute to the pathogenesis of acute sickle cell crises and end-organ damage. Therefore, a therapeutic regime to target and inhibit the XO-dependent production of O.sub.2. and
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H.sub.2O.sub.2 should be effective in treating SCD patients by preserving.NO functions and endothelial dependent function in SCD patients. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Keeping Current In order to stay informed about patents and patent applications dealing with sepsis, 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 “sepsis” (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 sepsis. You can also use this procedure to view pending patent applications concerning sepsis. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 6. BOOKS ON SEPSIS Overview This chapter provides bibliographic book references relating to sepsis. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on sepsis 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 “sepsis” (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 sepsis: •
Nutrition Support: Enteral and Parenteral Nutrition. 3rd ed Source: San Marcos, CA: Nutrition Dimension. 1997. 174 p. Contact: Available from Nutrition Dimension. P.O. Box 6488, Eureka, CA 95502. (888) 781-5388 or (707) 442-9487. Fax (707) 442-0364. E-mail:
[email protected]. PRICE: $89.00. Summary: Nutrition support is complex nutrition care provided to patients who are, or have been, critically ill. The term also applies to care provided to those patients with disease states that affect their nutritional status or their ability to utilize particular nutrients. This book is a continuing education course that provides practical guidelines and references for the nutrition care practitioner, focusing on the clinical practitioner's role. Included are methods of nutrition assessment, an overview of enteral and parenteral regimens, and guidelines for the nutrition support of patients with specific diseases and conditions. These conditions include gastrointestinal disorders, stress and
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sepsis, obesity, diabetes mellitus, respiratory failure, renal disease, liver disease, cancer patients, and AIDS and HIV-positive patients. A final chapter considers the transition to home care, including guidelines for home nutrition support and complications of longterm total parenteral nutrition (TPN). Each chapter includes charts, tables, and references. The text includes case studies, review questions with answers, and an objective post-test. (AA-M). •
Total Parenteral Nutrition. 2nd ed Source: Boston, MA: Little, Brown and Company. 1991. 486 p. Contact: Available from Little, Brown and Company. Order Department, 200 West Street, Waltham, MA 02154. PRICE: $91. ISBN: 0316283797. Summary: This medical textbook provides an overview of total parenteral nutrition (TPN). Twenty-seven chapters are presented in three sections: general principles, specific aspects, and supplemental techniques. The chapters address indications for TPN; complications; pharmaceutical considerations in TPN; patient and staff education; nutrition and immunity; nutritional assessment; energy requirements for TPN; acute renal failure; nutritional support in cardiac and pulmonary diseases; preoperative TPN; inflammatory bowel disease; fistulas; nutritional support in hepatic failure; TPN for patients with burns; pediatrics; sepsis; TPN in the cancer patient; home parenteral nutrition; peripheral amino acids; lipid emulsions; and enteral nutrition. Each chapter, written by experts in the field, includes numerous references. A detailed subject index concludes the volume.
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Oral and Cutaneous Manifestations of Hematogenously Disseminated Systemic Infections: A Monograph Source: Research Triangle Park, NC: Glaxo, Inc. 1993. 79 p. Contact: Available from Glaxo-Wellcome Education Resource Center. 5 Moore Drive, Research Triangle Park, NC 27709. (800) 824-2896. PRICE: Single copy free. Stock Number GVL251. Summary: This monograph describes oral and dermatologic manifestations resulting from systemic infections. Written as a continuing education tool for physicians, the monograph features 26 sections, each of which includes a description of dermatologic manifestations, other clinical features, laboratory findings, and epidemiologic factors. Diseases covered include AIDS, blastomycosis, candidiasis, coccidioidomycosis, cryptococcoses, erythema infectiousum (Fifth disease), gonococcemia, gram-negative bacterial sepsis, hand-foot-and-mouth disease, infectious mononucleosis, infective endocarditis, Kawasaki syndrome, leprosy, lyme disease, meningococcemia, Rocky Mountain spotted fever, roseola, rubella (German measles), rubeola (measles), scarlet fever, secondary (disseminated) syphilis, staphylococcal scalded skin syndrome, toxic shock syndrome, typhoid fever, varicella (chickenpox), and Vibrio vulnificus infection. Each section is illustrated with full-color photographs depicting patients with manifestations of the disease under consideration. The monograph includes a glossary of illustrations to help with diagnosis and classification. The monograph concludes with a self-test and instructions for receiving continuing medical education credits. A subject index is also included. 12 references.
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Low Dose Chemotherapy With CNS Prophylaxis and Zidovudine (AZT) Maintenance for AIDS - Related Lymphoma: Preliminary Results of A Multi - Institutional Study Source: 25th Proceedings of Annual Meeting of the American Society of Clinical Oncology; Vol., March 1989. p. 5. Contact: US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS, 6700-B Rockledge Dr, Bethesda, MD, 20892-7620, (301) 496-0545, http://www.niaid.nih.gov. Summary: Use of intensive, multi-agent chemotherapy (chemo) in AIDS-related lymphoma may be associated with severe marrow suppression and early demise due to infection. In an attempt to ascertain if lower dose chemo, with CNS prophylaxis, would improve response rates, the following regimen was used: Day 1: Cytoxan, 300 mg/m2; Adriamycin 25 mg/m2; vincristine 1.4 mg/m2; bleomycin 4 u/m2; Decadron 3 mg/m2 po day 1-5. Day 15: methotrexate 500 mg/m2 with folinic acid 50 mg q 6 hr x 8. With absence of CNS or marrow involvement, Ara-C, 30 mg IT was given on days 1, 8, 15, 21 of cycle 1. With CNS or marrow involvement, 2400 rads to whole brain was also given. At completion of 4-6 mo of total chemo, AZT (200 mg q 4 hr) x 1 yr was begun. This prospective trial began in 6/87; 38 patients (pts) are registered; 31 are now evaluable. Complete response (CR) occurred in 14 (45 percent), with an additional 2 pts in early clinical CR (total CR = 52 percent). No response or progressive disease occurred in 14 (45 percent), and 1 had PR. Of 16 CR pts, 4 subsequently died, 2 of opportunistic infection. In 68 chemo cycles, a nadir granulocyte count of less than 1000 was seen in 16 (24 percent), and less than 500 in 19 percent of these. Nadir platelet count less than 100K was seen in 5/68 (7 percent). Fever occurred in 13/68 cycles, with granulocyte count greater than 500 in 12 of these, and documented sepsis in 2/13. Other toxicity was minimal. We conclude: (1) Low dose chemo with CNS therapy may be effective in approx half of these pts; (2) Details are presented.
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 “sepsis” at online booksellers’ Web sites, you may discover nonmedical books that use the generic term “sepsis” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “sepsis” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
Abdominal Sepsis (Digestive Surgery, Vol. 13, No.4-5, 1996) by M.W. Wuechler, D. Thomson; ISBN: 3805563523; http://www.amazon.com/exec/obidos/ASIN/3805563523/icongroupinterna
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Advances in the Diagnosis and Management of the Patient with Severe Sepsis by Robert A. Balk; ISBN: 1853154946; http://www.amazon.com/exec/obidos/ASIN/1853154946/icongroupinterna
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Bacterial Endotoxins: Basic Science to Anti-Sepsis Strategies: Proceedings of the Fourth International Conference on Endotoxins (Icea Iv, Held in) by Jack Levin
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(Editor), et al; ISBN: 0471021814; http://www.amazon.com/exec/obidos/ASIN/0471021814/icongroupinterna •
Bacterial Endotoxins: Cytokine Mediators and New Therapies for Sepsis: Proceedings of the Third International Conference on Endotoxins, Held in amst by Augueste Sturk (Editor), et al; ISBN: 0471560960; http://www.amazon.com/exec/obidos/ASIN/0471560960/icongroupinterna
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Clinical Trials for the Treatment of Sepsis (Update in Intensive Care and Emergency Medicine, Vol 19) by W.J. Sibbald, J.-L. Vincent (Editor); ISBN: 0387583807; http://www.amazon.com/exec/obidos/ASIN/0387583807/icongroupinterna
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Controversies in Surgical Sepsis by S. Karran (Author); ISBN: 0275913457; http://www.amazon.com/exec/obidos/ASIN/0275913457/icongroupinterna
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Cytokines in Severe Sepsis & Septic Shock by Heinz Redl (Editor), G. Schlag (Editor); ISBN: 3764358777; http://www.amazon.com/exec/obidos/ASIN/3764358777/icongroupinterna
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Decision Making in Surgical Sepsis (Clinical Decision Making Series) by Ronald Lee Nichols, et al; ISBN: 1556640536; http://www.amazon.com/exec/obidos/ASIN/1556640536/icongroupinterna
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Emergency Surgery: Trauma, Shock, Sepsis, Burns by John S. Najarian; ISBN: 0815163347; http://www.amazon.com/exec/obidos/ASIN/0815163347/icongroupinterna
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Endotoxin and Sepsis : Molecular Mechanisms of Pathogenesis, Host Resistance, and Therapy by Jack Levin (Editor), et al; ISBN: 0471194328; http://www.amazon.com/exec/obidos/ASIN/0471194328/icongroupinterna
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Evolving Concepts in Sepsis and Septic Shock by Peter Q., MD Eichacker (Editor), Jerome, MD Pugin (Editor); ISBN: 0792372352; http://www.amazon.com/exec/obidos/ASIN/0792372352/icongroupinterna
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Host Defense Dysfunction in Trauma, Shock and Sepsis; ISBN: 3540553290; http://www.amazon.com/exec/obidos/ASIN/3540553290/icongroupinterna
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Host Defense Dysfunction in Trauma, Shock and Sepsis: Mechanisms and Therapeutic Approaches by Eugen Faist, et al; ISBN: 0387553290; http://www.amazon.com/exec/obidos/ASIN/0387553290/icongroupinterna
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Immune Consequences of Trauma, Shock, and Sepsis: Mechanisms and Therapeutic Approaches by E. Faist, et al; ISBN: 0387190090; http://www.amazon.com/exec/obidos/ASIN/0387190090/icongroupinterna
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Immunotherapy of Gram-Negative Bacterial Sepsis (Medical Intelligence Unit) by Randall S. Burd, et al; ISBN: 1879702045; http://www.amazon.com/exec/obidos/ASIN/1879702045/icongroupinterna
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Injury & Sepsis Survival: Basic Mechanisms & Medical Treatment by P. A. Burke, R. A. Forse; ISBN: 0824794834; http://www.amazon.com/exec/obidos/ASIN/0824794834/icongroupinterna
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Intra-Abdominal Sepsis: Proceedings of a Symposium Held in Nijmegen, the Netherlands, Feb 9-10, 1979.Ed by H.H.M. De Boer (201P); ISBN: 0839114974; http://www.amazon.com/exec/obidos/ASIN/0839114974/icongroupinterna
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Market for Sepsis Therapeutics and Preventative Agents [DOWNLOAD: PDF] by Kalorama Information (Author); ISBN: B00005R8YF; http://www.amazon.com/exec/obidos/ASIN/B00005R8YF/icongroupinterna
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Mediators of Sepsis (Update in Intensive Care and Emergency Medicine) by L.G. Thijs (Editor), M. Lamy (Editor); ISBN: 3540558411; http://www.amazon.com/exec/obidos/ASIN/3540558411/icongroupinterna
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Modulation of the Inflammatory Response in Severe Sepsis: International Symposium, Madrid, September 16-17, 1993 (Progress in Surgery, Vol 20) by J.M. Tellado, et al; ISBN: 3805560419; http://www.amazon.com/exec/obidos/ASIN/3805560419/icongroupinterna
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Neonatal Sepsis and Meningitis by Alistair Philip; ISBN: 0816122539; http://www.amazon.com/exec/obidos/ASIN/0816122539/icongroupinterna
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Novel Therapeutic Strategies in the Treatment of Sepsis by David C. Morrison (Editor), John L. Ryan (Editor); ISBN: 0824796616; http://www.amazon.com/exec/obidos/ASIN/0824796616/icongroupinterna
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Nutrition in Cancer and Trauma Sepsis: Proceedings of the 6th Congress of the European Society of Parenteral and Enteral Nutrition (Espen, Milan, O) by F. Bozzetti (Editor), et al; ISBN: 3805539592; http://www.amazon.com/exec/obidos/ASIN/3805539592/icongroupinterna
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Pathophysiology of Shock, Sepsis, and Organ Failure by H. Redl (Editor), Gunther Schlag; ISBN: 038754223X; http://www.amazon.com/exec/obidos/ASIN/038754223X/icongroupinterna
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Pathophysiology of Shock, Sepsis, and Organ Failure; ISBN: 354054223X; http://www.amazon.com/exec/obidos/ASIN/354054223X/icongroupinterna
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Perspectives on Sepsis and Septic Shock (New Horizons) by William J. Sibbald; ISBN: 0936145501; http://www.amazon.com/exec/obidos/ASIN/0936145501/icongroupinterna
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Protein Metabolism in Sepsis (Medical Intelligence Unit) by Per-Olof, M.D. Hasselgren; ISBN: 1879702770; http://www.amazon.com/exec/obidos/ASIN/1879702770/icongroupinterna
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Pulmonary Sepsis by Fernando Aldana-Huyo, Guillermo Ortiz Ruiz; ISBN: 0387204512; http://www.amazon.com/exec/obidos/ASIN/0387204512/icongroupinterna
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Reoperation for Postoperative Intra-Abdominal Sepsis by Peter Aeberhard; ISBN: 3456813015; http://www.amazon.com/exec/obidos/ASIN/3456813015/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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Sepsis by Graham Masterton; ISBN: 1587671018; http://www.amazon.com/exec/obidos/ASIN/1587671018/icongroupinterna
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Sepsis by William J. Holloway; ISBN: 0879930101; http://www.amazon.com/exec/obidos/ASIN/0879930101/icongroupinterna
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Sepsis and Multiorgan Failure by Alan Fein (Editor), et al; ISBN: 0683030973; http://www.amazon.com/exec/obidos/ASIN/0683030973/icongroupinterna
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Sepsis and Multiple Organ Dysfunction: A Multidisciplinary Approach by Edwin Deitch, et al; ISBN: 0702021652; http://www.amazon.com/exec/obidos/ASIN/0702021652/icongroupinterna
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Sepsis and Organ Dysfunction: Epidemiology and Scoring Systems: Pathophysiology and Therapy by Arthur Baue (Editor), et al; ISBN: 8847002974; http://www.amazon.com/exec/obidos/ASIN/8847002974/icongroupinterna
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Sepsis and Organ Dysfunction: From Basics to Clinical Approach by J. L. Vincent (Editor), et al; ISBN: 8847000521; http://www.amazon.com/exec/obidos/ASIN/8847000521/icongroupinterna
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Sepsis and Organ Dysfunction: From Chaos to Rationale by A. E. Baue (Editor), et al; ISBN: 8847001781; http://www.amazon.com/exec/obidos/ASIN/8847001781/icongroupinterna
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Sepsis: An Interdisciplinary Challenge; ISBN: 3540177639; http://www.amazon.com/exec/obidos/ASIN/3540177639/icongroupinterna
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Sepsis: An Interdisciplinary Challenge by K. Reinhart, K. Eyrich (Editor); ISBN: 0387177639; http://www.amazon.com/exec/obidos/ASIN/0387177639/icongroupinterna
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Shock, Sepsis and Organ Failure: Second Wiggers Bernard Conference by G. Schlag (Editor), et al; ISBN: 3540538313; http://www.amazon.com/exec/obidos/ASIN/3540538313/icongroupinterna
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Shock, Sepsis, and Organ Failure: Brain Damage Secondary to HemorrhagicTraumatic Shock, Sepsis, and Traumatic Brain Injury by G. Schlag (Editor), et al; ISBN: 3540624198; http://www.amazon.com/exec/obidos/ASIN/3540624198/icongroupinterna
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Shock, Sepsis, and Organ Failure: I Brain Damage Secondary to HemorrhagicTraumatic Shock: II Brain Damage Secondary to Sepsis: III Brain Damage Secondary to Traumatic Brain Injury by Austria)/ Schlag, Gunther/ Traber, D. Wiggers Bernard Conference 1996 Krumbach; ISBN: 0387624198; http://www.amazon.com/exec/obidos/ASIN/0387624198/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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Shock, Sepsis, and Organ Failure: Third Wiggers Bernard Conference: Cytokine Network by Gunther Schlag, et al; ISBN: 0387553398; http://www.amazon.com/exec/obidos/ASIN/0387553398/icongroupinterna
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Strategies for the management of chronic bronchial sepsis : proceedings of a symposium held at the Charing Cross Hospital, London, UK, 2 November, 1983; ISBN: 0906817749; http://www.amazon.com/exec/obidos/ASIN/0906817749/icongroupinterna
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Surgical sepsis; ISBN: 0808912089; http://www.amazon.com/exec/obidos/ASIN/0808912089/icongroupinterna
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The diagnosis and management of the cancer patient with sepsis by David V. Schapira; ISBN: 093540497X; http://www.amazon.com/exec/obidos/ASIN/093540497X/icongroupinterna
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The emerging market for sepsis therapeutics and preventive agents; ISBN: 1562412876; http://www.amazon.com/exec/obidos/ASIN/1562412876/icongroupinterna
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The Pathophysiology of Sepsis and Multi-Organ Failure (Medical Intelligence Unit) by Mitchell P. Fink; ISBN: 0412114518; http://www.amazon.com/exec/obidos/ASIN/0412114518/icongroupinterna
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The Sepsis Text by J. L. Vincent (Editor), et al; ISBN: 079237620X; http://www.amazon.com/exec/obidos/ASIN/079237620X/icongroupinterna
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Trauma, Sepsis, and Shock: The Physiological Basis of Therapy (Science and Practice of Surgery Series, No 15) by George H.A., Jr. Clowes (Editor); ISBN: 0824775023; http://www.amazon.com/exec/obidos/ASIN/0824775023/icongroupinterna
Chapters on Sepsis In order to find chapters that specifically relate to sepsis, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and sepsis 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 “sepsis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on sepsis: •
Benign Stricture of the Bile Ducts Source: in Sherlock, S.; Dooley, J. Diseases of the Liver and Biliary System. Malden, MA: Blackwell Science, Inc. 2002. p.629-637. Contact: Available from Blackwell Science, Inc. 350 Main Street, Commerce Place, Malden, MA 02148. (800) 215-1000 or (617) 388-8250. Fax (617) 388-8270. E-mail:
[email protected]. Website: www.blackwell-science.com. PRICE: $178.95. ISBN: 0632055820. Summary: Benign strictures of the biliary system are uncommon and usually follow surgery, in particular cholecystectomy, laparoscopic or open. They may also complicate liver transplantation. Cystic lesions of the liver and bile ducts are increasingly being diagnosed. This chapter on benign stricture of the bile ducts is from a textbook that presents a comprehensive and up-to-date account of diseases of the liver and biliary system. The authors note that other causes are primary sclerosing cholangitis, chronic pancreatitis, and abdominal trauma. Clinical features are cholestasis with or without sepsis and pain. Diagnosis is by cholangiography. In most cases, the underlying cause is clear from the clinical data. The authors conclude that in all benign strictures of the bile duct, the outcome depends on the experience and judgment of the team of surgeon, endoscopist and radiologist, in selecting and performing the most suitable corrective procedure tailored to the individual patient. 7 figures. 1 table. 33 references.
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Liver Transplantation: Prevention and Treatment of Rejection Source: in McDonald, J.W.D.; Burroughs, A.K.; Feagan, B.G., eds. Evidence Based Gastroenterology and Hepatology. London, UK: BMJ Publishing Group. 1999. p. 491511. Contact: Available from BMJ Publishing Group. BMA Books, BMA House, Tavistock Square, London WCIH 9JR. Fax 44 (0)20 7383 6402. E-mail:
[email protected]. Website: www.bmjbooks.com. PRICE: Contact publisher for price. Summary: Liver transplant recipients are a heterogeneous group of individuals, with different predisposing factors and cofactors for the development of rejection. This chapter on the prevention and treatment of rejection in liver transplantation is from a book that emphasizes the approaches of evidence based medicine in gastroenterology (the study of the gastrointestinal tract and gastrointestinal diseases) and hepatology (the study of the liver and liver diseases). The authors of this chapter note that the success of hepatic (liver) transplantation has resulted in its widespread use for endstage and fulminant liver disease. Current immunosuppressive agents lack specificity and there is still a need to maintain a balance between over-immunosuppression, with its potential risk of life threatening sepsis, and under-immunosuppression leading to graft loss from rejection. At present, the vast majority of liver transplant recipients need to take life long immunosuppressive therapy. The gold standard for diagnosis of graft rejection is histological; rejection is classified as acute (occurring between 5 and 30 days after liver transplantation) or chronic (after 60 days from transplantation). Chronic rejection usually develops after an unresolved episode of acute rejection, or after multiple episodes of acute rejection, or quietly during a period of months to years with few or no clinically apparent acute episodes of cellular rejection. The authors consider the prognostic factors for rejection, including the number of acute rejection episodes, severity, and timing. The authors also consider strategies for weaning patients off immunosuppression, including steroid withdrawal, total withdrawal, and the use of subtherapeutic doses of immunosuppression; and choice of immunosuppressive agents, including calcineurin inhibitors, microemulsified cyclosporin, mycophenolate mofetil, ursodeoxycholic acid (UDCA), and trials comparing mono and combination therapies. 7 tables. 88 references.
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Renal Dysfunction and Postoperative Renal Failure in Obstructive Jaundice Source: in Arroyo, V., et al, eds. Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment. Malden, MA: Blackwell Science, Inc. 1999. p.7998. 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: Patients with obstructive jaundice (OJ) have an increased risk for a wide array of postoperative complications, namely, bleeding, infections, poor wound healing, and kidney (renal) failure. The three major consequences of biliary obstruction: immunosuppression, malnutrition, and hemodynamic (blood flow) disturbances, are all implicated in the pathogenesis of these complications. This chapter on kidney dysfunction and postoperative kidney failure in OJ is from a textbook on ascites and renal dysfunction in liver disease. The author reviews evidence linking biliary obstruction with kidney dysfunction, emphasizing the pathogenesis (development) of this association according to the most recent experimental and clinical data. This
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knowledge will improve the perioperative care of patients with obstructive jaundice. The author notes that prevention of perioperative kidney dysfunction is best achieved by accurate monitoring of fluid replacement and diuresis, and avoidance of all potentially nephrotoxic drugs, particularly aminoglycoside antibiotics. Preoperative internal biliary drainage, coupled with appropriate rehydration and metabolic support, appears to be a promising adjunct for improving the condition of patients with OJ, particularly of those with severe hyperbilirubinemia, sepsis, or advanced malnutrition. 5 figures. 9 tables. 75 references. •
Hepatic Regeneration Source: in Textbook of Gastroenterology. 4th ed. [2-volume set]. Hagerstown, MD: Lippincott Williams and Wilkins. 2003. p. 621-633. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-6423. Fax: (301) 223-2400. Website: www.lww.com. PRICE: $289.00. ISBN: 781728614. Summary: The liver exhibits unusual properties of regeneration after partial hepatectomy (surgical removal) or toxic injury. This evolutionarily conserved response is a logical adaptive response of organisms because the liver is the major detoxifying organ of the body and first in line to be injured by ingested toxins. This chapter on hepatic regeneration is from a lengthy, two-volume textbook that integrates the various demands of science, technology, expanding information, good judgment, and common sense into the diagnosis and management of gastrointestinal patients. Topics include the basic characteristics of liver regeneration, mechanisms of liver regeneration, liver function during liver regeneration, cytokine-dependent and independent pathways in regeneration, and liver regeneration in human disease. The authors conclude that based on molecular analyses of liver regeneration, it is now better understood how the liver is able to regenerate and have the functional capacity that is required to maintain metabolic homeostasis during proliferation. In pathological processes such as fulminant hepatic failure and sepsis, in which hepatic function may be lost, it is now possible to assess parameters of liver function. 6 figures. 1 table. 106 references.
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Glucose Homeostasis and Hypoglycemia Source: in Wilson, J.D., et al., eds. Williams Textbook of Endocrinology. 9th ed. Philadelphia, PA: W.B. Saunders Company. 1998. p. 939-971. Contact: Available from W.B. Saunders Company. Book Order Fulfillment Department. 11830 Westline Industrial Drive, Saint Louis, MO 63146-9988. (800) 545-2522 or (314) 4537010. Fax (800) 568-5136 or (314) 453-7095. E-mail:
[email protected]. Website: www.wbsaunders.com. PRICE: $150.00 plus shipping and handling. ISBN: 0721661521. Summary: This chapter focuses on glucose homeostasis and hypoglycemia. The chapter begins with a discussion of the physiology of systemic glucoregulation, including glucose metabolism; the effect of fasting, feeding, and exercise on systemic glucose balance; hormonal, neural, and substrate glucoregulatory factors; and glucose counterregulation. Topics related to glucose metabolism include the origin and fate of glucose, hepatic glucose metabolism, and glucose utilization. Other topics include the control of glucoregulatory factors, the correction and prevention of hypoglycemia, and the principles of glucose counterregulation. The chapter next examines the pathophysiology of hypoglycemia, focusing on the clinical manifestations of hypoglycemia, the diagnosis of hypoglycemia, postabsorptive versus postprandial hypoglycemia, and the clinical classification of hypoglycemia. This is followed by a
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discussion of hypoglycemia in type 1 and type 2 diabetes. Topics related to hypoglycemia in type 1 diabetes include the frequency, impact, prevention, and treatment of hypoglycemia and the risk factors for this condition. The chapter continues with a discussion of the causes of postabsorptive hypoglycemia including drugs such as insulin or a sulfonylurea; hepatic, cardiac, and renal diseases, sepsis, and inanition; cortisol and growth hormone deficiencies and glucagon and epinephrine deficiencies; nonbeta cell tumors; and endogenous hyperinsulinism. Causes of hypoglycemia unique to infancy or childhood include transient intolerance of fasting, maternal diabetes, and enzymatic defects. Final topics include postprandial hypoglycemia, treatment of postabsorptive hypoglycemia, and care of the patient with suspected hypoglycemia. 22 figures. 3 tables. 391 references. •
Abdominal Abscesses Source: in Snape, W.J., ed. Consultations in Gastroenterology. Philadelphia, PA: W.B. Saunders Company. 1996. p. 117-121. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 545-2522. Fax (800) 874-6418 or (407) 352-3445. PRICE: $125.00. ISBN: 0721646700. Summary: This chapter from a gastroenterology textbook covers abdominal abscesses. The authors define abscess as a collection of pus; and abdominal includes intraperitoneal and retroperitoneal sites. Abscesses within viscera (i.e., liver, gallbladder, pancreas) are not considered. Common sites for the occurrence of abscesses include both right and left subphrenic spaces, the pelvis, and intrahepatic space. Topics include the development of abscesses; the organisms usually responsible; characteristic clinical manifestations; subphrenic abscesses; confirming the diagnosis; and treatment options. The principal local manifestations include fever and abdominal pain, accompanied often by abdominal distension and ileus. Profound endotoxemia or bacteremia may result in septic shock. The cornerstone of the effective treatment of an abdominal abscess is adequate drainage of the purulent contents. Antibiotic treatment is therefore adjunctive. Without draining, mortality approaches 90 percent. The general medical condition of the patient with an abdominal abscess must also be closely monitored. Complications of sepsis include disseminated intravascular coagulation, adult respiratory distress syndrome, acute tubular necrosis, decreased systemic vascular resistance with shock, and hyperbilirubinemia. The author stresses that these conditions must be recognized and promptly corrected with the appropriate supportive measures, preferably in an intensive care setting. 2 figures. 12 references. (AA-M).
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Appendicitis Source: in Brandt, L., et al., eds. Clinical Practice of Gastroenterology. Volume One. Philadelphia, PA: Current Medicine. 1999. p. 733-738. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 545-2522. Fax (800) 874-6418 or (407) 352-3445. Website: www.wbsaunders.com. PRICE: $235.00 plus shipping and handling. ISBN: 0443065209 (two volume set); 0443065217 (volume 1); 0443065225 (volume 2). Summary: This chapter on appendicitis is from a lengthy textbook that brings practitioners up to date on the complexities of gastroenterology practice, focusing on the essentials of patient care. The authors of this chapter review the incidence, etiology, pathophysiology, anatomy, microbiology, diagnosis, and treatment of appendicitis; with an additional section on appendicitis in special circumstances, including in patients with
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AIDS, in pregnancy, in the young and elderly, periappendiceal abscess, and chronic appendicitis. Appendicitis continues to be one of the most common surgical emergencies in clinical practice. With a long differential diagnosis and varied presentation (symptoms), the diagnosis of acute appendicitis can be challenging. Prompt diagnosis and appendectomy (removal of the appendicitis) remain important for preventing sepsis. 3 figures. 25 references. •
Diarrhea Source: in Reisman, A.B.; Setevens, D.L., eds. Telephone Medicine: A Guide for the Practicing Physician. Philadelphia, PA: American College of Physicians. p. 123-142. Contact: Available from American College of Physicians (ACP). 190 N. Independence Mall West, Philadelphia, PA 19106-1572. (800) 523-1546 or (215) 351-2600. Website: www.acponline.org. PRICE: $40.00 plus shipping and handling. ISBN: 0943126878. Summary: This chapter on diarrhea is from a reference book for practicing physicians who are providing information for their patients over the telephone. The author notes that most episodes of acute diarrhea are self-limited and do not require or result in physician assistance. The chapter summarizes key points, then outlines an approach to diagnosing acute diarrhea and its sequelae in the adult patient. Topics include epidemiology, utility of early telephone evaluation, traveler's diarrhea, the general approach to the telephone evaluation, determining whether the patient is dehydrated, invasive versus noninvasive diarrhea, how to determine which patients need to be seen immediately (emergency room) and which patients can wait a few days to be seen (physician's office), recommended fluid intake, recommended anti-diarrheal medications, what to tell the patient, and what to document. The author notes that although most patients with acute diarrhea improve with symptomatic treatment at home, the physician needs to identify patients at high risk for complications such as severe dehydration, sepsis, and death. Physicians must also identify those requiring non-urgent referral for evaluation for underlying programs, such as colon cancer or inflammatory bowel disease. Finally, aggressive home treatment with the proper medications and appropriate fluids will lead to rapid symptomatic improvement in many patients and may prevent progression to severe dehydration. A patient care diagnostic algorithm is provided. 1 figure. 8 tables. 11 references.
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Examination and Diseases of the Anorectum Source: in Feldman, M.; Friedman, L.S.; Sleisenger, M.H. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 7th ed. [2-volume set]. St. Louis, MO: Saunders. 2002. p. 2277-2293. Contact: Available from Elsevier. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 545-2522. Fax (800) 568-5136. Website: www.us.elsevierhealth.com. PRICE: $229.00 plus shipping and handling. ISBN: 0721689736. Summary: This chapter on examination and diseases of the anorectum is from a comprehensive and authoritative textbook that covers disorders of the gastrointestinal tract, biliary tree, pancreas, and liver, as well as the related topics of nutrition and peritoneal disorders. Topics include anatomy, examination of the anus and rectum (inspection, palpation, endoscopy), hemorrhoids, anal fissure, anal sepsis (abscesses and fistulas), special fistulas, anal cancer, anal warts, pruritis (itching) ani, anal stenosis (narrowing), unexplained anal pain, hidradenitis suppurative, pilonidal disease, and rectal foreign body. The chapter includes a mini-outline with page citations, illustrations, and extensive references. 7 figures. 3 tables. 100 references.
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Infection in Vascular Access Procedures Source: in Wilson, S.E. Vascular Access: Principles and Practice. 4th ed. St. Louis, MO: Mosby, Inc. 2002. p. 189-203. Contact: Available from Elsevier, Health Sciences Division, 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 325-4177. Website: www.us.elsevierhealth.com. PRICE: $99.00. ISBN: 0323011888. Summary: This chapter on infection in vascular access (VA) procedures is from a text that reviews the principles and practice of vascular access, including that used for hemodialysis and for critical care, chemotherapy, and nutrition. Infection is the most common complication of vascular access surgery after thrombosis (clotting) and is a frequent cause of hospitalization of hemodialysis patients. Infection of surgical sites or graft material may prematurely end the function of autogenous or prosthetic fistulas and threatens life, through hemorrhage or systemic sepsis, and jeopardizes limb, through disruption of arterial supply. The authors review the pathogenesis of vascular access infection in the hemodialysis patient and discuss its presentation, prevention, and management. Other topics include altered immune response, altered natural barriers to infection, altered bacterial flora, role of the access type and site, bacteriology, clinical features (symptoms), prevention, treatment of sepsis, the effect of human immunodeficiency virus (HIV), and hemodialysis equipment. 4 figures. 144 references.
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Pediatric Liver Disease Source: in Friedman, L.S. and Keeffe, E.B., eds. Handbook of Liver Disease. Philadelphia, PA: Churchill-Livingstone. 1998. p. 315-325. Contact: Available from W.B. Saunders Company. Book Order Fulfillment Department, 6277 Sea Harbor Drive, Orlando, FL 32887-4430. (800) 545-2522. Fax (800) 874-6418. Email:
[email protected]. PRICE: $73.00 plus shipping and handling. ISBN: 0443055203. Summary: This chapter on pediatric liver disease is from a comprehensive handbook in outline format that offers easy access to information on the full range of liver disorders and covers symptoms, signs, differential diagnoses, and treatments. The authors note that acquired liver diseases seen in adults are rare in children. Congenital or metabolic disorders are more common There is physiologic immaturity of the liver during the perinatal period, and significant maturational changes in hepatic metabolic processes occur during childhood; these affect the presentation of and reaction to exposure to viruses and toxins. Liver disease may present as hyperbilirubinemia, hepatomegaly, liver cell failure, cirrhosis (liver scarring), cystic disease of the liver, portal hypertension, or systemic disease from secondary effects of liver disease. These secondary effects may be life threatening and include metabolic derangement such as hypoglycemia, coagulopathy secondary to low levels of vitamin K dependent clotting factors resulting in intracranial hemorrhage in the infant, persistent toxic exposure, as may be seen in diseases such as galactosemia or frustosemia, sepsis as a cause of liver disease or as a result of secondary immunodeficiency from malnutrition, or portal hypertension with potential gastrointestinal bleeding. 2 figures. 5 references.
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Radical Cystectomy in Men Source: in Graham, S.D., Jr., et al., eds. Glenn's Urologic Surgery. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins. 1998. p. 187-194.
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Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-3030 or (301) 714-2300. Fax (301) 824-7390. Website: lww.com. PRICE: $199.00 plus shipping and handling. ISBN: 0397587376. Summary: This chapter on radical cystectomy in men is from an exhaustive textbook on urologic surgery. The extent of the radical operation in the male includes the removal of the bladder, its peritoneal covering, the perivesical fat, the lower ureters, the prostate, the seminal vesicles, and the vasa deferentia. The author notes that contemporary cystectomy is associated with very low mortality. Furthermore, the advent of nerve sparing cystectomy and orthotopic bladder substitution has significantly reduced functional losses and provided many patients with good locoregional control as well as a good quality of life. The major indication for cystectomy in men is carcinoma of the bladder. The author reviews the surgical techniques, including preparation of the patient, anesthesia and instrumentation, position and initial exposure, lymphadenectomy, cystoprostatectomy, one stage cystoprostatourethrectomy, radical cystoprostatectomy with orthotopic bladder substitution, and postoperative management. The two most serious complications that may occur during the procedure are excessive blood loss or rectal perforation. The postoperative mortality following contemporary cystectomy is 2 percent or less. The most common postoperative complication is prolonged ileus. Septic complications, including abdominal and or pelvic abscesses, wound sepsis, and septicemia are not uncommon. 8 figures. 9 references. •
Rectovaginal Fistulae Source: in Bayless, T.M. and Hanauer, S.B. Advanced Therapy of Inflammatory Bowel Disease. Hamilton, Ontario: B.C. Decker Inc. 2001. p. 515-518. Contact: Available from B.C. Decker Inc. 20 Hughson Street South, P.O. Box 620, L.C.D. 1 Hamilton, Ontario L8N 3K7. (905) 522-7017 or (800) 568-7281. Fax (905) 522-7839. Email:
[email protected]. Website: www.bcdecker.com. PRICE: $129.00 plus shipping and handling. ISBN: 1550091220. Summary: This chapter on rectovaginal fistulae is from the second edition of a book devoted to the details of medical, surgical, and supportive management of patients with Crohn's disease (CD) and ulcerative colitis (UC), together known as inflammatory bowel disease (IBD). Women with CD have about a 3 to 5 percent incidence of developing a rectovaginal fistula. This problem can be devestating for some women, and it is difficult to eradicate. Most are true anovaginal fistulae, as they arise from the anal canal and fistulize into the vagina, perineal body, or labia. However, some are true rectovaginal fistulae from proximal disease, such as ileal disease, penetrating the upper vagina. This chapter discusses only true anovaginal fistulae, referring to them as rectovaginal fistulae (RVF), since this is the conventional misnomer. In treatment planning, the physician weighs the patient's symptoms and treatment goals against her general condition and results of the physical examination. All patients found to have rectovaginal fistulae need to have any sepsis drained as the first line of any treatment option. For patients with mild to moderate symptoms, medical treatment can be considered (usually antibiotics). The author then discusses surgical management, including fecal diversion, proctectomy, and surgical fistula closure (flap repair, transperineal repair, transabdominal repair, and the use of fibrin glue). 1 figure. 1 table. 5 references.
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Endoscopy in Evaluating Ileal Pouches Source: in Bayless, T.M. and Hanauer, S.B. Advanced Therapy of Inflammatory Bowel Disease. Hamilton, Ontario: B.C. Decker Inc. 2001. p. 225-227. Contact: Available from B.C. Decker Inc. 20 Hughson Street South, P.O. Box 620, L.C.D. 1 Hamilton, Ontario L8N 3K7. (905) 522-7017 or (800) 568-7281. Fax (905) 522-7839. Email:
[email protected]. Website: www.bcdecker.com. PRICE: $129.00 plus shipping and handling. ISBN: 1550091220. Summary: This chapter on the use of endoscopy in evaluating ileal pouches is from the second edition of a book devoted to the details of medical, surgical, and supportive management of patients with Crohn's disease (CD) and ulcerative colitis (UC), together known as inflammatory bowel disease (IBD). The authors describe the use of endoscopy to evaluate the continent ileostomy (Kock pouch) which is based on the concept of a reservoir of bowel with a reverse intussusception to create a valve. The valve projects into the lumen of the pouch and creates continence. As stool fills the pouch and pressure increases, it presses on the outer portion of the valve, squeezing it shut. Defecation is accomplished by passing a tube through the stoma into the pouch, overcoming the resistance of the valve. This allows stool to flow out through the tube, emptying the pouch. The authors also describe the use of endoscopy to evaluate the ileoanal pouch anastomosis (IPAA), in which the entire diseased colon and rectum are removed, but the anal sphincters are preserved. A new rectum is formed from the terminal ileum (ileal pouch); attaching the pouch to the anal canal restores defecation to the standard transanal route with satisfactory fecal continence. Problems with the IPAA that may be evaluated with endoscopy include surveillance for dysplasia (growth of dysfunctional tissue), pelvic sepsis, small bowel obstruction, pouchitis, stricture formation, and fecal incontinence and fistula (abnormal passageway). 3 references.
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Persons with Diabetes and HIV/AIDS Source: in Powers, M.A., ed. Handbook of Diabetes Medical Nutrition Therapy. Gaithersburg, MD: Aspen Publishers, Inc. 1996. p. 649-658. Contact: Available from Aspen Publishers. P.O. Box 990, Frederick, MD 21705-9727. (800) 638-8437. Fax (301) 695-7931. PRICE: $89.00. ISBN: 0834206315. Summary: This chapter, from a handbook of diabetes medical nutrition therapy, covers the patient care management for diabetes and HIV/AIDS. After a brief review of the epidemiology of HIV, the author covers diabetes in HIV disease, the role of nutrition therapy, nutrition evaluation, diabetes education, enteral nutrition support in diabetic HIV/AIDS patients, and the use of parenteral nutrition in diabetic HIV/AIDS patients. The author stresses that because the HIV-infected patient may be less able to recover from nutritional compromise, earlier intervention and closer monitoring for complications related to food safety, aspiration, and catheter sepsis will play important roles in balancing the burden of intervention with its benefit. 5 figures. 11 references.
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Ureteral Stricture Source: in Graham, S.D., Jr., et al., eds. Glenn's Urologic Surgery. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins. 1998. p. 173-178. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-3030 or (301) 714-2300. Fax (301) 824-7390. Website: lww.com. PRICE: $199.00 plus shipping and handling. ISBN: 0397587376.
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Summary: Ureteral strictures (scar tissue in the ureter that reduces the opening of the tube) may result from a variety of causes, including stone passage, endoscopic urologic procedures, radiation therapy, open or laparoscopic surgery, and penetrating traumatic injuries. This chapter on ureteral strictures is from an exhaustive textbook on urologic surgery. Although the need for surgical repair of a ureteral injury may be immediately evident in some cases, many patients with ureteral obstruction and or fistulas do not present until weeks or months following surgery. In particular, ureteral strictures that result from endoscopic manipulation of the upper urinary tract may not be noted for prolonged intervals because of the slow development of ureteral fibrosis (thickening of the tissue). The presentation of patients with ureteral strictures is variable and may range from acute flank pain with sepsis and pyelonephritis to the incidental finding of hydronephrosis in an asymptomatic individual. The indications for surgical management of ureteral strictures, disruptions, and fistulas (an abnormal passage out of the ureter) are dependent on the etiology of the lesion and the clinical situation. The author reviews the surgical techniques used, including ureteroureterostomy, the psoas hitch procedure, and the Boari flap procedure; complications and results are also discussed. The author concludes that surgical repair of ureteral strictures is associated with excellent long term success rates. The most important factors responsible for these results include selection of the most appropriate surgical technique, based on the site and length of stricture. 4 figures. 6 references.
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CHAPTER 7. MULTIMEDIA ON SEPSIS Overview In this chapter, we show you how to keep current on multimedia sources of information on sepsis. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.
Audio Recordings The Combined Health Information Database contains abstracts on audio productions. To search CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find audio productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Sound Recordings.” Type “sepsis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for sound recordings on sepsis: •
AIDS Update Contact: California Medical Association, Audio Digest Foundation, 1577 E Chevy Chase Dr, Glendale, CA, 91206, (213) 245-8505. Summary: This soundrecording contains the transcripts of talks given to update physicians on AIDS and the practice of gastroenterology. The first speaker, Dr. John Cello, discusses the equipment, supplies, and universal endoscopy precautions used at the University of California San Francisco School of Medicine. He then discusses esophageal complaints, hepatic parenchymal disease, biliary tract disease, AIDS-related diarrhea, and therapies for each. Dr. Friedman's talk concerns gastrointestinal (GI) tract manifestations of HIV disease. It covers diarrhea and its etiologic agents; dysphagia/odynophagia; jaundice, hepatomegaly, or abnormal liver function; and their causative agents. The last speaker, Dr. Steven Wexner, discusses anorectal involvement in HIV disease. He describes Kaposi's sarcoma rectal lesions; HSV-2; Herpes proctitis; lumbosacral radiculopathy syndrome; anal carcinoma; and perianal sepsis. The cassette is accompanied by pre- and post-tests.
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CHAPTER 8. PERIODICALS AND NEWS ON SEPSIS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover sepsis.
News Services and Press Releases One of the simplest ways of tracking press releases on sepsis 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 “sepsis” (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 sepsis. 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 “sepsis” (or synonyms). The following was recently listed in this archive for sepsis: •
Mast cell enzyme impairs sepsis survival in mice Source: Reuters Medical News Date: March 09, 2004
•
Study suggests statins may decrease sepsis risk Source: Reuters Medical News Date: February 23, 2004
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•
Polyethylene glycol 15-20 protects against sepsis Source: Reuters Medical News Date: February 11, 2004
•
Drotrecogin alfa appears safe for children with severe sepsis Source: Reuters Medical News Date: January 05, 2004
•
Peptide construct protects against sepsis in mice Source: Reuters Medical News Date: November 25, 2003
•
Vena caval filter appears safe in patients with sepsis Source: Reuters Medical News Date: November 19, 2003
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Drotrecogin prolongs survival in sepsis patients 75 and older Source: Reuters Medical News Date: July 17, 2003
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New drug saves elderly sepsis patients Source: Reuters Health eLine Date: July 14, 2003
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Tifacogin does not reduce mortality in sepsis patients with high INR Source: Reuters Medical News Date: July 08, 2003
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Sepsis infections may be underestimated in newborns Source: Reuters Health eLine Date: June 06, 2003
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Sepsis incidence on the rise in U.S. Source: Reuters Medical News Date: April 17, 2003
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In US, life-threatening sepsis on the rise Source: Reuters Health eLine Date: April 17, 2003
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NICE to assess statins and new cancer, asthma, sepsis and dementia therapies Source: Reuters Medical News Date: April 01, 2003
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Lipopolysaccharide-binding protein a nonspecific marker of sepsis Source: Reuters Medical News Date: February 07, 2003
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Molecular Staging to find sepsis biomarkers for Lilly Source: Reuters Industry Breifing Date: January 27, 2003
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Bacterial lipoprotein tolerance protects against experimental septic shock Source: Reuters Medical News Date: January 24, 2003
•
Drotrecogin alfa survival benefit in high-risk sepsis patients maintained over long term Source: Reuters Medical News Date: November 06, 2002
Periodicals and News
•
Experts debate safety and efficacy of activated protein C for sepsis Source: Reuters Medical News Date: September 26, 2002
•
New sepsis drug Xigris reported to be cost effective Source: Reuters Medical News Date: September 18, 2002
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Interleukin-10 controls onset of irreversible septic shock in animal model Source: Reuters Medical News Date: September 11, 2002
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Gram-negative sepsis replaces Gram-positive sepsis among VLBW infants Source: Reuters Medical News Date: July 25, 2002
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Plasma procalcitonin levels provide early marker of septic shock Source: Reuters Medical News Date: May 23, 2002
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Combination test shows promise in early diagnosis of neonatal sepsis Source: Reuters Medical News Date: January 16, 2002
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Investigational sepsis drug fails in phase III trial Source: Reuters Medical News Date: November 21, 2001
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FDA approves Lilly sepsis drug Source: Reuters Health eLine Date: November 21, 2001
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Early goal-directed therapy, intensive glycemic control reduce sepsis mortality Source: Reuters Medical News Date: November 07, 2001
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Sepsis drug may be nearing FDA approval Source: Reuters Health eLine Date: October 30, 2001
•
Investigational drug to treat sepsis receives FDA approvable letter Source: Reuters Medical News Date: October 30, 2001
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Vascular reactivity test may help diagnose septicemia in neonates Source: Reuters Medical News Date: October 24, 2001
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New treatment for sepsis splits FDA panel Source: Reuters Medical News Date: October 17, 2001
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FDA panel to review investigational sepsis drug Source: Reuters Medical News Date: October 15, 2001
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New report warns that sepsis could kill 146,000 Europeans each year Source: Reuters Medical News Date: October 02, 2001
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Clotting pathway in meningococcal sepsis identified Source: Reuters Medical News Date: August 09, 2001
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Neutrophil CD11b and interleukin 8 markers early-onset neonatal sepsis Source: Reuters Medical News Date: July 10, 2001
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G-CSF may reduce mortality of low birthweight infants with sepsis, neutropenia Source: Reuters Medical News Date: May 15, 2001
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Bacterial sepsis now a frequent cause of ICU admission among AIDS patients Source: Reuters Medical News Date: April 13, 2001
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Lilly's Zovant for sepsis wins priority review from FDA Source: Reuters Industry Breifing Date: March 28, 2001
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Use of hydroxyethylstarch linked with renal failure in patients with severe sepsis Source: Reuters Industry Breifing Date: March 22, 2001
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Glaxo, Sepsicure to collaborate on sepsis treatment Source: Reuters Industry Breifing Date: February 22, 2001
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Interleukin Genetics wins patent on discovery of link between gene variant and sepsis risk Source: Reuters Industry Breifing Date: February 20, 2001
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Intrapartum antibiotics linked with increased rate of neonatal gram-negative sepsis Source: Reuters Medical News Date: February 13, 2001
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Recombinant activated protein C reduces mortality rate of severe sepsis Source: Reuters Medical News Date: February 09, 2001
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Lilly's experimental sepsis drug exhibits efficacy in phase III trial Source: Reuters Industry Breifing Date: February 09, 2001
•
Drug cuts sepsis deaths Source: Reuters Health eLine Date: February 09, 2001 The NIH
Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine.
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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 “sepsis” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “sepsis” (or synonyms). If you know the name of a company that is relevant to sepsis, 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 “sepsis” (or synonyms).
Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “sepsis” (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 sepsis: •
Etanercept: A New Drug for the Treatment of Psoriatic Arthritis Source: Psoriasis Forum. 8(1): 1,4,5. Spring 2002.
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Contact: National Psoriasis Foundation. P.O. Box 9009, Portland, OR 97207-9009. (800) 723-9166 ext. 12 or (503) 244-7404. Fax: (503) 245-0626. Email:
[email protected]. Website: www.psoriasis.org. Summary: This newsletter article discusses etanercept, the first FDA-approved drug for treating psoriatic arthritis. This drug was approved by the FDA for treating patients with RA in 1998 and has also been used to treat juvenile rheumatoid arthritis. Both topical and systemic therapies are used to treat psoriatic arthritis. Systemic therapies which include UVB and PUVA can cause organ toxicity. Etarnercept works by inhibiting the tumor necrosis factor-alpha (TNF-alpha)that is found in elevated levels in the skin and synovium of patients with psoriatic arthritis. The drug is administered subcutaneously by the patient. The most common side effect of etanercept is injectionsite reactions. Ninety percent of these were resolved without treatment. Other side effects include infections, sepsis, and rarely, tuberculosis, neurologic events, and pancytopenia. Overall, etanercept is well tolerated with an excellent safety profile and provides patients with psoriasis a new treatment option.
Academic Periodicals covering Sepsis Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to sepsis. In addition to these sources, you can search for articles covering sepsis that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”
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CHAPTER 9. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for sepsis. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a non-profit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with sepsis. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The
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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to sepsis: Aminoglycosides •
Systemic - U.S. Brands: Amikin; Garamycin; G-Mycin; Jenamicin; Kantrex; Nebcin; Netromycin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202027.html
Antifungals, Azole •
Systemic - U.S. Brands: Diflucan; Nizoral; Sporanox http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202697.html
•
Vaginal - U.S. Brands: FemCare; Femizol-M; Femstat 3; Gyne-Lotrimin; GyneLotrimin Combination Pack; Gyne-Lotrimin3; Gyne-Lotrimin3 Combination Pack; Miconazole-7; Monistat 1; Monistat 3; Monistat 3 Combination Pack; Monistat 5 Tampon; Monistat 7; Monistat 7 Combination Pack http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202294.html
Erythromycin •
Ophthalmic - U.S. Brands: Ilotycin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202220.html
Gentamicin •
Ophthalmic - U.S. Brands: Garamycin; Gentacidin; Gentafair; Gentak; OcuMycin; Spectro-Genta http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202604.html
•
Topical - U.S. Brands: Garamycin; Gentamar; G-Myticin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202258.html
Tobramycin •
Ophthalmic - U.S. Brands: AKTob; Tobrex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202570.html
Vancomycin •
Oral - U.S. Brands: Vancocin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202589.html
•
Systemic - U.S. Brands: Vancocin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202590.html
Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.
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Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.
Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to sepsis by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “sepsis” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for sepsis: •
Chimeric, Humanized Monocional Antibody to Staphyl http://www.rarediseases.org/nord/search/nodd_full?code=1057
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•
Chimeric, Humanized Monoclonal Antibody to Staphyl http://www.rarediseases.org/nord/search/nodd_full?code=1062
•
Beractant (trade name: Survanta Intratracheal Suspension) http://www.rarediseases.org/nord/search/nodd_full?code=591
If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.
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APPENDICES
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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.
NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant 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/
11
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
•
HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
•
NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
•
Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
•
Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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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
•
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 “sepsis” (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 75665 487 85 398 216 76851
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 “sepsis” (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/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
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.
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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 sepsis 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 sepsis. 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 sepsis. 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 “sepsis”:
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Guides on sepsis Sepsis http://www.nlm.nih.gov/medlineplus/sepsis.html
•
Other guides Autoimmune Diseases http://www.nlm.nih.gov/medlineplus/autoimmunediseases.html Bacterial Infections http://www.nlm.nih.gov/medlineplus/bacterialinfections.html Critical Care http://www.nlm.nih.gov/medlineplus/criticalcare.html Immune System and Disorders http://www.nlm.nih.gov/medlineplus/immunesystemanddisorders.html Infant and Toddler Health http://www.nlm.nih.gov/medlineplus/infantandtoddlerhealth.html Neurologic Diseases http://www.nlm.nih.gov/medlineplus/neurologicdiseases.html Respiratory Diseases http://www.nlm.nih.gov/medlineplus/respiratorydiseases.html
Within the health topic page dedicated to sepsis, the following was listed: •
General/Overviews Sepsis: What You Should Know http://www.sccm.org/pdf/Sepsis%2520ICU%2520.pdf
•
Diagnosis/Symptoms Blood Cultures Source: American Association for Clinical Chemistry http://labtestsonline.org/understanding/analytes/blood_culture/test.html
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Treatment FDA Approves First Biologic Treatment for Sepsis Source: Food and Drug Administration http://www.fda.gov/bbs/topics/NEWS/2001/NEW00780.html
•
Specific Conditions/Aspects Blood Poisoning (Septicemia) Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AN00716 Guide to Severe Sepsis Source: Society of Critical Care Medicine http://www.sccm.org/press_room/sepsis_guide.asp
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Myths and Facts about Sepsis and Severe Sepsis Source: Society of Critical Care Medicine http://www.sccm.org/press_room/sepsis_myths.asp •
Children Blood Culture Source: Nemours Foundation http://kidshealth.org/parent/general/sick/labtest3.html Sepsis Source: Nemours Foundation http://kidshealth.org/parent/pregnancy_newborn/medical_problems/sepsis.html
•
Organizations National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov/
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Prevention/Screening Consumers Need to Be Aware of Threat of Sepsis Source: Society of Critical Care Medicine http://www.sccm.org/press_room/press_releases/2002/sepsis_threat.asp
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Research Key to Accurately Diagnosing Sepsis Lies in Consensus Definition Source: Society of Critical Care Medicine http://www.sccm.org/press_room/press_releases/2002/sepsis_definition.asp Research Brief: Stop Cell Death, Help Treat Sepsis? Source: National Institute of General Medical Sciences http://www.nigms.nih.gov/news/releases/brief_coopersmith.html
•
Statistics Sepsis Statistics Source: Society of Critical Care Medicine http://www.sccm.org/press_room/sepsis_statistics.asp
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.
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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 sepsis. 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: •
Anal Fistulas: Symptoms and Treatment Source: Milwaukee, WI: International Foundation for Functional Gastrointestinal Disorders (IFFGD). 1998. 2 p. Contact: Available from International Foundation for Functional Gastrointestinal Disorders (IFFGD). P.O. Box 170864, Milwaukee, WI 53217. (888) 964-2001 or (414) 9641799. Fax (414) 964-7176. E-mail:
[email protected]. Website: www.iffgd.org. PRICE: $0.50 plus shipping and handling; bulk copies available. Order number: 138. Summary: This fact sheet for patients and their families outlines the symptoms of and treatment for anal fistulas. An anal fistula is an abnormal connection between the anal canal and the skin. The fact sheet first reviews the anatomy of the anal canal, focusing on the sphincter muscles. The fact sheet then reviews the cause and symptoms of anal fistulae, noting that nearly all anal fistulae are a result of an anorectal abscess. The primary symptom of an anal fistula is persistent drainage because of chronic, low grade sepsis (infection) after treatment of the acute abscess. Diagnosis of an anal fistula rests on identifying the external opening on the perianal skin and the internal opening in the anal canal (this often requires examination under anesthesia in the operating room). The goals of treatment are the elimination of sepsis and of the fistula tract, the prevention of recurrence, and the preservation of continence. Treatment requires surgery in an operating room under general or regional anesthesia. The fact sheet briefly reviews the types of surgical techniques utilized to treat anal fistulae. 1 figure. 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 “sepsis” (or synonyms). The following was recently posted: •
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=sepsis 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
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ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to sepsis. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
•
Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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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/
•
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 sepsis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with sepsis. 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 sepsis. 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.
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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 “sepsis” (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 “sepsis”. 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 “sepsis” (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 “sepsis” (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.22
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
22
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)23: •
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/
23
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
Finding Medical Libraries 233
•
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/
Finding Medical Libraries 235
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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
•
Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
•
Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
•
Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on sepsis: •
Basic Guidelines for Sepsis Plasmodium Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000621.htm Sepsis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000666.htm Septic shock Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000668.htm Septicemia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001355.htm
•
Signs & Symptoms for Sepsis Abdominal pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003120.htm
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Agitated Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003212.htm Agitation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003212.htm Change in mental status Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm Changes in mental status Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm Chest pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003079.htm Chills Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003091.htm Coagulopathy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001304.htm Coma Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003202.htm Comatose Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003202.htm Confusion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm Constipation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003125.htm Cough Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003072.htm Cyanosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm Decreased or no urine output Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003147.htm Decreased urine output Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003147.htm Diarrhea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003126.htm Dyspnea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm
Online Glossaries 239
Dysuria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003145.htm Elevated temperature Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003090.htm Erythema Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Fever Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003090.htm Flank pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003113.htm Headache Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003024.htm Hyperventilation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003071.htm Hypotension Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003083.htm Jaundice Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003243.htm Joint pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003261.htm Lethargic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Lethargy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Low blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003083.htm Low urine output Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003147.htm Oliguria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003147.htm Pale Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003244.htm Petechiae Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm
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Photophobia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003041.htm Rapid heart rate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003077.htm Restlessness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003212.htm Rigors Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003091.htm Skin rash Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Swelling, overall Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm Tachycardia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003077.htm Tachypnea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003071.htm Vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm •
Diagnostics and Tests for Sepsis ALT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003473.htm Blood culture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003744.htm Blood cultures Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003744.htm Blood differential Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003657.htm Blood gases Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003855.htm Blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003398.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm CSF culture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003769.htm
Online Glossaries 241
CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Differential Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003657.htm Fibrin degradation products Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003655.htm Fibrinogen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003650.htm Latex agglutination test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003334.htm MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm Peripheral smear Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003665.htm Platelet count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003647.htm Prothrombin time Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003652.htm PT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003652.htm PTT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003653.htm Urine culture Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003751.htm White blood cell count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003643.htm •
Background Topics for Sepsis Biliary system Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002240.htm Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm Central nervous system Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002311.htm Hypothermia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000038.htm
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Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Intravenous Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002383.htm Low body temperature Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000038.htm Physical examination Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002274.htm Respiratory Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002290.htm Shock Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000039.htm Toxins Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002331.htm Vaccinations Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002024.htm Waterhouse-Friderichsen syndrome Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000609.htm
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
•
MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
•
Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
•
Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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SEPSIS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Abscess: A localized, circumscribed collection of pus. [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] Accommodation: Adjustment, especially that of the eye for various distances. [EU] Acetaldehyde: A colorless, flammable liquid used in the manufacture of acetic acid, perfumes, and flavors. It is also an intermediate in the metabolism of alcohol. It has a general narcotic action and also causes irritation of mucous membranes. Large doses may cause death from respiratory paralysis. [NIH] Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak antiinflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [NIH] 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] Acidemia: Increased acidity of blood. [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] Acremonium: A mitosporic fungal genus with many reported ascomycetous teleomorphs. Cephalosporin antibiotics are derived from this genus. [NIH] 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] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [NIH]
Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH]
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Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [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] Acute tubular: A severe form of acute renal failure that develops in people with severe illnesses like infections or with low blood pressure. Patients may need dialysis. Kidney function often improves if the underlying disease is successfully treated. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] 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] Adjunctive Therapy: Another treatment used together with the primary treatment. Its purpose is to assist the primary treatment. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH]
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Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adsorption: The condensation of gases, liquids, or dissolved substances on the surfaces of solids. It includes adsorptive phenomena of bacteria and viruses as well as of tissues treated with exogenous drugs and chemicals. [NIH] Adsorptive: It captures volatile compounds by binding them to agents such as activated carbon or adsorptive resins. [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] 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] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]
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]
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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 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] 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] Alkalosis: A pathological condition that removes acid or adds base to the body fluids. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]
Allantois: An embryonic diverticulum of the hindgut of reptiles, birds, and mammals; in man its blood vessels give rise to those of the umbilical cord. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] 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] Allogeneic bone marrow transplantation: A procedure in which a person receives stem cells, the cells from which all blood cells develop, from a compatible, though not genetically identical, donor. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Allopurinol: A xanthine oxidase inhibitor that decreases uric acid production. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] 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] Alternative Splicing: A process whereby multiple protein isoforms are generated from a single gene. Alternative splicing involves the splicing together of nonconsecutive exons during the processing of some, but not all, transcripts of the gene. Thus a particular exon may be connected to any one of several alternative exons to form messenger RNA. The alternative forms produce proteins in which one part is common while the other part is different. [NIH] Alveolar Process: The thickest and spongiest part of the maxilla and mandible hollowed out into deep cavities for the teeth. [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] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Aminoquinolines: Quinolines substituted in any position by one or more amino groups. [NIH]
Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]
Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [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] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH]
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Anal Fissure: A small tear in the anus that may cause itching, pain, or bleeding. [NIH] Anal Fistula: A channel that develops between the anus and the skin. Most fistulas are the result of an abscess (infection) that spreads to the skin. [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] Anaphylaxis: An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. [NIH] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anastomosis: A procedure to connect healthy sections of tubular structures in the body after the diseased portion has been surgically removed. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] 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] 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]
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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] Anthrax: An acute bacterial infection caused by ingestion of bacillus organisms. Carnivores may become infected from ingestion of infected carcasses. It is transmitted to humans by contact with infected animals or contaminated animal products. The most common form in humans is cutaneous anthrax. [NIH] Antiallergic: Counteracting allergy or allergic conditions. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Antibody-Dependent Cell Cytotoxicity: The phenomenon of antibody-mediated target cell destruction by non-sensitized effector cells. The identity of the target cell varies, but it must possess surface IgG whose Fc portion is intact. The effector cell is a "killer" cell possessing Fc receptors. It may be a lymphocyte lacking conventional B- or T-cell markers, or a monocyte, macrophage, or polynuclear leukocyte, depending on the identity of the target cell. The reaction is complement-independent. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] 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-inflammatory: Having to do with reducing inflammation. [NIH]
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Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH] 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] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Appendectomy: An operation to remove the appendix. [NIH] Appendicitis: Acute inflammation of the vermiform appendix. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatase: An enzyme which converts androgens to estrogens by desaturating ring A of the steroid. This enzyme complex is located in the endoplasmic reticulum of estrogenproducing cells including ovaries, placenta, testicular Sertoli and Leydig cells, adipose, and brain tissues. The enzyme complex has two components, one of which is the CYP19 gene product, the aromatase cytochrome P-450. The other component is NADPH-cytochrome P450 reductase which transfers reducing equivalents to P-450(arom). EC 1.14.13.-. [NIH] Aromatic: Having a spicy odour. [EU] Arterial: Pertaining to an artery or to the arteries. [EU]
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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] 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. [NIH]
Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articular: Of or pertaining to a joint. [EU] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [NIH] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Endopeptidases: A sub-subclass of endopeptidases that depend on an aspartic acid residue for their activity. EC 3.4.23. [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] 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] Atelectasis: Incomplete expansion of the lung. [NIH] Atopic: Pertaining to an atopen or to atopy; allergic. [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] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Autacoids: A chemically diverse group of substances produced by various tissues in the body that cause slow contraction of smooth muscle; they have other intense but varied pharmacologic activities. [NIH]
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Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autopsy: Postmortem examination of the body. [NIH] Avian: A plasmodial infection in birds. [NIH] Avidity: The strength of the interaction of an antiserum with a multivalent antigen. [NIH] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [NIH] Baclofen: A GABA derivative that is a specific agonist at GABA-B receptors. It is used in the treatment of spasticity, especially that due to spinal cord damage. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission. [NIH] Bacteraemia: The presence of bacteria in the blood. [EU] 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] 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 toxin: A toxic substance, made by bacteria, that can be modified to kill specific tumor cells without harming normal cells. [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] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Bacteriuria: The presence of bacteria in the urine with or without consequent urinary tract infection. Since bacteriuria is a clinical entity, the term does not preclude the use of urine/microbiology for technical discussions on the isolation and segregation of bacteria in the urine. [NIH] Barbiturate: A drug with sedative and hypnotic effects. Barbiturates have been used as sedatives and anesthetics, and they have been used to treat the convulsions associated with epilepsy. [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
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pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Benzaldehyde: A colorless oily liquid used as a flavoring agent and to make dyes, perfumes, and pharmaceuticals. Benzaldehyde is chemically related to benzene. [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-Defensins: Defensins found mainly in epithelial cells. [NIH] Beta-Lactamases: Enzymes found in many bacteria which catalyze the hydrolysis of the amide bond in the beta-lactam ring. Well known antibiotics destroyed by these enzymes are penicillins and cephalosporins. EC 3.5.2.6. [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] Bewilderment: Impairment or loss of will power. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH]
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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 agent: A substance that makes a loose mixture stick together. For example, binding agents can be used to make solid pills from loose powders. [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] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological Assay: A method of measuring the effects of a biologically active substance using an intermediate in vivo or in vitro tissue or cell model under controlled conditions. It includes virulence studies in animal fetuses in utero, mouse convulsion bioassay of insulin, quantitation of tumor-initiator systems in mouse skin, calculation of potentiating effects of a hormonal factor in an isolated strip of contracting stomach muscle, etc. [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] Bioluminescence: The emission of light by living organisms such as the firefly, certain mollusks, beetles, fish, bacteria, fungi and protozoa. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biomechanics: The study of the application of mechanical laws and the action of forces to living structures. [NIH] Biomolecular: A scientific field at the interface between advanced computing and biotechnology. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bioterrorism: The use of biological agents in terrorism. This includes the malevolent use of
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bacteria, viruses, or toxins against people, animals, or plants. [NIH] Biotype: A group of individuals having the same genotype. [NIH] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blastomycosis: A fungal infection that may appear in two forms: 1) a primary lesion characterized by the formation of a small cutaneous nodule and small nodules along the lymphatics that may heal within several months; and 2) chronic granulomatous lesions characterized by thick crusts, warty growths, and unusual vascularity and infection in the middle or upper lobes of the lung. [NIH] Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors. [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 Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] 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 Cements: Adhesives used to fix prosthetic devices to bones and to cement bone to
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bone in difficult fractures. Synthetic resins are commonly used as cements. A mixture of monocalcium phosphate, monohydrate, alpha-tricalcium phosphate, and calcium carbonate with a sodium phosphate solution is also a useful bone paste. [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 Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [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] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]
Breakdown: A physical, metal, or nervous collapse. [NIH] 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] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchiolitis: Inflammation of the bronchioles. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchoalveolar Lavage: Washing out of the lungs with saline or mucolytic agents for diagnostic or therapeutic purposes. It is very useful in the diagnosis of diffuse pulmonary infiltrates in immunosuppressed patients. [NIH] Bronchoscope: A thin, lighted tube used to examine the inside of the trachea and bronchi, the air passages that lead into the lungs. [NIH] Bronchoscopy: Endoscopic examination, therapy or surgery of the bronchi. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU]
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Bupivacaine: A widely used local anesthetic agent. [NIH] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge of electricity. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcineurin: A calcium- and calmodulin-binding protein present in highest concentrations in the central nervous system. Calcineurin is composed of two subunits. A catalytic subunit, calcineurin A, and a regulatory subunit, calcineurin B, with molecular weights of about 60 kD and 19 kD, respectively. Calcineurin has been shown to dephosphorylate a number of phosphoproteins including histones, myosin light chain, and the regulatory subunit of cAMP-dependent protein kinase. It is involved in the regulation of signal transduction and is the target of an important class of immunophilin-immunosuppressive drug complexes in T-lymphocytes that act by inhibiting T-cell activation. EC 3.1.3.-. [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 Chloride: A salt used to replenish calcium levels, as an acid-producing diuretic, and as an antidote for magnesium poisoning. [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] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [EU]
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Candidosis: An infection caused by an opportunistic yeasts that tends to proliferate and become pathologic when the environment is favorable and the host resistance is weakened. [NIH]
Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary 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] Capping: A 7-methyl guanosine cap attached to the 5'-end of eucaryotic mRNAs by a phosphodiester linkage. The cap is believed to increase the stability of the message, since most nucleases require a 5'-3'or 3'-5'bond in order to cleave the RNA. [NIH] Capsular: Cataract which is initiated by an opacification at the surface of the lens. [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] Carboxy: Cannabinoid. [NIH] Carboxylic Acids: Organic compounds containing the carboxy group (-COOH). This group of compounds includes amino acids and fatty acids. Carboxylic acids can be saturated, unsaturated, or aromatic. [NIH] Carcinogen: Any substance that causes cancer. [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] Cardiogenic: Originating in the heart; caused by abnormal function of the heart. [EU] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH]
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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] 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] Catastrophic Illness: An acute or prolonged illness usually considered to be life-threatening or with the threat of serious residual disability. Treatment may be radical and is frequently costly. [NIH] Catecholamines: A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [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] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Cat-Scratch Disease: A self-limiting bacterial infection of the regional lymph nodes caused by Afipia felis, a gram-negative bacterium recently identified by the Centers for Disease Control and Prevention and by Bartonella henselae. It usually arises one or more weeks following a feline scratch, with raised inflammatory nodules at the site of the scratch being the primary symptom. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caveolae: Endocytic/exocytic cell membrane structures rich in glycosphingolipids, cholesterol, and lipid-anchored membrane proteins that function in endocytosis (potocytosis), transcytosis, and signal transduction. Caveolae assume various shapes from open pits to closed vesicles. Caveolar coats are composed of caveolins. [NIH] Caveolins: The main structural proteins of caveolae. Several distinct genes for caveolins have been identified. [NIH] Cefamandole: Semisynthetic wide-spectrum cephalosporin with prolonged action, probably due to beta-lactamase resistance. It is used also as the nafate. [NIH] Cefotaxime: Semisynthetic broad-spectrum cephalosporin. [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]
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Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [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 Membrane Structures: Structures which are part of the cell membrane or have cell membrane as a major part of their structure. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cellobiose: A disaccharide consisting of two glucose units in beta (1-4) glycosidic linkage. Obtained from the partial hydrolysis of cellulose. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] 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] Cephalosporins: A group of broad-spectrum antibiotics first isolated from the Mediterranean fungus Acremonium (Cephalosporium acremonium). They contain the betalactam moiety thia-azabicyclo-octenecarboxylic acid also called 7-aminocephalosporanic acid. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU]
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Cerebral Arteries: The arteries supplying the cerebral cortex. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] 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] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] 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] Chemotaxis: The movement of cells or organisms toward or away from a substance in response to its concentration gradient. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chenodeoxycholic Acid: A bile acid, usually conjugated with either glycine or taurine. It acts as a detergent to solubilize fats for intestinal absorption and is reabsorbed by the small intestine. It is used as cholagogue, a choleretic laxative, and to prevent or dissolve gallstones. [NIH] Chest Pain: Pressure, burning, or numbness in the chest. [NIH] Chickenpox: A mild, highly contagious virus characterized by itchy blisters all over the body. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Chloroquine: The prototypical antimalarial agent with a mechanism that is not well understood. It has also been used to treat rheumatoid arthritis, systemic lupus erythematosus, and in the systemic therapy of amebic liver abscesses. [NIH] Cholangiography: Radiographic examination of the bile ducts. [NIH] Cholangitis: Inflammation of a bile duct. [NIH] Cholecystectomy: Surgical removal of the gallbladder. [NIH]
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Cholecystectomy, Laparoscopic: Excision of the gallbladder through an abdominal incision using a laparoscope. [NIH] Cholecystitis: Inflammation of the gallbladder. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Choleretic: A choleretic agent. [EU] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [NIH]
Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Cholic Acid: A major primary bile acid produced in the liver and usually conjugated with glycine or taurine. It facilitates fat absorption and cholesterol excretion. [NIH] Chorea: Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. [NIH] Choreatic Disorders: Acquired and hereditary conditions which feature chorea as a primary manifestation of the disease process. [NIH] Chorion: The outermost extraembryonic membrane. [NIH] Chromaffin System: The cells of the body which stain with chromium salts. They occur along the sympathetic nerves, in the adrenal gland, and in various other organs. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic granulocytic leukemia: A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic myeloid leukemia. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Cilastatin: A renal dehydropeptidase-I and leukotriene D4 dipeptidase inhibitor. Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-I, which resides in the brush
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border of the renal tubule, cilastatin is administered with imipenem to increase its effectiveness. The drug also inhibits the metabolism of leukotriene D4 to leukeotriene E4. [NIH]
Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Circulatory system: The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clathrin: The main structural coat protein of coated vesicles which play a key role in the intracellular transport between membranous organelles. Clathrin also interacts with cytoskeletal proteins. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Cleave: A double-stranded cut in DNA with a restriction endonuclease. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] 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 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] Coated Vesicles: Vesicles formed when cell-membrane coated pits invaginate and pinch off. The outer surface of these vesicles are covered with a lattice-like network of coat proteins, such as clathrin, coat protein complex proteins, or caveolins. [NIH] Coccidioidomycosis: An infectious disease caused by a fungus, Coccidioides immitis, that is prevalent in the western United States and is acquired by inhalation of dust containing the spores. [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]
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Coliphages: Viruses whose host is Escherichia coli. [NIH] Colistin: Cyclic polypeptide antibiotic from Bacillus colistinus. It is composed of Polymyxins E1 and E2 (or Colistins A, B, and C) which act as detergents on cell membranes. Colistin is less toxic than Polymyxin B, but otherwise similar; the methanesulfonate is used orally. [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] Collagenases: Enzymes that catalyze the degradation of collagen by acting on the peptide bonds. EC 3.4.24.-. [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] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [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] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Commensal: 1. Living on or within another organism, and deriving benefit without injuring or benefiting the other individual. 2. An organism living on or within another, but not causing injury to the host. [EU] 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
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activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complement Activation: The sequential activation of serum components C1 through C9, initiated by an erythrocyte-antibody complex or by microbial polysaccharides and properdin, and producing an inflammatory response. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] 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] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] 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] Contact dermatitis: Inflammation of the skin with varying degrees of erythema, edema and vesinculation resulting from cutaneous contact with a foreign substance or other exposure. [NIH]
Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continence: The ability to hold in a bowel movement or urine. [NIH] Continent Ileostomy: An operation to create a pouch from part of the small intestine. Stool
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that collects in the pouch is removed by inserting a small tube through an opening made in the abdomen. [NIH] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] 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] Convalescence: The period of recovery following an illness. [NIH] Convulsion: A violent involuntary contraction or series of contractions of the voluntary muscles. [EU] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneal Ulcer: Loss of epithelial tissue from the surface of the cornea due to progressive erosion and necrosis of the tissue; usually caused by bacterial, fungal, or viral infection. [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 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] 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] Coumarins: Synthetic or naturally occurring substances related to coumarin, the deltalactone of coumarinic acid. Coumarin itself occurs in the tonka bean. The various coumarins have a wide range of proposed actions and uses including as anticoagulants, pharmaceutical aids, indicators and reagents, photoreactive substances, and antineoplastic agents. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Creatine: An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. [NIH]
Creatine Kinase: A transferase that catalyzes formation of phosphocreatine from ATP + creatine. The reaction stores ATP energy as phosphocreatine. Three cytoplasmic isoenzymes have been identified in human tissues: MM from skeletal muscle, MB from myocardial tissue, and BB from nervous tissue as well as a mitochondrial isoenzyme. Macro-creatine kinase refers to creatine kinase complexed with other serum proteins. EC 2.7.3.2. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] 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] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] 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] Cystectomy: Used for excision of the urinary bladder. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cysteine Endopeptidases: Endopeptidases which have a cysteine involved in the catalytic process. This group of enzymes is inactivated by sulfhydryl reagents. EC 3.4.22. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of
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cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]
Cystitis: Inflammation of the urinary bladder. [EU] Cytidine: A pyrimidine nucleoside that is composed of the base cytosine linked to the fivecarbon sugar D-ribose. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] 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] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] 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] 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]
Dantrolene: Skeletal muscle relaxant that acts by interfering with excitation-contraction coupling in the muscle fiber. It is used in spasticity and other neuromuscular abnormalities. Although the mechanism of action is probably not central, dantrolene is usually grouped with the central muscle relaxants. [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
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data and facts apart from bibliographic references to them. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Defecation: The normal process of elimination of fecal material from the rectum. [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] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Dehydroepiandrosterone: DHEA. A substance that is being studied as a cancer prevention drug. It belongs to the family of drugs called steroids. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Demyelinating Diseases: Diseases characterized by loss or dysfunction of myelin in the central or peripheral nervous system. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [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] Dermatitis: Any inflammation of the skin. [NIH] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH]
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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] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastolic: Of or pertaining to the diastole. [EU] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU] 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] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] 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] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH]
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Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] 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] Diuresis: Increased excretion of urine. [EU] Diuretic: A drug that increases the production of urine. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] 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] Dreams: A series of thoughts, images, or emotions occurring during sleep which are dissociated from the usual stream of consciousness of the waking state. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] 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] Dysphagia: Difficulty in swallowing. [EU]
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Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophin: A muscle protein localized in surface membranes which is the product of the Duchenne/Becker muscular dystrophy gene. Individuals with Duchenne muscular dystrophy usually lack dystrophin completely while those with Becker muscular dystrophy have dystrophin of an altered size. It shares features with other cytoskeletal proteins such as spectrin and alpha-actinin but the precise function of dystrophin is not clear. One possible role might be to preserve the integrity and alignment of the plasma membrane to the myofibrils during muscle contraction and relaxation. MW 400 kDa. [NIH] Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] 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] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocardiogram: Measurement of electrical activity during heartbeats. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [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] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]
Ellagic Acid: A fused four ring compound occurring free or combined in galls. Isolated from the kino of Eucalyptus maculata Hook and E. Hemipholia F. Muell. Activates Factor XII of the blood clotting system which also causes kinin release; used in research and as a dye. [NIH]
Emboli: 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] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [NIH]
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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] Embryology: The study of the development of an organism during the embryonic and fetal stages of life. [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Empiric: Empirical; depending upon experience or observation alone, without using scientific method or theory. [EU] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]
Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU] Endocardium: The innermost layer of the heart, comprised of endothelial cells. [NIH] Endocrine Glands: Ductless glands that secrete substances which are released directly into the circulation and which influence metabolism and other body functions. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic
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endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endophthalmitis: Suppurative inflammation of the tissues of the internal structures of the eye; not all layers of the uvea are affected. Fungi, necrosis of intraocular tumors, and retained intraocular foreign bodies often cause a purulent endophthalmitis. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the body. [NIH] Endosomes: Cytoplasmic vesicles formed when coated vesicles shed their clathrin coat. Endosomes internalize macromolecules bound by receptors on the cell surface. [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] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH] Enteral Nutrition: Nutritional support given via the alimentary canal or any route connected to the gastrointestinal system (i.e., the enteral route). This includes oral feeding, sip feeding, and tube feeding using nasogastric, gastrostomy, and jejunostomy tubes. [NIH] Enteric bacteria: Single-celled microorganisms that lack chlorophyll. Some bacteria are capable of causing human, animal, or plant diseases; others are essential in pollution control
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because they break down organic matter in the air and in the water. [NIH] Enterocolitis: Inflammation of the intestinal mucosa of the small and large bowel. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]
Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
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] Eosinophilia: Abnormal increase in eosinophils in the blood, tissues or organs. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemiologic Factors: Events, characteristics, or other definable entities that have the potential to bring about a change in a health condition or other defined outcome. [NIH] 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] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]
Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] ERV: The expiratory reserve volume is the largest volume of gas that can be expired from the end-expiratory level. [NIH] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythrocyte Indices: Quantification of size and cell hemoglobin content or concentration of
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the erythrocyte, usually derived from erythrocyte count, blood hemoglobin concentration, and hematocrit. Includes the mean cell volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC). Use also for cell diameter and thickness. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Escalation: Progressive use of more harmful drugs. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophageal Varices: Stretched veins in the esophagus that occur when the liver is not working properly. If the veins burst, the bleeding can cause death. [NIH] Esophagitis: Inflammation, acute or chronic, of the esophagus caused by bacteria, chemicals, or trauma. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [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]
Estrone: 3-Hydroxyestra-1,3,5(10)-trien-17-one. A metabolite of estradiol but possessing less biological activity. It is found in the urine of pregnant women and mares, in the human placenta, and in the urine of bulls and stallions. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), estrone may reasonably be anticipated to be a carcinogen (Merck, 11th ed). [NIH] 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] 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] Excipient: Any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; a vehicle. [EU] 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] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excrete: To get rid of waste from the body. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons
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alternating with intron sequences. [NIH] 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] Expiratory Reserve Volume: The extra volume of air that can be expired with maximum effort beyond the level reached at the end of a normal, quiet expiration. Common abbreviation is ERV. [NIH] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [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] 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] Faecal: Pertaining to or of the nature of feces. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fasciitis: Inflammation of the fascia. There are three major types: 1) Eosinophilic fasciitis, an inflammatory reaction with eosinophilia, producing hard thickened skin with an orangepeel configuration suggestive of scleroderma and considered by some a variant of scleroderma; 2) Necrotizing fasciitis, a serious fulminating infection (usually by a beta hemolytic Streptococcus) causing extensive necrosis of superficial fascia; 3) Nodular/Pseudosarcomatous/Proliferative fasciitis, characterized by a rapid growth of fibroblasts with mononuclear inflammatory cells and proliferating capillaries in soft tissue, often the forearm; it is not malignant but is sometimes mistaken for fibrosarcoma. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatal Outcome: Death resulting from the presence of a disease in an individual, as shown by a single case report or a limited number of patients. This should be differentiated from death, the physiological cessation of life and from mortality, an epidemiological or statistical concept. [NIH]
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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] Febrile: Pertaining to or characterized by fever. [EU] Fecal Incontinence: Failure of voluntary control of the anal sphincters, with involuntary passage of feces and flatus. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Fenoldopam: A dopamine D1 receptor agonist that is used as an antihypertensive agent. It lowers blood pressure through arteriolar vasodilation. [NIH] Ferrichrome: A cyclic peptide consisting of three residues of delta-N-hydroxy-delta-Nacetylornithine. It acts as an iron transport agent in Ustilago sphaerogena. [NIH] Fetal Membranes: Thin layers of tissue which surround the embryo or fetus and provide for its nutrition, respiration, excretion and protection; they are the yolk sac, allantois, amnion, and chorion. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosarcoma: A type of soft tissue sarcoma that begins in fibrous tissue, which holds bones, muscles, and other organs in place. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [NIH] Flank Pain: Pain emanating from below the ribs and above the ilium. [NIH] Flatus: Gas passed through the rectum. [NIH] Fluid Therapy: Therapy whose basic objective is to restore the volume and composition of the body fluids to normal with respect to water-electrolyte balance. Fluids may be administered intravenously, orally, by intermittent gavage, or by hypodermoclysis. [NIH] 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
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be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Flutamide: An antiandrogen with about the same potency as cyproterone in rodent and canine species. [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] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fosfomycin: An antibiotic produced by Streptomyces fradiae. [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] Fulminant Hepatic Failure: Liver failure that occurs suddenly in a previously healthy person. The most common causes of FHF are acute hepatitis, acetaminophen overdose, and liver damage from prescription drugs. [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, 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] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Galactosemia: Buildup of galactose in the blood. Caused by lack of one of the enzymes needed to break down galactose into glucose. [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] Gamma-interferon: Interferon produced by T-lymphocytes in response to various mitogens and antigens. Gamma interferon appears to have potent antineoplastic, immunoregulatory
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and antiviral activity. [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] Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [NIH] Gangrenous: A circumscribed, deep-seated, suppurative inflammation of the subcutaneous tissue of the eyelid discharging pus from several points. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] 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] Gastric: Having to do with the stomach. [NIH] Gastric Acid: Hydrochloric acid present in gastric juice. [NIH] Gastric atrophy: A condition in which the stomach muscles shrink and become weak. The digestive (peptic) glands may also shrink, resulting in a lack of digestive juices. [NIH] Gastric Juices: Liquids produced in the stomach to help break down food and kill bacteria. [NIH]
Gastric Mucosa: Surface epithelium in the stomach that invaginates into the lamina propria, forming gastric pits. Tubular glands, characteristic of each region of the stomach (cardiac, gastric, and pyloric), empty into the gastric pits. The gastric mucosa is made up of several different kinds of cells. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastritis: Inflammation of the stomach. [EU] Gastroenterology: A subspecialty of internal medicine concerned with the study of the physiology and diseases of the digestive system and related structures (esophagus, liver, gallbladder, and pancreas). [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastrostomy: Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gelatinases: A class of enzymes that catalyzes the degradation of gelatin by acting on the peptide bonds. EC 3.4.24.-. [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]
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Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]
Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] 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] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gestational Age: Age of the conceptus. In humans, this may be assessed by medical history, physical examination, early immunologic pregnancy tests, radiography, ultrasonography, and amniotic fluid analysis. [NIH] 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] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]
Glomeruli: Plural of glomerulus. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucans: Polysaccharides composed of repeating glucose units. They can consist of branched or unbranched chains in any linkages. [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
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(drugs). [NIH] Glucokinase: A group of enzymes that catalyzes the conversion of ATP and D-glucose to ADP and D-glucose 6-phosphate. They are found in invertebrates and microorganisms and are highly specific for glucose. (Enzyme Nomenclature, 1992) EC 2.7.1.2. [NIH] Gluconeogenesis: The process by which glucose is formed from a non-carbohydrate source. [NIH]
Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]
Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]
Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycolysis: The pathway by which glucose is catabolized into two molecules of pyruvic acid with the generation of ATP. [NIH]
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Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] 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-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-Negative Bacterial Infections: Infections caused by bacteria that show up as pink (negative) when treated by the gram-staining 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] Gram-Positive Bacteria: Bacteria which retain the crystal violet stain when treated by Gram's method. [NIH] Granule: A small pill made from sucrose. [EU] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Growth: 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] Growth Plate: The area between the epiphysis and the diaphysis within which bone growth occurs. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and
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pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Gynecology: A medical-surgical specialty concerned with the physiology and disorders primarily of the female genital tract, as well as female endocrinology and reproductive physiology. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] 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 failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartbeat: One complete contraction of the heart. [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] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemofiltration: Extracorporeal ultrafiltration technique without hemodialysis for treatment of fluid overload and electrolyte disturbances affecting renal, cardiac, or pulmonary function. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to
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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] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] 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] Hemorrhoids: Varicosities of the hemorrhoidal venous plexuses. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocyte: A liver cell. [NIH] Hepatology: The field of medicine concerned with the functions and disorders of the liver. [NIH]
Hepatomegaly: Enlargement of the liver. [NIH] Hepatotoxic: Toxic to liver cells. [EU] 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] Heritability: The proportion of observed variation in a particular trait that can be attributed
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to inherited genetic factors in contrast to environmental ones. [NIH] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes virus: A member of the herpes family of viruses. [NIH] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterodimers: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Hexokinase: An enzyme that catalyzes the conversion of ATP and a D-hexose to ADP and a D-hexose 6-phosphate. D-Glucose, D-mannose, D-fructose, sorbitol, and D-glucosamine can act as acceptors; ITP and dATP can act as donors. The liver isoenzyme has sometimes been called glucokinase. (From Enzyme Nomenclature, 1992) EC 2.7.1.1. [NIH] Hidradenitis: The inflammation of a sweat gland (usually of the apocrine type). The condition can be idiopathic or occur as a result of or in association with another underlying condition. Neutrophilic eccrine hidradenitis is a relatively rare variant that has been reported in patients undergoing chemotherapy, usually for non-Hodgkin lymphomas or leukemic conditions. [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] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homotypic: Adhesion between neutrophils. [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
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hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] 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] Hydronephrosis: Abnormal enlargement of a kidney, which may be caused by blockage of the ureter (such as by a kidney stone) or chronic kidney disease that prevents urine from draining into the bladder. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxamic Acids: A class of weak acids with the general formula R-conhoh. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypersensitivity, Immediate: Hypersensitivity reactions which occur within minutes of exposure to challenging antigen due to the release of histamine which follows the antigenantibody reaction and causes smooth muscle contraction and increased vascular permeability. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypotensive: Characterized by or causing diminished tension or pressure, as abnormally low blood pressure. [EU] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral
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walls of the third ventricle. [NIH] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] 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] Ileal: Related to the ileum, the lowest end of the small intestine. [NIH] Ileostomy: Surgical creation of an external opening into the ileum for fecal diversion or drainage. Loop or tube procedures are most often employed. [NIH] Ileum: The lower end of the small intestine. [NIH] Ileus: Obstruction of the intestines. [EU] Imipenem: Semisynthetic thienamycin that has a wide spectrum of antibacterial activity against gram-negative and gram-positive aerobic and anaerobic bacteria, including many multiresistant strains. It is stable to beta-lactamases. Clinical studies have demonstrated high efficacy in the treatment of infections of various body systems. Its effectiveness is enhanced when it is administered in combination with cilastatin, a renal dipeptidase inhibitor. [NIH] Immaturity: The state or quality of being unripe or not fully developed. [EU] Immersion: The placing of a body or a part thereof into a liquid. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH]
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Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunologic Factors: Biologically active substances whose activities affect or play a role in the functioning of the immune system. [NIH] Immunology: The study of the body's immune system. [NIH] Immunophilin: A drug for the treatment of Parkinson's disease. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] 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] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] 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] Incidental: 1. Small and relatively unimportant, minor; 2. Accompanying, but not a major part of something; 3. (To something) Liable to occur because of something or in connection with something (said of risks, responsibilities, .) [EU] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH]
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Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indolent: A type of cancer that grows slowly. [NIH] Indomethacin: A non-steroidal anti-inflammatory agent (NSAID) that inhibits the enzyme cyclooxygenase necessary for the formation of prostaglandins and other autacoids. It also inhibits the motility of polymorphonuclear leukocytes. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant Nutrition: Nutrition of children from birth to 2 years of age. [NIH] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Infectious Mononucleosis: A common, acute infection usually caused by the Epstein-Barr virus (Human herpesvirus 4). There is an increase in mononuclear white blood cells and other atypical lymphocytes, generalized lymphadenopathy, splenomegaly, and occasionally hepatomegaly with hepatitis. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]
Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [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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Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] 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] 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] Intercellular Adhesion Molecule-1: A cell-surface ligand with a role in leukocyte adhesion and inflammation. Its production is induced by gamma-interferon and it is required for neutrophil migration into inflamed tissue. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH]
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Interleukin-18: Cytokine which resembles IL-1 structurally and IL-12 functionally. It enhances the cytotoxic activity of NK cells and CTLs, and appears to play a role both as neuroimmunomodulator and in the induction of mucosal 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-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] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] 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] Intestinal: Having to do with the intestines. [NIH] Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intraocular: Within the eye. [EU] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [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]
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Intussusception: A rare disorder. A part of the intestines folds into another part of the intestines, causing blockage. Most common in infants. Can be treated with an operation. [NIH]
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] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [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] 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] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] 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]
Jejunostomy: Surgical formation of an opening through the abdominal wall into the jejunum, usually for enteral hyperalimentation. [NIH] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [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] 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]
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Ketone Bodies: Chemicals that the body makes when there is not enough insulin in the blood and it must break down fat for its energy. Ketone bodies can poison and even kill body cells. When the body does not have the help of insulin, the ketones build up in the blood and then "spill" over into the urine so that the body can get rid of them. The body can also rid itself of one type of ketone, called acetone, through the lungs. This gives the breath a fruity odor. Ketones that build up in the body for a long time lead to serious illness and coma. [NIH] Ketosis: A condition of having ketone bodies build up in body tissues and fluids. The signs of ketosis are nausea, vomiting, and stomach pain. Ketosis can lead to ketoacidosis. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kidney Pelvis: The flattened, funnel-shaped expansion connecting the ureter to the kidney calices. [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] 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] Laceration: 1. The act of tearing. 2. A torn, ragged, mangled wound. [EU] Lactation: The period of the secretion of milk. [EU] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Laparotomy: A surgical incision made in the wall of the abdomen. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH]
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Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lavage: A cleaning of the stomach and colon. Uses a special drink and enemas. [NIH] Least-Squares Analysis: A principle of estimation in which the estimates of a set of parameters in a statistical model are those quantities minimizing the sum of squared differences between the observed values of a dependent variable and the values predicted by the model. [NIH] 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] Length of Stay: The period of confinement of a patient to a hospital or other health facility. [NIH]
Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Leprosy: A chronic granulomatous infection caused by Mycobacterium leprae. The granulomatous lesions are manifested in the skin, the mucous membranes, and the peripheral nerves. Two polar or principal types are lepromatous and tuberculoid. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukocytosis: A transient increase in the number of leukocytes in a body fluid. [NIH] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]
Lidocaine: A local anesthetic and cardiac depressant used as an antiarrhythmia agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine. [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] Ligase: An enzyme that repairs single stranded discontinuities in double-stranded DNA molecules in the cell. Purified DNA ligase is used in gene cloning to join DNA molecules together. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Likelihood Functions: Functions constructed from a statistical model and a set of observed data which give the probability of that data for various values of the unknown model parameters. Those parameter values that maximize the probability are the maximum likelihood estimates of the parameters. [NIH] Linear Models: Statistical models in which the value of a parameter for a given value of a factor is assumed to be equal to a + bx, where a and b are constants. The models predict a
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linear regression. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Regeneration: Repair or renewal of hepatic tissue. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [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] Locoregional: The characteristic of a disease-producing organism to transfer itself, but typically to the same region of the body (a leg, the lungs, .) [EU] Logistic Models: Statistical models which describe the relationship between a qualitative dependent variable (that is, one which can take only certain discrete values, such as the presence or absence of a disease) and an independent variable. A common application is in epidemiology for estimating an individual's risk (probability of a disease) as a function of a given risk factor. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lumbar puncture: A procedure in which a needle is put into the lower part of the spinal column to collect cerebrospinal fluid or to give anticancer drugs intrathecally. Also called a spinal tap. [NIH] Lumen: The cavity or channel within a tube or tubular organ. [EU] Luminescence: The property of giving off light without emitting a corresponding degree of
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heat. It includes the luminescence of inorganic matter or the bioluminescence of human matter, invertebrates and other living organisms. For the luminescence of bacteria, bacterial luminescence is available. [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] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [NIH] Lyme Disease: An infectious disease caused by a spirochete, Borrelia burgdorferi, which is transmitted chiefly by Ixodes dammini and pacificus ticks in the United States and Ixodes ricinis in Europe. It is a disease with early and late cutaneous manifestations plus involvement of the nervous system, heart, eye, and joints in variable combinations. The disease was formerly known as Lyme arthritis and first discovered at Old Lyme, Connecticut. [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]
Lymphadenectomy: A surgical procedure in which the lymph nodes are removed and examined to see whether they contain cancer. Also called lymph node dissection. [NIH] Lymphadenopathy: Disease or swelling of the lymph nodes. [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] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokine: A soluble protein produced by some types of white blood cell that stimulates other white blood cells to kill foreign invaders. [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] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macrophage Activation: The process of altering the morphology and functional activity of
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macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (MAF) and the macrophage migration-inhibitory factor (MMIF), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. [NIH] Macula: A stain, spot, or thickening. Often used alone to refer to the macula retinae. [EU] Macula Lutea: An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the superior pole of the eye and slightly below the level of the optic disk. [NIH] Macular Degeneration: Degenerative changes in the macula lutea of the retina. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] 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] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammary: Pertaining to the mamma, or breast. [EU] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in
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wound healing, angiogenesis, and tumor cell metastasis. [NIH] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Mechanical ventilation: Use of a machine called a ventilator or respirator to improve the exchange of air between the lungs and the atmosphere. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megacolon: Pathological enlargement of the colon. [NIH] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] 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] Membrane: A very thin layer of tissue that covers a surface. [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] Meningioma: A type of tumor that occurs in the meninges, the membranes that cover and protect the brain and spinal cord. Meningiomas usually grow slowly. [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] Menopause: Permanent cessation of menstruation. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH]
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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] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metalloendopeptidases: Endopeptidases which use a metal, normally zinc, in the catalytic mechanism. This group of enzymes is inactivated by metal chelators. EC 3.4.24. [NIH] 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] 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] Methacrylate: A vinyl monomer. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [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] Microbiological: Pertaining to microbiology : the science that deals with microorganisms, including algae, bacteria, fungi, protozoa and viruses. [EU] 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] 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.
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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
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] 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] Mitral Valve: The valve between the left atrium and left ventricle of the heart. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] 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
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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] Monokines: Soluble mediators of the immune response that are neither antibodies nor complement. They are produced largely, but not exclusively, by monocytes and macrophages. [NIH] Mononuclear: A cell with one nucleus. [NIH] Mononucleosis: The presence of an abnormally large number of mononuclear leucocytes (monocytes) in the blood. The term is often used alone to refer to infectious mononucleosis. [EU]
Monotherapy: A therapy which uses only one drug. [EU] 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] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] 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] Mucociliary Clearance: Rate of ciliary and secretory activity of the respiratory submucosal glands. It is a non-specific host defense mechanism, measurable in vivo by mucus transfer, ciliary beat frequency, and clearance of radioactive tracers. [NIH] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]
Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multiple Organ Failure: A progressive condition usually characterized by combined failure
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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] Multiple Trauma: Physical insults or injuries occurring simultaneously in several parts of the body. [NIH] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [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] Muscle Proteins: The protein constituents of muscle, the major ones being ACTINS and MYOSIN. More than a dozen accessary proteins exist including troponin, tropomyosin, and dystrophin. [NIH] Muscle relaxant: An agent that specifically aids in reducing muscle tension, as those acting at the polysynaptic neurons of motor nerves (e.g. meprobamate) or at the myoneural junction (curare and related compounds). [EU] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myalgia: Pain in a muscle or muscles. [EU] Mycobacterium: A genus of gram-positive, aerobic bacteria. Most species are free-living in soil and water, but the major habitat for some is the diseased tissue of warm-blooded hosts. [NIH]
Mycophenolate mofetil: A drug that is being studied for its effectiveness in preventing graft-versus-host disease and autoimmune disorders. [NIH] 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] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [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]
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] Myopia: That error of refraction in which rays of light entering the eye parallel to the optic axis are brought to a focus in front of the retina, as a result of the eyeball being too long from front to back (axial m.) or of an increased strength in refractive power of the media of the eye (index m.). Called also nearsightedness, because the near point is less distant than it is in emmetropia with an equal amplitude of accommodation. [EU] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myristate: Pharmacological activator of protein kinase C. [NIH] Nadir: The lowest point; point of greatest adversity or despair. [EU] 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] 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 Mucosa: The mucous membrane lining the nasal cavity. [NIH] Nasogastric: The process of passing a small, flexible plastic tube through the nose or mouth into the stomach or small intestine. [NIH] Nasopharynx: The nasal part of the pharynx, lying above the level of the soft palate. [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.
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Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Nearsightedness: The common term for myopia. [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] Necrotizing Enterocolitis: A condition in which part of the tissue in the intestines is destroyed. Occurs mainly in under-weight newborn babies. A temporary ileostomy may be necessary. [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] Nephropathy: Disease of the kidneys. [EU] Nephrotoxic: Toxic or destructive to kidney cells. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [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] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurogenic: Loss of bladder control caused by damage to the nerves controlling the bladder. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon,
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and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] Neurosciences: The scientific disciplines concerned with the embryology, anatomy, physiology, biochemistry, pharmacology, etc., of the nervous sytem. [NIH] Neurosecretory Systems: A system of neurons that has the specialized function to produce and secrete hormones, and that constitutes, in whole or in part, an endocrine organ or system. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutralization: An act or process of neutralizing. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophil: A type of white blood cell. [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] Niche: The ultimate unit of the habitat, i. e. the specific spot occupied by an individual organism; by extension, the more or less specialized relationships existing between an organism, individual or synusia(e), and its environment. [NIH] Nitrates: Inorganic or organic salts and esters of nitric acid. These compounds contain the NO3- radical. [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]
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
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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] 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] Nosocomial: Pertaining to or originating in the hospital, said of an infection not present or incubating prior to admittance to the hospital, but generally occurring 72 hours after admittance; the term is usually used to refer to patient disease, but hospital personnel may also acquire nosocomial infection. [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] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleolus: A small dense body (sub organelle) within the nucleus of eukaryotic cells, visible by phase contrast and interference microscopy in live cells throughout interphase. Contains RNA and protein and is the site of synthesis of ribosomal RNA. [NIH] Nucleoproteins: Proteins conjugated with nucleic acids. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurseries: Facilities which provide care for infants. [NIH] Nursing Care: Care given to patients by nursing service personnel. [NIH] Nutrition Assessment: Evaluation and measurement of nutritional variables in order to assess the level of nutrition or the nutritional status of the individual. Nutrition surveys may be used in making the assessment. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Nutritional Support: The administration of nutrients for assimilation and utilization by a patient by means other than normal eating. It does not include fluid therapy which normalizes body fluids to restore water-electrolyte balance. [NIH] Obstetrics: A medical-surgical specialty concerned with management and care of women during pregnancy, parturition, and the puerperium. [NIH] Occult: Obscure; concealed from observation, difficult to understand. [EU] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU]
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Odour: A volatile emanation that is perceived by the sense of smell. [EU] Odynophagia: A painful condition of the esophagus. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [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] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] 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] 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]
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] Osmolality: The concentration of osmotically active particles in solution expressed in terms of osmoles of solute per kilogram of solvent. The osmolality is directly proportional to the colligative properties of solutions; osmotic pressure, boiling point elevation, freezing point depression, and vapour pressure lowering. [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] Osteogenesis: The histogenesis of bone including ossification. It occurs continuously but particularly in the embryo and child and during fracture repair. [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] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment
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in a clinic or dispensary connected with the hospital. [NIH] Ovariectomy: The surgical removal of one or both ovaries. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [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] 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] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU]
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Palpation: Application of fingers with light pressure to the surface of the body to determine consistence of parts beneath in physical diagnosis; includes palpation for determining the outlines of organs. [NIH] 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] Pancytopenia: Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. [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] 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] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parenteral Nutrition: The administering of nutrients for assimilation and utilization by a patient who cannot maintain adequate nutrition by enteral feeding alone. Nutrients are administered by a route other than the alimentary canal (e.g., intravenously, subcutaneously). [NIH] Partial Thromboplastin Time: Test of the intrinsic (factors VIII, IX, XI, and XII) and common (fibrinogen, prothrombin, factors V and X) pathways of coagulation in which a mixture of plasma and phospholipid platelet substitute (e.g., crude cephalins, soybean phosphatides) is recalcified and the time required for the appearance of fibrin strands measured. Activation may be provided by contact with the glass tube or exposure to activators (e.g., ellagic acid, particulate silicates such as diatomaceous earth or kaolin) before addition of the calcium chloride. It is used as a screening test and to monitor heparin therapy. [NIH] Particle: A tiny mass of material. [EU] Partnership Practice: A voluntary contract between two or more doctors who may or may not share responsibility for the care of patients, with proportional sharing of profits and losses. [NIH] Parturition: The act or process of given birth to a child. [EU] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]
Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU]
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Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Care Management: Generating, planning, organizing, and administering medical and nursing care and services for patients. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvic inflammatory disease: A bacteriological disease sometimes associated with intrauterine device (IUD) usage. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [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] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: An ulceration of the mucous membrane of the esophagus, stomach or duodenum, caused by the action of the acid gastric juice. [NIH] Peptic Ulcer Hemorrhage: Bleeding from a peptic ulcer. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Chain Initiation: The process whereby the formation of a peptide chain is started. This process requires (1) the 30s subunit, (2) the mRNA coding for the polypeptide to be made, (3) Met-tRNAi, (4) initiation factors, and (5) GTP. [NIH] Peptide Hydrolases: A subclass of enzymes from the hydrolase class that catalyze the hydrolysis of peptide bonds. Exopeptidases and endopeptidases make up the sub-subclasses for this group. EC 3.4. [NIH] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perianal: Located around the anus. [EU] 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] Perineal: Pertaining to the perineum. [EU]
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Perineum: The area between the anus and the sex organs. [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] 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] Perioperative Care: Interventions to provide care prior to, during, and immediately after surgery. [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 stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Peripheral Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in 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] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove
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dead cells. Phagocytes include macrophages. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [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] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharyngitis: Inflammation of the throat. [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] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylates: Attached to a phosphate group. [NIH] Phosphorylating: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH]
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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] 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] Plague: An acute infectious disease caused by Yersinia pestis that affects humans, wild rodents, and their ectoparasites. This condition persists due to its firm entrenchment in sylvatic rodent-flea ecosystems throughout the world. Bubonic plague is the most common form. [NIH] Plant Diseases: Diseases of plants. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasma Volume: Volume of plasma in the circulation. It is usually measured by indicator dilution techniques. [NIH] 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]
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Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Platelet 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] 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]
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]
Pneumonia: Inflammation of the lungs. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [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] Polymethyl Methacrylate: Polymerized methyl methacrylate monomers which are used as sheets, moulding, extrusion powders, surface coating resins, emulsion polymers, fibers, inks, and films (From International Labor Organization, 1983). This material is also used in tooth implants, bone cements, and hard corneal contact lenses. [NIH]
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Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] 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 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] Porosity: Condition of having pores or open spaces. This often refers to bones, bone implants, or bone cements, but can refer to the porous state of any solid substance. [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] Portal Hypertension: High blood pressure in the portal vein. This vein carries blood into the liver. Portal hypertension is caused by a blood clot. This is a common complication of cirrhosis. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [NIH] Positive pressure ventilation: Provision of oxygen under pressure by a mechanical respirator. [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] Postoperative Complications: Pathologic processes that affect patients after a surgical procedure. They may or may not be related to the disease for which the surgery was done, and they may or may not be direct results of the surgery. [NIH] Postoperative Period: The period following a surgical operation. [NIH] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] 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] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful
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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 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] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Pregnancy Tests: Tests to determine whether or not an individual is pregnant. [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] Preoperative: Preceding an operation. [EU] Presumptive: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] 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] Primary Biliary Cirrhosis: A chronic liver disease. Slowly destroys the bile ducts in the liver. This prevents release of bile. Long-term irritation of the liver may cause scarring and cirrhosis in later stages of the disease. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Primary Sclerosing Cholangitis: Irritation, scarring, and narrowing of the bile ducts inside and outside the liver. Bile builds up in the liver and may damage its cells. Many people with this condition also have ulcerative colitis. [NIH] Private Practice: Practice of a health profession by an individual, offering services on a person-to-person basis, as opposed to group or partnership practice. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH]
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Procaine: A local anesthetic of the ester type that has a slow onset and a short duration of action. It is mainly used for infiltration anesthesia, peripheral nerve block, and spinal block. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1016). [NIH] Proctectomy: An operation to remove the rectum. [NIH] Proctitis: Inflammation of the rectum. [EU] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Proestrus: Phase of the estrous cycle preceding estrus during which the Graafian follicle undergoes maturation. Applies to animals. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Progressive disease: Cancer that is increasing in scope or severity. [NIH] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Proliferating Cell Nuclear Antigen: Nuclear antigen with a role in DNA synthesis, DNA repair, and cell cycle progression. PCNA is required for the coordinated synthesis of both leading and lagging strands at the replication fork during DNA replication. PCNA expression correlates with the proliferation activity of several malignant and non-malignant cell types. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [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] 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
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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] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [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 Isoforms: Different forms of a protein that may be produced from different genes, or from the same gene by alternative splicing. [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]
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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] Protein Subunits: Single chains of amino acids that are the units of a multimeric protein. They can be identical or non-identical subunits. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors. EC 2.7.10. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycans: Glycoproteins which have a very high polysaccharide content. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]
Prothrombin Time: Measurement of clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen, prothrombin, and factors V, VII, and X. It is used for monitoring anticoagulant therapy with coumarins. [NIH] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoal: Having to do with the simplest organisms in the animal kingdom. Protozoa are single-cell organisms, such as ameba, and are different from bacteria, which are not members of the animal kingdom. Some protozoa can be seen without a microscope. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH]
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Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychogenic: Produced or caused by psychic or mental factors rather than organic factors. [EU]
Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]
Puerperium: Period from delivery of the placenta until return of the reproductive organs to their normal nonpregnant morphologic state. In humans, the puerperium generally lasts for six to eight weeks. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Gas Exchange: The exchange of oxygen and carbon dioxide between alveolar air and pulmonary capillary blood. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Pyelonephritis: Inflammation of the kidney and its pelvis, beginning in the interstitium and rapidly extending to involve the tubules, glomeruli, and blood vessels; due to bacterial infection. [EU] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH]
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Pyrogens: Substances capable of increasing body temperature; they may be of microbial origin, often polysaccharides and may contaminate distilled water. [NIH] Pyruvate Decarboxylase: Catalyzes the decarboxylation of an alpha keto acid to an aldehyde and carbon dioxide. Thiamine pyrophosphate is an essential cofactor. In lower organisms, which ferment glucose to ethanol and carbon dioxide, the enzyme irreversibly decarboxylates pyruvate to acetaldehyde. EC 4.1.1.1. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quinoxaline: AMPA/Kainate antagonist. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radical cystectomy: Surgery to remove the bladder as well as nearby tissues and organs. [NIH]
Radicular: Having the character of or relating to a radicle or root. [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] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiologist: A doctor who specializes in creating and interpreting pictures of areas inside the body. The pictures are produced with x-rays, sound waves, or other types of energy. [NIH]
Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] 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
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diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectovaginal Fistula: Abnormal communication between the rectum and the vagina. [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] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [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] Refractive Power: The ability of an object, such as the eye, to bend light as light passes through it. [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] Regional lymph node: In oncology, a lymph node that drains lymph from the region around a tumor. [NIH] Regression Analysis: Procedures for finding the mathematical function which best describes the relationship between a dependent variable and one or more independent variables. In linear regression (see linear models) the relationship is constrained to be a straight line and least-squares analysis is used to determine the best fit. In logistic regression (see logistic models) the dependent variable is qualitative rather than continuously variable and likelihood functions are used to find the best relationship. In multiple regression the dependent variable is considered to depend on more than a single independent variable. [NIH]
Rehydration: The restoration of water or of fluid content to a body or to substance which has become dehydrated. [EU] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH]
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Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal Replacement Therapy: Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys. [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] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Research Design: A plan for collecting and utilizing data so that desired information can be obtained with sufficient precision or so that an hypothesis can be tested properly. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Resolving: The ability of the eye or of a lens to make small objects that are close together, separately visible; thus revealing the structure of an object. [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 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] 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] Response Elements: Nucleotide sequences, usually upstream, which are recognized by specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promotor and enhancer regions. [NIH]
Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH]
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Resuscitation: The restoration to life or consciousness of one apparently dead; it includes such measures as artificial respiration and cardiac massage. [EU] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retroperitoneal: Having to do with the area outside or behind the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Rhabdomyolysis: Necrosis or disintegration of skeletal muscle often followed by myoglobinuria. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] 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] Ristocetin: An antibiotic mixture of two components, A and B, obtained from Nocardia lurida (or the same substance produced by any other means). It is no longer used clinically because of its toxicity. It causes platelet agglutination and blood coagulation and is used to assay those functions in vitro. [NIH]
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Rod: A reception for vision, located in the retina. [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] Rubella: An acute, usually benign, infectious disease caused by a togavirus and most often affecting children and nonimmune young adults, in which the virus enters the respiratory tract via droplet nuclei and spreads to the lymphatic system. It is characterized by a slight cold, sore throat, and fever, followed by enlargement of the postauricular, suboccipital, and cervical lymph nodes, and the appearances of a fine pink rash that begins on the head and spreads to become generalized. Called also German measles, roetln, röteln, and three-day measles, and rubeola in French and Spanish. [EU] Saline: A solution of salt and water. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Sarcomere: The repeating structural unit of a striated muscle fiber. [NIH] Scarlet Fever: Infection with group A streptococci that is characterized by tonsillitis and pharyngitis. An erythematous rash is commonly present. [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] 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] Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Sclerotherapy: Treatment of varicose veins, hemorrhoids, gastric and esophageal varices, and peptic ulcer hemorrhage by injection or infusion of chemical agents which cause localized thrombosis and eventual fibrosis and obliteration of the vessels. [NIH]
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Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Sebaceous gland: Gland that secretes sebum. [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] 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] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Seminal vesicles: Glands that help produce semen. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensibility: The ability to receive, feel and appreciate sensations and impressions; the quality of being sensitive; the extend to which a method gives results that are free from false negatives. [NIH] Sensory loss: A disease of the nerves whereby the myelin or insulating sheath of myelin on the nerves does not stay intact and the messages from the brain to the muscles through the nerves are not carried properly. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Septicaemia: A term originally used to denote a putrefactive process in the body, but now usually referring to infection with pyogenic micro-organisms; a genus of Diptera; the severe type of infection in which the blood stream is invaded by large numbers of the causal. [NIH] Septicemia: Systemic disease associated with the presence and persistence of pathogenic microorganisms or their toxins in the blood. Called also blood poisoning. [EU] Sequela: Any lesion or affection following or caused by an attack of disease. [EU] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serine Endopeptidases: Any member of the group of endopeptidases containing at the active site a serine residue involved in catalysis. EC 3.4.21. [NIH]
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Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serotypes: A cause of haemorrhagic septicaemia (in cattle, sheep and pigs), fowl cholera of birds, pasteurellosis of rabbits, and gangrenous mastitis of ewes. It is also commonly found in atrophic rhinitis of pigs. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] 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] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin Aging: The process of aging due to changes in the structure and elasticity of the skin over time. It may be a part of physiological aging or it may be due to the effects of ultraviolet radiation, usually through exposure to sunlight. [NIH] Skin graft: Skin that is moved from one part of the body to another. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH]
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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]
Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Sorbitol: A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. [NIH] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] 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
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bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] 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 Cord Injuries: Penetrating and non-penetrating injuries to the spinal cord resulting from traumatic external forces (e.g., wounds, gunshot; whiplash injuries; etc.). [NIH] Spinal Nerve Roots: The paired bundles of nerve fibers entering and leaving the spinal cord at each segment. The dorsal and ventral nerve roots join to form the mixed segmental spinal nerves. The dorsal roots are generally afferent, formed by the central projections of the spinal (dorsal root) ganglia sensory cells, and the ventral roots efferent, comprising the axons of spinal motor and autonomic preganglionic neurons. There are, however, some exceptions to this afferent/efferent rule. [NIH] Spinal tap: A procedure in which a needle is put into the lower part of the spinal column to collect cerebrospinal fluid or to give anticancer drugs intrathecally. Also called a lumbar puncture. [NIH] Spirochete: Lyme disease. [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] Splenectomy: An operation to remove the spleen. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Spondylitis: Inflammation of the vertebrae. [EU] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH] Spores: The reproductive elements of lower organisms, such as protozoa, fungi, and cryptogamic plants. [NIH] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]
Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] Staphylococcal Infections: Infections with bacteria of the genus Staphylococcus. [NIH] Staphylococcal Scalded Skin Syndrome: A disease of infants due to group 2 phage type 17 staphylococci that produce an epidermolytic exotoxin. Superficial fine vesicles and bullae form and rupture easily, resulting in loss of large sheets of epidermis. [NIH] Steatosis: Fatty degeneration. [EU] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] Stents: Devices that provide support for tubular structures that are being anastomosed or for body cavities during skin grafting. [NIH]
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Sterile: Unable to produce children. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Steroid therapy: Treatment with corticosteroid drugs to reduce swelling, pain, and other symptoms of inflammation. [NIH] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stoma: A surgically created opening from an area inside the body to the outside. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptococcal: Caused by infection due to any species of streptococcus. [NIH] Streptococcal Infections: Infections with bacteria of the genus Streptococcus. [NIH] Streptococci: A genus of spherical Gram-positive bacteria occurring in chains or pairs. They are widely distributed in nature, being important pathogens but often found as normal commensals in the mouth, skin, and intestine of humans and other animals. [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] Streptokinase: Streptococcal fibrinolysin . An enzyme produced by hemolytic streptococci. It hydrolyzes amide linkages and serves as an activator of plasminogen. It is used in thrombolytic therapy and is used also in mixtures with streptodornase (streptodornase and streptokinase). EC 3.4.-. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] 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] Stump: The end of the limb after amputation. [NIH] 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
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disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Substrate: A substance upon which an enzyme acts. [EU] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppositories: A small cone-shaped medicament having cocoa butter or gelatin at its basis and usually intended for the treatment of local conditions in the rectum. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Suppurative: Consisting of, containing, associated with, or identified by the formation of pus. [NIH] Supraspinal: Above the spinal column or any spine. [NIH] Surface Plasmon Resonance: A biosensing technique in which biomolecules capable of binding to specific analytes or ligands are first immobilized on one side of a metallic film. Light is then focused on the opposite side of the film to excite the surface plasmons, that is, the oscillations of free electrons propagating along the film's surface. The refractive index of light reflecting off this surface is measured. When the immobilized biomolecules are bound by their ligands, an alteration in surface plasmons on the opposite side of the film is created which is directly proportional to the change in bound, or adsorbed, mass. Binding is measured by changes in the refractive index. The technique is used to study biomolecular interactions, such as antigen-antibody binding. [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]
Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sweat Glands: Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. [NIH]
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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] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of disease. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Syphilis: A contagious venereal disease caused by the spirochete Treponema pallidum. [NIH]
Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systemic therapy: Treatment that uses substances that travel through the bloodstream, reaching and affecting cells all over the body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Tachypnea: Rapid breathing. [NIH] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Teichoic Acids: Bacterial polysaccharides that are rich in phosphodiester linkages. They are the major components of the cell walls and membranes of many bacteria. [NIH] Teicoplanin: Glycopeptide antibiotic complex from Actinoplanes teichomyceticus active against gram-positive bacteria. It consists of five major components each with a different fatty acid moiety. [NIH] Telomere: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs. [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] Testicular: Pertaining to a testis. [EU]
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Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Tetravalent: Pertaining to a group of 4 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [NIH] Thalidomide: A pharmaceutical agent originally introduced as a non-barbiturate hypnotic, but withdrawn from the market because of its known tetratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor alpha from monocytes, and modulates other cytokine action. [NIH] Theophylline: Alkaloid obtained from Thea sinensis (tea) and others. It stimulates the heart and central nervous system, dilates bronchi and blood vessels, and causes diuresis. The drug is used mainly in bronchial asthma and for myocardial stimulation. Among its more prominent cellular effects are inhibition of cyclic nucleotide phosphodiesterases and antagonism of adenosine receptors. [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] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombolytic Therapy: Use of infusions of fibrinolytic agents to destroy or dissolve thrombi in blood vessels or bypass grafts. [NIH] 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]
Thromboplastin: Constituent composed of protein and phospholipid that is widely distributed in many tissues. It serves as a cofactor with factor VIIa to activate factor X in the extrinsic pathway of blood coagulation. [NIH] Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH]
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Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Ticks: Blood-sucking arachnids of the order Acarina. [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] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Extracts: Preparations made from animal tissues or organs; they usually contain many components, any one of which may be pharmacologically or physiologically active; extracts may contain specific, but uncharacterized factors or proteins with specific actions. [NIH]
Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonicity: The normal state of muscular tension. [NIH] Tonsillitis: Inflammation of the tonsils, especially the palatine tonsils. It is often caused by a bacterium. Tonsillitis may be acute, chronic, or recurrent. [NIH] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxemia: A generalized intoxication produced by toxins and other substances elaborated by an infectious agent. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] 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] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] 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] 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] Triad: Trivalent. [NIH] Trichomoniasis: An infection with the protozoan parasite Trichomonas vaginalis. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]
Tropomyosin: A protein found in the thin filaments of muscle fibers. It inhibits contraction of the muscle unless its position is modified by troponin. [NIH] Troponin: One of the minor protein components of skeletal muscle. Its function is to serve as the calcium-binding component in the troponin-tropomyosin B-actin-myosin complex by conferring calcium sensitivity to the cross-linked actin and myosin filaments. [NIH] 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] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tularemia: A plague-like disease of rodents, transmissible to man. It is caused by Francisella tularensis and is characterized by fever, chills, headache, backache, and weakness. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body.
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Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [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] 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] Typhoid fever: The most important member of the enteric group of fevers which also includes the paratyphoids. [NIH] Typhoid fever: The most important member of the enteric group of fevers which also includes the paratyphoids. [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] 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] Ultrafiltration: The separation of particles from a suspension by passage through a filter with very fine pores. In ultrafiltration the separation is accomplished by convective transport; in dialysis separation relies instead upon differential diffusion. Ultrafiltration occurs naturally and is a laboratory procedure. Artificial ultrafiltration of the blood is referred to as hemofiltration or hemodiafiltration (if combined with hemodialysis). [NIH] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10 megahertz. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]
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]
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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] Ureter: One of a pair of thick-walled tubes that transports urine from the kidney pelvis to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Uridine Phosphorylase: An enzyme that catalyzes the transfer of ribose from uridine to orthophosphate, forming uracil and ribose 1-phosphate. EC 2.4.2.3. [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]
Urinate: To release urine from the bladder to the outside. [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] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH] Ursodeoxycholic Acid: An epimer of chenodeoxycholic acid. It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve gallstones. It is used as a cholagogue and choleretic. [NIH] Urticaria: A vascular reaction of the skin characterized by erythema and wheal formation due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Uvea: The middle coat of the eyeball, consisting of the choroid in the back of the eye and the ciliary body and iris in the front of the eye. [NIH] Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [NIH]
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Vancomycin: Antibacterial obtained from Streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear. [NIH] Varicella: Chicken pox. [EU] Varicose: The common ulcer in the lower third of the leg or near the ankle. [NIH] Varicose vein: An abnormal swelling and tortuosity especially of the superficial veins of the legs. [EU] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] 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] 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] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venereal: Pertaining or related to or transmitted by sexual contact. [EU] 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] 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] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives
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oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [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] Viral Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Viremia: The presence of viruses in the blood. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virulent: A virus or bacteriophage capable only of lytic growth, as opposed to temperate phages establishing the lysogenic response. [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] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] 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] Warts: Benign epidermal proliferations or tumors; some are viral in origin. [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
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and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xanthine: An urinary calculus. [NIH] Xanthine Oxidase: An iron-molybdenum flavoprotein containing FAD that oxidizes hypoxanthine, some other purines and pterins, and aldehydes. Deficiency of the enzyme, an autosomal recessive trait, causes xanthinuria. EC 1.1.3.22. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Yolk Sac: An embryonic membrane formed from endoderm and mesoderm. In reptiles and birds it incorporates the yolk into the digestive tract for nourishing the embryo. In placental mammals its nutritional function is vestigial; however, it is the source of most of the intestinal mucosa and the site of formation of the germ cells. It is sometimes called the vitelline sac, which should not be confused with the vitelline membrane of the egg. [NIH] Zoster: A virus infection of the Gasserian ganglion and its nerve branches, characterized by discrete areas of vesiculation of the epithelium of the forehead, the nose, the eyelids, and the cornea together with subepithelial infiltration. [NIH] Zygote: The fertilized ovum. [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]
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INDEX A Abdomen, 4, 103, 243, 256, 266, 275, 292, 294, 296, 310, 311, 312, 325, 330, 331, 334, 340 Abdominal, 24, 191, 192, 193, 195, 198, 201, 237 Abdominal Pain, 98, 198, 243, 312, 337 Abscess, 5, 40, 71, 198, 199, 228, 243, 248 Acatalasia, 243, 259 Acceptor, 243, 296, 309 Accommodation, 243, 304 Acetaldehyde, 243, 322 Acetaminophen, 26, 243, 279 Acetylcholine, 243, 306 Acidemia, 65, 243 Acidosis, 30, 41, 137, 145, 177, 243 Acremonium, 243, 260 Acrylonitrile, 243, 326 Actin, 17, 29, 36, 243, 303, 304, 336 Acute leukemia, 86, 243, 317 Acute lymphoblastic leukemia, 85, 243, 244 Acute lymphocytic leukemia, 243, 244 Acute myelogenous leukemia, 244 Acute myeloid leukemia, 113, 244 Acute nonlymphocytic leukemia, 244 Acute renal, 3, 16, 39, 84, 104, 190, 244, 285 Acute tubular, 198, 244 Acyl, 179, 244 Adaptability, 244, 260 Adaptation, 6, 244 Adenine, 150, 244, 321 Adenosine, 144, 171, 244, 257, 288, 313, 334 Adenosine Triphosphate, 144, 171, 244, 313 Adenovirus, 27, 45, 56, 70, 180, 244 Adjunctive Therapy, 78, 97, 107, 244 Adjustment, 243, 244 Adjuvant, 102, 104, 139, 244, 280 Adolescence, 244, 311 Adrenal Cortex, 245, 266, 267, 276, 318 Adrenal Medulla, 245, 274, 275, 307 Adrenergic, 36, 37, 245, 271, 275, 333 Adsorption, 86, 92, 245 Adsorptive, 245 Adverse Effect, 43, 245, 328 Aerobic, 245, 288, 301, 303, 309
Aerobic Metabolism, 245, 309 Aerobic Respiration, 245, 309 Affinity, 10, 14, 23, 104, 135, 142, 176, 245, 251, 329 Affinity Chromatography, 15, 245 Agar, 245, 267, 314 Agarose, 245, 285 Age of Onset, 245, 337 Agonist, 16, 26, 176, 245, 252, 271, 278 Airway, 39, 54, 246 Albumin, 41, 246, 285, 314 Aldehydes, 246, 341 Algorithms, 246, 254 Alimentary, 246, 274, 310 Alkaline, 243, 246, 247, 257 Alkaloid, 176, 246, 302, 334 Alkalosis, 41, 246 Alkylating Agents, 246, 337 Allantois, 246, 278 Alleles, 34, 67, 246 Allergen, 246, 269 Allergic Rhinitis, 180, 246 Allogeneic, 73, 87, 246, 283 Allogeneic bone marrow transplantation, 87, 246 Allograft, 152, 246 Allopurinol, 187, 246 Alpha Particles, 246, 322 Alpha-1, 246, 313 Alpha-Defensins, 246, 269 Alternative medicine, 211, 247 Alternative Splicing, 176, 247, 319 Alveolar Process, 247, 324 Alveoli, 247, 339 Amebiasis, 247, 300 Ameliorating, 146, 163, 247 Amino Acid Sequence, 247, 249, 276, 281 Aminoquinolines, 136, 247 Ammonia, 247, 282, 332, 337 Amnion, 247, 278 Amniotic Fluid, 247, 281 Amplification, 13, 28, 148, 247 Ampulla, 247, 262, 274 Amputation, 247, 331 Anaerobic, 247, 288 Anaesthesia, 76, 102, 104, 116, 247, 290 Anal, 199, 201, 202, 205, 228, 247, 248, 278 Anal Fissure, 199, 248
344
Sepsis
Anal Fistula, 228, 248 Analgesic, 243, 248, 288, 302, 308 Analog, 183, 248 Analogous, 182, 248, 336 Analytes, 164, 165, 226, 248, 332 Anaphylatoxins, 248, 265 Anaphylaxis, 147, 180, 248 Anaplasia, 248 Anastomosis, 202, 248 Anatomical, 248, 251, 261, 265, 270, 289, 310, 326 Androgens, 245, 248, 250, 266 Anemia, 22, 114, 128, 148, 248, 279, 284, 298, 302 Anesthesia, 16, 24, 201, 228, 246, 248, 318 Anesthetics, 248, 252, 275 Aneurysm, 248, 339 Angiogenesis, 138, 152, 157, 181, 248, 299 Animal model, 6, 22, 23, 29, 35, 56, 58, 135, 157, 159, 209, 248 Anions, 139, 246, 248, 293, 328, 332 Anode, 248, 249 Anorectal, 4, 205, 228, 249 Anorexia, 156, 249, 337 Antagonism, 136, 249, 257, 270, 334 Anthrax, 86, 249 Antiallergic, 249, 266 Antibacterial, 69, 249, 288, 330, 339 Antibody-Dependent Cell Cytotoxicity, 249, 294 Anticoagulant, 6, 44, 144, 249, 319, 320 Antigen-Antibody Complex, 249, 264 Antihypertensive, 249, 278 Anti-infective, 145, 249, 287, 293 Anti-inflammatory, 23, 28, 44, 138, 145, 161, 243, 249, 251, 266, 281, 288, 290 Anti-Inflammatory Agents, 250, 251, 266 Antimetabolite, 250, 300 Antimicrobial, 29, 38, 61, 67, 84, 96, 103, 153, 173, 250, 269 Antineoplastic, 246, 250, 255, 266, 267, 279, 300, 340 Antioxidant, 5, 6, 18, 23, 43, 74, 250, 309 Antipyretic, 243, 250 Antiserum, 40, 250, 252 Antiviral, 164, 250, 280, 291 Anuria, 250, 294 Anus, 199, 247, 248, 249, 250, 256, 264, 311, 312, 323 Apolipoproteins, 151, 250, 296 Apoptosis, 7, 18, 23, 26, 29, 30, 44, 57, 70, 86, 100, 147, 173, 250, 259
Appendectomy, 199, 250 Appendicitis, 198, 250 Aqueous, 35, 250, 253, 268, 273, 287, 295, 296 Arachidonic Acid, 250, 319 Arginine, 73, 81, 145, 187, 248, 250, 306, 336 Aromatase, 26, 250 Aromatic, 153, 173, 250, 258, 313, 331 Arterial, 16, 39, 72, 74, 113, 137, 177, 200, 250, 251, 262, 287, 320, 333 Arteries, 187, 250, 251, 255, 261, 266, 296, 300, 303, 321, 339 Arteriolar, 33, 251, 256, 278 Arterioles, 32, 251, 255, 258, 300, 304, 339 Arteriosus, 251, 321 Arteriovenous, 251, 300 Artery, 87, 124, 248, 250, 251, 266, 272, 273, 304, 321, 324 Articular, 251, 308 Ascites, 196, 251 Aspartic, 251, 273 Aspartic Endopeptidases, 251, 274 Aspiration, 32, 139, 202, 251 Aspirin, 147, 251 Assay, 11, 13, 19, 21, 22, 154, 164, 174, 181, 251, 288, 325 Astrocytes, 185, 251 Asymptomatic, 111, 124, 203, 243, 247, 251, 310 Atelectasis, 139, 251 Atopic, 141, 152, 160, 251 Atrium, 251, 301, 340 Atrophy, 28, 134, 251 Attenuated, 7, 13, 251, 270 Attenuation, 7, 12, 251 Atypical, 251, 290 Autacoids, 251, 290 Autodigestion, 252, 310 Autoimmune disease, 35, 136, 137, 141, 147, 160, 252, 303 Autoimmunity, 136, 252 Autonomic, 243, 252, 307, 312, 330 Autopsy, 44, 95, 252 Avian, 135, 252 Avidity, 57, 252 B Bacillus, 74, 86, 249, 252, 264, 316 Baclofen, 96, 252 Bacteraemia, 117, 252 Bacteremia, 4, 9, 50, 54, 58, 62, 64, 68, 130, 137, 154, 166, 168, 174, 177, 185, 198
345
Bacterial Infections, 14, 23, 124, 127, 135, 140, 154, 157, 174, 183, 185, 226, 252, 260 Bacterial Physiology, 244, 252 Bacterial toxin, 9, 146, 170, 252 Bactericidal, 62, 70, 252, 276 Bacteriophage, 70, 252, 314, 336, 340 Bacterium, 69, 141, 252, 259, 285, 335 Bacteriuria, 4, 252 Barbiturate, 252, 334 Basal Ganglia, 252, 262, 280 Basal Ganglia Diseases, 252, 262 Base, 9, 61, 137, 150, 244, 246, 253, 268, 269, 281, 293, 294, 333, 337 Basement Membrane, 156, 253, 277, 294 Basophils, 253, 283, 295 Benign, 195, 253, 280, 284, 305, 322, 326, 340 Benzaldehyde, 137, 253 Benzene, 253 Beta-Defensins, 253, 269 Beta-Lactamases, 253, 288 Beta-Thromboglobulin, 253, 292 Bewilderment, 253, 265 Bilateral, 76, 113, 253 Bile, 24, 195, 253, 254, 261, 262, 279, 286, 293, 296, 317, 331, 333, 338 Bile Acids, 24, 253, 331, 333 Bile Acids and Salts, 253 Bile duct, 195, 253, 254, 261, 279, 317 Bile Pigments, 253, 293 Biliary, 24, 76, 195, 196, 199, 205, 241, 254, 262, 310 Biliary Tract, 205, 254, 310 Bilirubin, 24, 246, 253, 254, 279, 287 Binding agent, 15, 254 Binding Sites, 7, 175, 181, 254 Bioassay, 254 Biochemical, 9, 10, 12, 15, 19, 20, 24, 55, 76, 150, 246, 250, 254, 294, 295, 308, 328 Biological Assay, 24, 254 Biological response modifier, 56, 181, 254, 291 Biological therapy, 254, 283 Biological Transport, 254, 270 Bioluminescence, 254, 297 Biomarkers, 76, 208, 254 Biomechanics, 144, 254 Biomolecular, 254, 332 Biopsy, 79, 124, 254 Biosynthesis, 18, 51, 159, 171, 250, 254, 319, 327 Biotechnology, 62, 71, 181, 211, 221, 254
Bioterrorism, 12, 47, 254 Biotype, 101, 255 Bivalent, 179, 255 Bladder, 201, 255, 267, 268, 287, 289, 303, 305, 319, 322, 338 Blastocyst, 255, 265, 314 Blastomycosis, 190, 255 Bleomycin, 191, 255 Blood Cell Count, 76, 145, 241, 255, 284 Blood Coagulation, 44, 141, 145, 255, 257, 325, 334 Blood Coagulation Factors, 255 Blood Glucose, 21, 117, 255, 285, 291 Blood Platelets, 255, 315, 328, 334 Blood pressure, 39, 124, 187, 239, 240 Blood vessel, 153, 166, 174, 183, 187 Blood-Brain Barrier, 54, 255 Blot, 36, 255 Body Composition, 131, 255 Body Fluids, 246, 254, 255, 257, 271, 278, 307, 324, 329, 336 Bolus, 155, 255 Bolus infusion, 255 Bone Cements, 255, 315, 316 Bone Development, 48, 256 Bone Marrow, 26, 42, 48, 128, 129, 144, 150 Bone Marrow Transplantation, 48, 87, 129, 256 Bone Resorption, 180, 256 Bowel, 152, 156, 180, 190, 199, 201, 202, 247, 256, 265, 270, 275, 290, 292, 312, 331, 337 Bowel Movement, 256, 265, 270, 331 Brachytherapy, 256, 292, 322 Bradykinin, 256, 306, 314 Branch, 235, 256, 297, 310, 321, 329, 334 Breakdown, 36, 72, 256, 270, 280 Broad-spectrum, 139, 256, 259, 260 Bronchi, 256, 275, 334, 335 Bronchial, 124, 194, 256, 286, 334 Bronchioles, 247, 256 Bronchiolitis, 112, 256 Bronchitis, 141, 256, 262 Bronchoalveolar Lavage, 124, 256 Bronchoscope, 124, 256 Bronchoscopy, 124, 256 Buccal, 256, 297 Bupivacaine, 257, 295 Burns, 49, 143, 144, 149, 182, 186, 187, 190, 192, 257 Burns, Electric, 257 Bypass, 153, 173, 257, 304, 334
346
Sepsis
C Cachexia, 36, 141, 156, 164, 175, 180, 257 Caffeine, 257, 321 Calcineurin, 196, 257 Calcium, 17, 30, 36, 55, 145, 256, 257, 264, 270, 298, 304, 310, 319, 320, 328, 336 Calcium Chloride, 257, 310 Calmodulin, 257 Calpain, 36, 257 Candidiasis, 190, 257 Candidosis, 257, 258 Capillary, 31, 64, 88, 116, 166, 256, 258, 321, 340 Capillary Permeability, 166, 256, 258 Capping, 27, 258 Capsular, 9, 13, 25, 40, 258 Capsules, 9, 258, 280 Carbohydrate, 35, 40, 48, 145, 258, 266, 282, 316, 327 Carbon Dioxide, 171, 258, 269, 280, 314, 321, 322, 324, 339 Carboxy, 258 Carboxylic Acids, 154, 258 Carcinogen, 258, 276, 300 Carcinogenic, 246, 253, 258, 290, 308, 318, 331 Carcinoma, 77, 134, 201, 205, 258, 267 Cardiac Output, 16, 258, 331 Cardiogenic, 16, 258 Cardiomyopathy, 147, 258 Cardiovascular, 17, 45, 57, 68, 101, 144, 147, 151, 155, 176, 258, 328, 339 Cardiovascular disease, 147, 151, 176, 258 Carrier Proteins, 258, 314 Case report, 90, 259, 263, 277 Case series, 72, 259, 263 Caspase, 29, 44, 57, 77, 259 Catabolism, 30, 36, 84, 259 Catalase, 28, 139, 243, 259 Catastrophic Illness, 168, 259 Catecholamines, 16, 37, 65, 91, 245, 259, 271 Catheter, 4, 62, 63, 71, 89, 106, 125, 127, 130, 202, 259, 292 Catheterization, 4, 162, 259, 292, 304 Cations, 259, 293 Cat-Scratch Disease, 148, 259 Causal, 18, 259, 285, 327 Cause of Death, 14, 15, 24, 29, 32, 38, 48, 58, 155, 161, 163, 166, 167, 177, 179, 183, 259 Caveolae, 61, 259
Caveolins, 259, 263 Cefamandole, 70, 259 Cefotaxime, 4, 259 Cell Adhesion, 260, 291 Cell Count, 145, 241, 260 Cell Cycle, 260, 318 Cell Death, 31, 44, 68, 107, 144, 154, 227, 250, 260, 305 Cell Differentiation, 260, 328 Cell Division, 252, 260, 283, 299, 300, 301, 314, 318, 327 Cell membrane, 254, 258, 259, 260, 264, 269, 313, 316 Cell Membrane Structures, 259, 260 Cell proliferation, 260, 292, 328 Cell Respiration, 245, 260, 301, 309, 324 Cell Survival, 8, 260, 283 Cellobiose, 260 Cellulose, 77, 260, 279, 314 Central Nervous System, 43, 54, 156 Central Nervous System Infections, 260, 284 Centrifugation, 64, 260, 284 Cephalosporins, 69, 154, 174, 253, 260 Cerebral, 180, 187, 252, 255, 260, 261, 275, 276, 278, 298 Cerebral Arteries, 187, 261 Cerebrospinal, 148, 261, 296, 330 Cerebrospinal fluid, 148, 261, 296, 330 Cerebrovascular, 253, 258, 261 Cerebrum, 260, 261 Cervical, 261, 326 Character, 163, 261, 269, 322 Chemokines, 14, 38, 145, 151, 165, 261 Chemotactic Factors, 14, 261, 265 Chemotaxis, 14, 261 Chemotherapeutic agent, 139, 261 Chemotherapy, 73, 84, 127, 128, 129, 149, 162, 191, 200, 261, 286 Chenodeoxycholic Acid, 261, 338 Chest Pain, 4, 261 Chickenpox, 190, 261 Chin, 185, 261, 299 Chlorophyll, 261, 274, 279 Chloroquine, 136, 261 Cholangiography, 195, 261 Cholangitis, 195, 261 Cholecystectomy, 195, 261, 262 Cholecystectomy, Laparoscopic, 195, 262 Cholecystitis, 72, 262 Cholera, 262, 328 Choleretic, 261, 262, 338
347
Cholestasis, 25, 26, 88, 90, 195, 262 Cholesterol, 151, 253, 259, 262, 266, 279, 296, 331 Cholesterol Esters, 262, 296 Cholic Acid, 14, 262 Chorea, 148, 262 Choreatic Disorders, 262 Chorion, 262, 278 Chromaffin System, 262, 273 Chromatin, 250, 262, 275 Chromosomal, 27, 176, 247, 262, 314, 333 Chromosome, 262, 284, 296, 327, 333, 336 Chronic Disease, 257, 262 Chronic granulocytic leukemia, 262 Chronic myelogenous leukemia, 180, 262 Chronic Obstructive Pulmonary Disease, 152, 262 Chylomicrons, 151, 262, 296 Cilastatin, 117, 262, 288 Ciliary, 251, 263, 302, 338 Circulatory system, 141, 263, 273 Cirrhosis, 79, 157, 200, 263, 316, 317 CIS, 29, 263, 325 Clathrin, 263, 274 Clear cell carcinoma, 263, 269 Cleave, 258, 263 Clinical Medicine, 263, 317 Clinical study, 43, 263 Clinical trial, 5, 21, 32, 61, 116, 123, 127, 131, 158, 221 Cloning, 11, 66, 162, 254, 263, 295 Coated Vesicles, 263, 274 Coccidioidomycosis, 190, 263 Coenzyme, 171, 263 Cofactor, 263, 320, 322, 334 Coliphages, 252, 264 Colistin, 79, 97, 264 Colitis, 78, 141, 152, 155, 156, 160, 180, 201, 202, 264 Collagen, 253, 264, 277, 278, 280, 298, 315 Collagenases, 156, 264 Collapse, 137, 144, 170, 248, 256, 264 Colloidal, 246, 264, 272, 328 Colon, 4, 77, 90, 199, 202, 264, 290, 294, 295, 299, 328, 337 Colostomy, 5, 264 Combination Therapy, 76, 264 Commensal, 91, 264 Complement, 7, 14, 44, 46, 51, 63, 64, 165, 184 Complement Activation, 46, 64, 248, 265 Complementation, 42, 265
Computational Biology, 221, 265 Conception, 43, 265, 278 Concomitant, 21, 28, 171, 265 Cone, 265, 293, 332 Confusion, 108, 238, 265, 271, 337, 338 Congestion, 265, 275 Congestive heart failure, 156, 169, 265 Conjugated, 253, 261, 262, 265, 268, 285, 307 Conjunctiva, 265, 290 Connective Tissue, 156, 256, 264, 265, 269, 278, 280, 297, 312, 325, 326, 333 Connective Tissue Cells, 265 Consciousness, 248, 265, 269, 271, 325 Constipation, 238, 265, 312 Constriction, 33, 265, 293, 339 Constriction, Pathologic, 265, 339 Consumption, 36, 265, 307, 309 Contact dermatitis, 180, 265 Contamination, 24, 75, 265 Continence, 202, 228, 265 Continent Ileostomy, 202, 265 Continuous infusion, 127, 266 Contractility, 16, 266 Contraindications, ii, 266 Control group, 266, 317 Conus, 266, 321 Convalescence, 13, 266 Convulsion, 254, 266 Coordination, 266, 303 Cornea, 266, 326, 331, 338, 341 Corneal Ulcer, 157, 266 Coronary, 124, 155, 258, 266, 300, 303 Coronary Arteriosclerosis, 266, 303 Coronary heart disease, 258, 266 Coronary Thrombosis, 266, 300, 303, 304 Cortex, 261, 266, 276, 278 Cortical, 113, 129, 266, 276 Corticosteroid, 116, 266, 331 Cortisol, 73, 78, 79, 198, 246, 267 Coumarins, 267, 320 Cranial, 267, 284, 312 Craniocerebral Trauma, 253, 267, 284 Creatine, 15, 267 Creatine Kinase, 15, 267 Creatinine, 4, 267, 294, 337 Critical Care, 16, 19, 20, 117, 118, 143, 144, 200, 226, 227, 228 Crossing-over, 267, 323 Cues, 46, 267 Culture Media, 85, 245, 267 Curative, 267, 306, 334
348
Sepsis
Cutaneous, 139, 190, 249, 255, 257, 265, 267, 297 Cyclic, 28, 257, 264, 267, 278, 283, 306, 313, 316, 319, 334 Cyproterone, 267, 279 Cystectomy, 200, 201, 267 Cysteine, 52, 55, 151, 257, 261, 267, 268, 269, 273 Cysteine Endopeptidases, 267, 273 Cystine, 267 Cystitis, 50, 268 Cytidine, 179, 268 Cytochrome, 35, 44, 250, 268 Cytomegalovirus, 180, 268 Cytoplasm, 250, 253, 260, 268, 275, 304, 325 Cytosine, 150, 268, 321 Cytoskeletal Proteins, 257, 263, 268, 272 Cytoskeleton, 17, 268, 291 Cytostatic, 26, 268 Cytotoxic, 31, 74, 144, 175, 268, 289, 292, 322, 328 Cytotoxicity, 51, 144, 268 Cytotoxins, 46, 268 D Dantrolene, 36, 64, 268 Databases, Bibliographic, 221, 268 De novo, 150, 269 Decarboxylation, 171, 269, 286, 322 Defecation, 202, 269 Defense Mechanisms, 77, 269, 291 Defensins, 13, 246, 253, 269 Degenerative, 28, 156, 266, 269, 285, 298, 308, 325 Dehydration, 199, 262, 269 Dehydroepiandrosterone, 73, 269 Deletion, 8, 28, 48, 61, 250, 269 Dementia, 208, 269 Demyelinating Diseases, 157, 269 Density, 12, 151, 260, 269, 296, 308, 315, 329 Depolarization, 269, 328 Deprivation, 187, 269 Dermatitis, 141, 152, 160, 180, 269 Dermis, 29, 269, 332 DES, 147, 248, 269 Desensitization, 176, 269 Detergents, 264, 269 Detoxification, 18, 35, 270 Deuterium, 270, 287 Diabetes Mellitus, 4, 141, 175, 178, 190, 270, 282, 285
Diabetic Retinopathy, 157, 270, 313 Diagnostic procedure, 133, 211, 270 Dialyzer, 270, 284 Diarrhea, 66, 199, 205, 238, 247, 270 Diarrhoea, 149, 270 Diastolic, 270, 287 Diathesis, 27, 270 Diffusion, 149, 254, 258, 270, 290, 337 Digestion, 246, 253, 256, 270, 292, 296, 311, 331 Digestive system, 132, 270, 280 Digestive tract, 270, 329, 341 Dihydroxy, 150, 270 Dilatation, 248, 270, 317, 339 Dilatation, Pathologic, 270, 339 Dilation, 256, 270, 339 Diltiazem, 36, 270 Dilution, 270, 314 Diploid, 265, 270, 314, 336 Direct, iii, 41, 48, 51, 53, 65, 143, 148, 154, 170, 174, 213, 263, 270, 271, 281, 316, 323 Discrete, 21, 270, 296, 341 Disinfectant, 271, 276 Disorientation, 265, 271 Dissection, 11, 139, 271, 297 Dissociation, 181, 245, 271, 293 Dissociative Disorders, 271 Distal, 271, 320 Diuresis, 197, 257, 271, 334 Diuretic, 155, 257, 271, 329 Dopamine, 271, 278, 306, 313 Dose-dependent, 175, 271 Dreams, 109, 271 Drug Interactions, 215, 271 Drug Tolerance, 271, 335 Duct, 81, 195, 247, 259, 271, 276, 326, 330, 332 Duodenum, 253, 271, 274, 311, 331 Dura mater, 271, 299, 309 Dyes, 253, 271, 306 Dysphagia, 205, 271 Dysplasia, 202, 272 Dystrophin, 272, 303 E Echocardiography, 92, 272 Edema, 17, 45, 54, 61, 265, 270, 272, 304, 307, 337 Effector, 13, 33, 41, 243, 249, 264, 272, 294, 313 Effector cell, 41, 249, 272, 294 Efficacy, 6, 7, 61, 69, 123, 125, 126, 127, 128, 130, 135, 154, 159, 174, 209, 210
349
Elasticity, 266, 272, 328 Elective, 176, 272 Electrocardiogram, 124, 272 Electrocoagulation, 263, 272 Electrolysis, 248, 259, 272 Electrolyte, 266, 272, 278, 284, 294, 301, 307, 316, 329, 337 Electrons, 250, 253, 272, 293, 309, 322, 332 Electrophoresis, 57, 272 Ellagic Acid, 272, 310 Emboli, 87, 272 Embolization, 87, 272 Embolus, 273, 290 Embryo, 247, 255, 256, 260, 273, 278, 281, 290, 308, 330, 341 Embryology, 273, 306 Emphysema, 262, 273 Empiric, 72, 83, 273 Empirical, 95, 117, 273 Emulsion, 273, 315 Emulsions, 190, 245, 273 Encapsulated, 70, 273 Encephalopathy, 83, 105, 273 Endemic, 262, 273, 298 Endocarditis, 47, 190, 257, 273 Endocardium, 273 Endocrine Glands, 273 Endocrine System, 138, 273, 305 Endocrinology, 79, 197, 273, 284 Endocytosis, 259, 273 Endogenous, 32, 46, 54, 138, 153, 174, 187, 198 Endopeptidases, 156, 251, 267, 273, 300, 311, 319, 327 Endophthalmitis, 76, 274 Endorphins, 274, 306 Endoscope, 274 Endoscopic, 203, 256, 274 Endoscopy, 81, 199, 202, 205, 274 Endosomes, 38, 273, 274 Endothelial cell, 17, 18, 22, 44, 49, 61, 75, 142, 143, 144, 183, 255, 273, 274, 292, 334 Endothelium, 58, 112, 172, 183, 274, 306, 315 Endothelium, Lymphatic, 274 Endothelium, Vascular, 274 Endothelium-derived, 274, 306 Endotoxemia, 17, 37, 39, 52, 64, 68, 137, 154, 155, 158, 166, 174, 177, 180, 181, 198, 274 Endotoxic, 52, 152, 175, 177, 274 Enhancer, 39, 51, 274, 324
Enkephalins, 274, 306 Enteral Nutrition, 190, 193, 202, 274 Enteric bacteria, 141, 274 Enterocolitis, 86, 131, 168, 275 Enteropeptidase, 275, 336 Environmental Health, 220, 222, 275 Enzymatic, 145, 181, 198, 257, 264, 275, 278, 286, 325 Enzyme Inhibitors, 275, 314 Eosinophilia, 275, 277 Eosinophils, 275, 283, 295 Epidemiologic Factors, 190, 275 Epidemiological, 275, 277 Epidermal, 275, 293, 340 Epidermis, 269, 275, 293, 321, 330 Epigastric, 275, 310 Epinephrine, 36, 198, 245, 271, 275, 306, 307, 337 Epithelial, 6, 39, 43, 46, 53, 54, 58, 134, 183, 185, 253, 254, 266, 275, 294 Epithelial Cells, 39, 46, 54, 58, 183, 253, 275, 294 Epithelium, 149, 163, 186, 253, 274, 275, 280, 341 Epitope, 42, 140, 275 Erection, 275, 317 ERV, 191, 222, 275, 277 Erythema, 190, 239, 265, 275, 338 Erythrocyte Indices, 255, 275 Erythrocytes, 187, 248, 255, 256, 257, 276, 285, 310, 323 Escalation, 140, 170, 276 Esophageal, 85, 205, 276, 326 Esophageal Varices, 276, 326 Esophagitis, 92, 276 Esophagus, 270, 276, 280, 308, 311, 313, 323, 331 Estradiol, 26, 83, 276 Estrogen, 25, 176, 250, 267, 276, 318 Estrogen receptor, 26, 176, 276 Estrone, 26, 276 Ethanol, 6, 18, 26, 276, 322 Eukaryotic Cells, 268, 276, 307, 308, 337 Evacuation, 265, 276 Evoke, 276, 331 Excipient, 146, 185, 276 Excitation, 268, 276, 306 Excitatory, 252, 276, 282 Excrete, 24, 250, 276, 294 Exhaustion, 42, 249, 276, 298 Exocrine, 85, 276, 310 Exogenous, 16, 38, 245, 273, 276, 319, 337
350
Sepsis
Exon, 176, 247, 276 Exotoxin, 47, 277, 330 Expiration, 277, 324 Expiratory, 275, 277 Expiratory Reserve Volume, 275, 277 Extensor, 277, 320 External-beam radiation, 277, 322 Extracellular, 6, 9, 32, 38, 41, 51, 135, 182 Extracellular Matrix, 114, 265, 277, 278, 291, 298 Extracellular Matrix Proteins, 277, 298 Extracellular Space, 277 Extracorporeal, 11, 78, 86, 109, 277, 284, 285 Eye Infections, 244, 277 F Faecal, 270, 277 Family Planning, 221, 277 Fasciitis, 72, 87, 277 Fat, 24, 201, 250, 253, 255, 256, 262, 266, 272, 273, 277, 294, 296, 303, 325, 329, 332 Fatal Outcome, 74, 277 Fatigue, 278, 284 Fatty acids, 171, 246, 258, 278, 282, 319 Febrile, 137, 177, 278, 298 Fecal Incontinence, 202, 278, 289 Feces, 265, 277, 278, 331 Fenoldopam, 16, 278 Ferrichrome, 10, 278 Fetal Membranes, 157, 278 Fetus, 43, 256, 278, 314, 330, 338 Fibrin, 6, 45, 201, 241, 255, 278, 310, 312, 314, 334 Fibrinogen, 241, 278, 310, 314, 315, 320, 334 Fibrinolysis, 145, 183, 278 Fibrinolytic, 147, 278, 334 Fibroblasts, 265, 277, 278, 292 Fibrosarcoma, 277, 278 Fibrosis, 149, 160, 203, 278, 326 Fissure, 199, 278 Fistula, 201, 202, 228, 278 Flank Pain, 203, 278 Flatus, 278, 280 Fluid Therapy, 278, 307 Fluorescence, 23, 278 Flutamide, 26, 279 Folate, 279 Fold, 30, 43, 46, 50, 278, 279, 300 Folic Acid, 149, 279 Foramen, 261, 279, 312 Forearm, 255, 277, 279
Fosfomycin, 65, 279 Fructose, 21, 279, 286 Fulminant Hepatic Failure, 26, 197, 279 Fungemia, 58, 130, 137, 177, 279 Fungi, 39, 127, 137, 148, 159, 169, 177, 179, 254, 274, 277, 279, 283, 300, 301, 330, 341 Fungus, 257, 260, 263, 279 G Galactosemia, 200, 279 Gallbladder, 198, 243, 254, 261, 262, 270, 279, 280 Gallstones, 253, 261, 279, 338 Gamma Rays, 279, 322 Gamma-interferon, 279, 291 Ganglia, 243, 252, 280, 305, 312, 330 Ganglion, 280, 308, 341 Gangrene, 77, 88, 112, 243, 280 Gangrenous, 280, 328 Gas, 54, 125, 247, 258, 270, 275, 278, 280, 287, 306, 324, 339 Gas exchange, 54, 280, 324, 339 Gastric, 32, 113, 134, 152, 155, 252, 280, 286, 311, 326 Gastric Acid, 32, 155, 280 Gastric atrophy, 134, 280 Gastric Juices, 280, 311 Gastric Mucosa, 134, 280 Gastrin, 280, 286 Gastritis, 134, 280 Gastroenterology, 77, 88, 92, 93, 96, 117, 196, 197, 198, 205, 280 Gastrointestinal, 135, 139, 146, 162, 189, 196, 197, 199, 200, 205, 228 Gastrointestinal tract, 146, 162, 196, 199, 276, 280, 328, 337 Gastrostomy, 274, 280 Gelatin, 116, 267, 280, 282, 332, 334 Gelatinases, 32, 156, 280 Gene Expression, 7, 15, 19, 22, 23, 24, 29, 30, 31, 41, 44, 46, 52, 58, 68, 174, 175, 187 Gene Therapy, 27, 57, 244, 281 Genetic Code, 281, 307 Genetic Engineering, 163, 254, 263, 281 Genetics, 11, 20, 21, 37, 55, 88, 89, 138, 148, 210, 281 Genital, 148, 263, 281, 284, 338 Genitourinary, 4, 146, 281, 338 Genomics, 12, 21, 56, 281 Genotype, 255, 281, 313 Germ Layers, 256, 281 Gestation, 281, 311, 314, 330 Gestational, 13, 78, 281
351
Gestational Age, 13, 281 Giardiasis, 281, 300 Gland, 138, 245, 262, 281, 286, 297, 298, 310, 314, 319, 327, 331, 332, 334, 335 Glomerular, 157, 281, 294, 324 Glomeruli, 281, 321 Glomerulus, 281, 305 Glucans, 7, 147, 281 Glucocorticoid, 36, 55, 89, 93, 281 Glucokinase, 282, 286 Gluconeogenesis, 21, 35, 282 Glucose Intolerance, 35, 270, 282 Glucose tolerance, 282 Glucose Tolerance Test, 282 Glucuronic Acid, 282, 285 Glutamate, 186, 282 Glutamic Acid, 145, 186, 279, 282, 306 Glutamine, 95, 129, 149, 282 Glycerol, 282, 313 Glycerophospholipids, 282, 313 Glycine, 253, 261, 262, 282, 306, 327 Glycogen, 35, 282, 313 Glycolysis, 6, 36, 282 Glycoprotein, 58, 278, 283, 294, 302, 334, 337 Glycosidic, 150, 260, 283, 313 Gonadal, 283, 331 Gonadotropin, 26, 283 Governing Board, 283, 317 Grade, 110, 228, 283 Graft, 39, 136, 152, 156, 160, 175, 180, 196, 200, 283, 286, 289, 303, 304 Graft Rejection, 156, 196, 283, 289 Graft-versus-host disease, 175, 283, 303 Gram-Negative Bacteria, 23, 31, 39, 66, 88, 134, 135, 143, 146, 159, 170, 183, 190, 192, 274, 283 Gram-Negative Bacterial Infections, 183, 283 Gram-Positive Bacteria, 159, 170, 283, 333 Granule, 283, 325 Granulocyte, 69, 90, 94, 128, 191, 283 Grasses, 279, 283 Growth factors, 4, 31, 51, 163, 283 Growth Plate, 27, 283 Guanine, 150, 283, 321 Guanylate Cyclase, 187, 283, 306 Gynecology, 86, 113, 116, 284 H Habitat, 284, 303, 306 Habitual, 261, 284 Hair follicles, 269, 284
Haploid, 284, 314 Haptens, 245, 284 Headache, 239, 257, 284, 290, 336 Headache Disorders, 284 Heart attack, 165, 258, 284 Heart failure, 156, 169, 284 Heartbeat, 5, 125, 284 Hematocrit, 255, 276, 284 Hematopoiesis, 43, 284 Hematopoietic Stem Cells, 43, 284 Heme, 6, 24, 52, 254, 268, 284, 309, 316 Hemodialysis, 41, 68, 83, 130, 200, 270, 284, 294, 337 Hemodynamics, 3, 75, 284 Hemofiltration, 65, 66, 68, 92, 110, 284, 337 Hemoglobin, 52, 126, 148, 248, 255, 275, 276, 284, 285, 316 Hemoglobin A, 148, 285, 316 Hemoglobinopathies, 281, 285 Hemolysis, 22, 285 Hemolytic, 277, 285, 331 Hemoperfusion, 84, 285 Hemorrhage, 26, 37, 83, 118, 200, 267, 272, 284, 285, 304, 321, 331, 340 Hemorrhoids, 4, 199, 285, 326 Hemostasis, 45, 112, 145, 285, 291, 328 Heparin, 6, 99, 126, 142, 147, 285, 310, 315 Hepatic, 25, 27, 28, 31, 48, 68, 81, 187, 190, 196, 197, 200, 205, 246, 282, 285, 296 Hepatitis, 26, 154, 279, 285, 290, 340 Hepatocyte, 11, 26, 30, 262, 285 Hepatology, 196, 285 Hepatomegaly, 200, 205, 285, 290 Hepatotoxic, 26, 285 Hereditary, 86, 262, 285 Heredity, 280, 281, 285 Heritability, 21, 285 Herpes, 92, 148, 180, 205, 286 Herpes virus, 180, 286 Herpes Zoster, 180, 286 Heterodimers, 286, 291 Heterogeneity, 245, 286 Heterotrophic, 279, 286 Hexokinase, 6, 286 Hidradenitis, 199, 286 Histamine, 248, 286, 287 Histidine, 47, 149, 286 Histocompatibility, 164, 286 Histology, 45, 286 Homeostasis, 6, 42, 43, 48, 162, 197, 286 Homogeneous, 20, 286
352
Sepsis
Homologous, 246, 255, 267, 281, 286, 303, 327, 333, 334, 336 Homotypic, 182, 286 Hormonal, 22, 197, 251, 254, 266, 286 Humoral, 13, 53, 144, 283, 286 Humour, 286 Hybrid, 287 Hybridization, 12, 147, 287 Hybridomas, 287, 292 Hydrogen, 139, 160, 187 Hydrogen Peroxide, 139, 187, 259, 287, 296, 332 Hydrolysis, 10, 22, 171, 251, 253, 260, 287, 311, 313, 316, 320, 336 Hydronephrosis, 203, 287 Hydrophobic, 14, 24, 151, 153, 173, 269, 282, 287, 296 Hydroxamic Acids, 156, 287 Hyperbilirubinemia, 197, 198, 200, 287, 293 Hyperglycemia, 21, 96, 287 Hypersensitivity, 246, 248, 269, 287, 325 Hypersensitivity, Immediate, 287 Hypertension, 74, 126, 155, 169, 200, 258, 284, 287, 316, 337 Hypnotic, 252, 287, 334 Hypoglycemia, 21, 197, 200, 287 Hypotension, 16, 33, 51, 52, 137, 145, 146, 159, 177, 185, 239, 287 Hypotensive, 52, 155, 287 Hypothalamic, 26, 287 Hypothalamus, 287, 314 Hypoxanthine, 150, 288, 341 Hypoxia, 28, 31, 35, 44, 144, 187, 288 Hypoxic, 28, 288, 300 I Ibuprofen, 94, 130, 288 Id, 119, 226, 228, 229, 234, 236, 288 Idiopathic, 286, 288 Ileal, 201, 202, 288 Ileostomy, 202, 288, 305 Ileum, 202, 288 Ileus, 198, 201, 288 Imipenem, 117, 262, 288 Immaturity, 200, 288 Immersion, 64, 288 Immune function, 26, 43, 55, 149, 164, 288, 289 Immune Sera, 288 Immune system, 11, 40, 43, 48, 56, 136, 138, 140, 143, 148, 153, 162, 173, 176
Immunity, 8, 11, 13, 25, 33, 38, 46, 56, 63, 135, 161, 178, 187, 190 Immunization, 9, 13, 134, 135, 159, 288, 289 Immunoassay, 65, 288 Immunocompromised, 4, 51, 69, 101, 288 Immunodeficiency, 69, 148, 175, 200, 288 Immunogenic, 136, 159, 289 Immunoglobulin, 53, 70, 97, 249, 289, 302 Immunologic, 9, 19, 40, 44, 162, 261, 281, 288, 289, 298, 322 Immunologic Factors, 9, 289 Immunology, 9, 40, 53, 84, 93, 97, 105, 109, 136, 244, 245, 289 Immunophilin, 257, 289 Immunosuppressant, 246, 289, 300 Immunosuppressive, 56, 155, 196, 257, 281, 289 Immunosuppressive Agents, 196, 289 Immunosuppressive therapy, 155, 196, 289 Immunotherapy, 47, 109, 136, 159, 192, 254, 269, 289 Impairment, 11, 43, 46, 110, 186, 253, 262, 277, 289, 299 Implant radiation, 289, 292, 322 Implantation, 265, 289 In situ, 143, 144, 289 In vitro, 6, 7, 8, 12, 14, 19, 23, 27, 31, 35, 36, 38, 40, 46, 47, 48, 49, 54, 61, 69, 138 Incidental, 203, 289 Incision, 262, 289, 293, 294 Incontinence, 202, 289 Incubated, 22, 36, 40, 289 Incubation, 170, 289 Incubation period, 170, 289 Indicative, 167, 191, 290, 310, 339 Indolent, 46, 290 Indomethacin, 118, 290 Induction, 8, 10, 17, 24, 29, 31, 32, 40, 51, 57, 59, 60, 159, 174, 248, 290, 292, 318 Infancy, 198, 290 Infant Nutrition, 149, 290 Infarction, 4, 45, 180, 290, 324 Infectious Mononucleosis, 190, 290, 302 Infiltration, 4, 68, 290, 318, 341 Inflammatory bowel disease, 152, 156, 180, 190, 199, 201, 202, 290 Influenza, 147, 180, 290 Infusion, 36, 50, 62, 69, 73, 90, 117, 126, 127, 155, 183, 290, 304, 326, 336 Ingestion, 6, 18, 249, 282, 290, 315
353
Inhalation, 12, 263, 290, 315 Initiation, 7, 41, 50, 57, 140, 153, 173, 290, 311, 318, 336 Initiator, 254, 290 Inner ear, 291, 339 Inorganic, 291, 297, 302, 306 Inotropic, 5, 16, 271, 291 Insight, 20, 43, 44, 49, 61, 291 Insulator, 291, 303 Insulin, 22, 30, 35, 50, 90, 156, 178, 198, 254, 282, 291, 294, 337 Insulin-dependent diabetes mellitus, 178, 291 Insulin-like, 30, 291 Integrins, 8, 291 Intensive Care, 14, 19, 32, 43, 48, 67, 71, 116, 130, 155, 159, 163, 166, 168, 169, 172, 177, 179, 192, 193, 198 Intensive Care Units, 19, 32, 43, 48, 85, 163, 166, 169, 177, 179, 291 Intercellular Adhesion Molecule-1, 164, 291 Interferon, 142, 164, 279, 291, 297 Interferon-alpha, 291 Interleukin-1, 39, 64, 66, 164, 172, 178, 180, 209, 291, 292 Interleukin-18, 39, 292 Interleukin-2, 291, 292 Interleukin-6, 153, 174, 292 Interleukin-8, 66, 152, 153, 174, 292 Interleukins, 289, 292 Intermittent, 155, 278, 292, 296 Internal Medicine, 19, 28, 33, 85, 92, 273, 280, 292 Internal radiation, 292, 322 Interstitial, 256, 277, 292, 305, 324 Intervertebral, 292, 322 Intestinal, 20, 46, 53, 91, 93, 125, 149, 160, 186, 246, 261, 275, 282, 292, 339, 341 Intestinal Mucosa, 186, 275, 292, 339, 341 Intestine, 46, 101, 143, 144, 162, 253, 256, 292, 294, 312, 331 Intoxication, 149, 292, 335, 341 Intracellular Membranes, 292, 299 Intrahepatic, 25, 198, 292 Intramuscular, 292, 310 Intraocular, 274, 292 Intraperitoneal, 198, 292 Intravascular, 48, 81, 111, 146, 165, 166, 183, 198, 292 Intravenous, 16, 25, 73, 97, 123, 124, 126, 146, 155, 183, 242, 279, 290, 292, 310
Intrinsic, 58, 139, 245, 253, 292, 310 Intubation, 259, 292 Intussusception, 202, 293 Invasive, 20, 53, 97, 139, 148, 155, 199, 288, 293, 298 Invertebrates, 282, 293, 297 Involuntary, 253, 262, 266, 278, 293, 304 Iodine, 61, 293 Ion Channels, 251, 293 Ionization, 293 Ionizing, 27, 44, 246, 293, 322 Ions, 24, 253, 257, 271, 272, 287, 293, 301, 320 Ischemia, 23, 35, 45, 143, 144, 147, 155, 169, 180, 187, 251, 293, 304, 324 Isoenzyme, 267, 286, 293 J Jaundice, 196, 205, 239, 287, 293 Jejunostomy, 274, 293 Joint, 157, 239, 251, 293, 308, 333 K Kb, 51, 220, 293 Keratinocytes, 292, 293 Keratoconus, 157, 293 Keto, 293, 322 Ketone Bodies, 294 Ketosis, 41, 294 Kidney Disease, 113, 132, 187, 220, 287, 294 Kidney Failure, 127, 196, 294 Kidney Failure, Acute, 294 Kidney Failure, Chronic, 294 Kidney Pelvis, 294, 338 Kidney stone, 287, 294, 338 Killer Cells, 164, 294 Kinetic, 35, 293, 294 L Labile, 19, 48, 264, 294 Laceration, 139, 294 Lactation, 149, 294, 318 Laminin, 253, 277, 294 Laparotomy, 5, 86, 107, 110, 294 Large Intestine, 270, 292, 294, 323, 329 Latent, 295, 317 Lavage, 6, 124, 143, 295 Least-Squares Analysis, 295, 323 Lectin, 46, 74, 295, 299 Length of Stay, 129, 295 Lens, 258, 295, 324 Leprosy, 190, 295 Lesion, 5, 203, 255, 295, 327, 337
354
Sepsis
Lethal, 34, 46, 48, 53, 60, 65, 93, 98, 116, 158, 252, 295 Leukemia, 77, 87, 129, 150, 160, 180, 262, 281, 295, 317 Leukocytes, 19, 23, 45, 143, 144, 253, 255, 256, 261, 275, 290, 291, 292, 295, 310, 337 Leukocytosis, 4, 98, 295 Leukopenia, 128, 146, 295 Library Services, 234, 295 Lidocaine, 125, 295 Life cycle, 279, 295 Ligament, 295, 319 Ligands, 7, 104, 181, 291, 295, 332 Ligase, 36, 295 Ligation, 5, 22, 36, 46, 57, 59, 67, 68, 295 Likelihood Functions, 295, 323 Linear Models, 295, 323 Linkage, 258, 260, 296 Lipid Peroxidation, 23, 92, 296, 309 Lipoprotein, 99, 151, 170, 171, 208, 283, 296 Liposome, 70, 296 Liver, 10, 13, 22, 24, 26, 28, 30, 41, 46, 48, 53, 54, 145, 149, 152, 154, 157, 160, 187, 190, 195, 196, 197, 198, 199, 200, 205 Liver Regeneration, 27, 197, 296 Liver Transplantation, 26, 195, 196, 296 Lobe, 124, 296 Localized, 5, 50, 56, 243, 272, 273, 290, 294, 296, 314, 326, 337, 338 Locomotion, 296, 314 Locoregional, 201, 296 Logistic Models, 296, 323 Long-Term Care, 8, 296 Loop, 28, 44, 288, 296 Low-density lipoprotein, 296 Lumbar, 114, 296, 330 Lumbar puncture, 114, 296, 330 Lumen, 149, 202, 274, 296 Luminescence, 11, 296 Lung Transplantation, 68, 108, 297 Lupus, 4, 160, 297, 333 Lutein Cells, 297, 318 Lyme Disease, 190, 297 Lymph, 54, 135, 261, 263, 274, 286, 290, 297, 323, 326 Lymph node, 54, 261, 297, 323, 326 Lymphadenectomy, 201, 297 Lymphadenopathy, 290, 297 Lymphatic, 160, 274, 290, 297, 326, 329, 330, 334 Lymphatic system, 297, 326, 329, 330, 334
Lymphoblastic, 297 Lymphoblasts, 243, 244, 297 Lymphocyte, 29, 44, 53, 68, 100, 136, 249, 294, 297, 298, 299 Lymphoid, 162, 249, 297 Lymphokine, 138, 297 Lymphoma, 28, 129, 191, 297 Lysine, 145, 297, 336 Lytic, 70, 297, 328, 340 M Macrophage, 29, 33, 49, 90, 128, 137, 155, 158, 164, 249, 291, 297 Macrophage Activation, 155, 297 Macula, 298 Macula Lutea, 298 Macular Degeneration, 157, 298 Magnetic Resonance Imaging, 166, 298 Major Histocompatibility Complex, 164, 298 Malaria, 70, 149, 175, 180, 298 Malaria, Falciparum, 298 Malaria, Vivax, 298 Malignant, 250, 277, 298, 302, 305, 318, 322, 326 Malignant tumor, 298, 302 Malnutrition, 48, 117, 149, 186, 196, 200, 246, 251, 257, 298 Mammary, 28, 298 Mandible, 247, 261, 298, 324 Manifest, 23, 139, 141, 298 Mastitis, 298, 328 Matrix metalloproteinase, 32, 156, 298 Maximum Tolerated Dose, 125, 271, 299 Mechanical ventilation, 32, 113, 299 Mediate, 6, 19, 21, 31, 36, 45, 52, 63, 137, 164, 185, 271, 294, 299 Mediator, 8, 19, 25, 33, 53, 80, 88, 100, 109, 187, 292, 299, 315, 328 Medical Records, 299, 325 Medicament, 151, 162, 182, 299, 332 MEDLINE, 221, 299 Megacolon, 78, 299 Megaloblastic, 279, 299 Meiosis, 255, 299, 303, 333, 334 Melanin, 299, 313, 337 Membrane, 8, 9, 10, 35, 36, 44, 47, 134, 142, 144, 146, 153, 156, 160, 170, 174, 175, 177, 181, 184, 185 Membrane Proteins, 8, 134, 181, 185, 259, 299 Memory, 13, 141, 249, 269, 299 Meninges, 260, 267, 271, 299
355
Meningioma, 160, 299 Meningitis, 9, 19, 50, 53, 61, 66, 69, 70, 101, 111, 168, 193, 299 Menopause, 299, 316 Mental, iv, 5, 132, 145, 220, 222, 238, 261, 265, 269, 271, 278, 299, 320, 321, 326, 337, 338 Mental Disorders, 132, 299, 320 Mental Health, iv, 5, 132, 220, 222, 299, 321 Mental Processes, 271, 299, 321 Mesenteric, 54, 300, 316 Mesentery, 300, 312 Meta-Analysis, 64, 68, 76, 300 Metabolic disorder, 200, 300 Metabolite, 126, 155, 276, 300, 318 Metalloendopeptidases, 274, 300 Metalloporphyrins, 35, 300 Metaphase, 255, 300, 334 Metastasis, 157, 299, 300 Methacrylate, 300, 315 Methotrexate, 191, 300 Metronidazole, 4, 300 MI, 134, 136, 152, 177, 242, 300 Microbe, 161, 300, 335 Microbiological, 170, 300 Microbiology, 25, 40, 58, 78, 90, 93, 100, 101, 108, 111, 116, 198, 244, 251, 252, 300 Microcirculation, 103, 117, 144, 300, 315 Microorganism, 139, 165, 263, 300, 310, 340 Micro-organism, 139, 153, 173, 300, 327 Microscopy, 9, 36, 253, 301, 307 Microspheres, 87, 301 Migration, 14, 18, 33, 38, 66, 70, 137, 143, 151, 186, 291, 298, 301 Mineralocorticoids, 245, 266, 301 Mitochondria, 15, 31, 301, 304, 308 Mitochondrial Swelling, 301, 305 Mitogen-Activated Protein Kinase Kinases, 301 Mitogen-Activated Protein Kinases, 182, 301 Mitosis, 250, 301 Mitral Valve, 71, 301 Mobility, 107, 158, 301 Mobilization, 17, 26, 150, 301 Modeling, 21, 24, 56, 301 Modification, 15, 51, 58, 160, 281, 301, 322 Modulator, 22, 301 Molecular Structure, 7, 301
Molecule, 25, 40, 42, 126, 145, 146, 154, 170, 174, 176, 182, 185 Monitor, 55, 111, 125, 267, 302, 307, 310 Monoclonal, 47, 65, 138, 159, 165, 216, 287, 302, 322 Monoclonal antibodies, 65, 138, 159, 302 Monocyte, 22, 146, 249, 302 Monokines, 175, 184, 302 Mononuclear, 93, 277, 290, 302, 337 Mononucleosis, 190, 302 Monotherapy, 76, 302 Morphine, 176, 302, 304, 308 Morphology, 141, 297, 302 Motility, 290, 302, 328 Mucociliary, 54, 302 Mucociliary Clearance, 54, 302 Mucolytic, 256, 302 Mucosa, 50, 134, 186, 280, 297, 302, 318 Mucus, 302, 337 Multicenter study, 73, 302 Multiple Myeloma, 180, 302 Multiple sclerosis, 141, 156, 160, 164, 178, 180, 303 Multiple Trauma, 186, 303 Multivalent, 252, 303 Muscle Contraction, 171, 272, 303 Muscle Fibers, 303, 304, 336 Muscle Proteins, 36, 303 Muscle relaxant, 268, 303 Mutagenesis, 11, 13, 42, 51, 303 Mutagens, 303 Myalgia, 290, 303 Mycobacterium, 63, 78, 87, 295, 303, 336 Mycophenolate mofetil, 196, 303 Myelin, 269, 303, 327 Myelodysplastic syndrome, 116, 303, 329 Myelogenous, 180, 303 Myeloid Cells, 185, 303 Myeloma, 129, 180, 303 Myocardial infarction, 4, 180, 253, 266, 300, 303, 304 Myocardial Ischemia, 169, 303 Myocardial Reperfusion, 304, 324 Myocardial Reperfusion Injury, 304, 324 Myocardium, 18, 300, 303, 304 Myofibrils, 36, 257, 272, 304 Myopia, 157, 304, 305, 323 Myosin, 17, 36, 257, 303, 304, 336 Myristate, 46, 304 N Nadir, 191, 304 Naive, 38, 49, 304
356
Sepsis
Narcotic, 243, 302, 304 Nasal Mucosa, 290, 304 Nasogastric, 274, 304 Nasopharynx, 25, 304 Natural killer cells, 164, 304 Nausea, 294, 304, 337, 338 NCI, 1, 128, 131, 219, 263, 305 Nearsightedness, 304, 305 Necrotizing Enterocolitis, 131, 168, 305 Neonatal, 9, 13, 14, 19, 43, 50, 53, 61, 64, 66, 67, 68, 166, 168, 177, 193, 209, 210, 228 Neoplasia, 55, 162, 305 Neoplasm, 305, 326, 337 Neoplastic, 248, 287, 297, 305 Nephritis, 152, 154, 305 Nephropathy, 294, 305 Nephrotoxic, 197, 305 Nerve, 201 Nervous System, 43, 54, 156, 241, 243, 253, 257, 260, 280, 282, 297, 299, 302, 303, 305, 306, 312, 328, 333, 334 Networks, 20, 181, 305 Neural, 197, 286, 305 Neuroendocrine, 134, 305 Neurogenic, 305, 338 Neurologic, 212, 226, 305 Neurology, 108, 305 Neuromuscular, 243, 268, 305, 316, 337 Neuronal, 154, 305, 306, 312 Neurons, 276, 280, 303, 305, 306, 330, 333 Neuropeptides, 257, 306 Neurosciences, 105, 306 Neurosecretory Systems, 273, 306 Neurotransmitter, 187, 243, 244, 256, 271, 282, 286, 293, 306, 307, 328, 332, 339 Neutralization, 23, 306 Neutrons, 246, 306, 322 Neutropenia, 128, 146, 210, 279, 306 Neutrophil, 8, 14, 18, 57, 62, 68, 108, 144, 187, 210, 291, 306 Niacin, 149, 306 Niche, 13, 306 Nitrates, 147, 306 Nitric acid, 306 Nitric Oxide, 17, 28, 31, 33, 35, 39, 51, 59, 60, 66, 70, 116, 124, 126, 138, 164, 172, 187, 193, 194 Nitrogen, 22, 41, 187, 245, 246, 248, 277, 282, 294, 300, 306 Nitrogen Dioxide, 187, 306 Norepinephrine, 39, 46, 245, 271, 306, 307
Nosocomial, 4, 47, 67, 103, 307 Nuclear, 15, 25, 27, 28, 31, 37, 41, 51, 67, 102, 117, 175, 252, 272, 276, 279, 280, 305, 307, 318 Nuclear Proteins, 25, 307 Nuclei, 27, 246, 272, 281, 298, 301, 306, 307, 320, 326 Nucleic acid, 134, 147, 150, 174, 176, 268, 281, 287, 288, 303, 306, 307, 321 Nucleic Acid Hybridization, 287, 307 Nucleolus, 307, 325 Nucleoproteins, 307 Nucleus, 250, 253, 262, 267, 268, 270, 275, 276, 279, 299, 302, 306, 307, 318, 320, 331 Nurseries, 19, 307 Nursing Care, 307, 311 Nutrition Assessment, 189, 307 Nutritional Status, 189, 307 Nutritional Support, 190, 280, 307 O Obstetrics, 86, 87, 113, 116, 307 Occult, 137, 148, 177, 307 Ocular, 157, 307 Odour, 250, 308, 337 Odynophagia, 205, 308 Oliguria, 145, 239, 294, 308 Oncogenic, 291, 308 Oncology, 113, 138, 191, 308, 323 Opacity, 269, 308 Operon, 10, 308, 318, 324 Opiate, 176, 302, 308 Opium, 302, 308 Optic Disk, 266, 270, 298, 308 Organelles, 260, 263, 268, 308 Osmolality, 47, 308 Osmoles, 308 Osmosis, 308 Osmotic, 180, 246, 301, 308, 328 Osseointegration, 256, 308 Osteoarthritis, 156, 180, 308 Osteogenesis, 256, 308 Osteoporosis, 141, 180, 308 Outpatient, 4, 20, 308 Ovariectomy, 26, 309 Ovaries, 250, 309 Ovary, 276, 309 Overdose, 32, 279, 309 Overexpress, 17, 44, 309 Ovum, 281, 295, 309, 318, 341 Oxidants, 67, 164, 309 Oxidation, 25, 28, 35, 171, 243, 250, 267, 268, 296, 309
357
Oxidation-Reduction, 309 Oxidative metabolism, 171, 245, 309 Oxidative Stress, 19, 23, 24, 55, 309 Oxygen Consumption, 309, 324 Oxygenase, 6, 24, 309 Oxygenation, 91, 309 P Pachymeningitis, 299, 309 Palate, 304, 309 Palliative, 267, 309, 334 Palpation, 199, 310 Pancreas, 94, 198, 199, 243, 254, 270, 280, 291, 310, 336, 337 Pancreatic, 81, 85, 143, 160, 180, 310 Pancreatic cancer, 160, 310 Pancreatitis, 45, 87, 94, 96, 195, 310 Pancytopenia, 212, 310 Parasite, 153, 173, 310, 336 Parenchyma, 183, 310 Parenteral, 71, 91, 129, 186, 189, 190, 193, 202, 310 Parenteral Nutrition, 71, 91, 129, 186, 189, 190, 202, 310 Partial Thromboplastin Time, 111, 310 Particle, 296, 310, 329, 336 Partnership Practice, 310, 317 Parturition, 307, 310, 318 Pathogen, 4, 13, 19, 37, 46, 53, 131, 135, 145, 157, 170, 175, 289, 310 Pathologic, 26, 243, 250, 254, 258, 266, 287, 310, 311, 316, 320, 324 Pathologic Processes, 250, 311 Pathologies, 17, 161, 311 Pathophysiology, 5, 20, 31, 33, 41, 56, 57, 169, 193, 194, 195, 197, 198, 199 Patient Care Management, 202, 311 Patient Education, 228, 232, 234, 242, 311 Pediatrics, 13, 76, 86, 88, 96, 97, 98, 101, 104, 114, 168, 190, 311 Pelvic, 4, 90, 146, 201, 202, 311, 319 Pelvic inflammatory disease, 90, 311 Pelvis, 198, 243, 294, 296, 309, 311, 321, 338 Penicillin, 249, 311 Penis, 311, 317 Pepsin, 311 Peptic, 134, 280, 311, 326 Peptic Ulcer, 134, 311, 326 Peptic Ulcer Hemorrhage, 311, 326 Peptide, 41, 50, 62, 125, 153, 161, 173, 176, 208 Peptide Chain Initiation, 41, 311 Peptide Hydrolases, 273, 311
Perforation, 201, 279, 311 Perfusion, 16, 28, 35, 50, 83, 145, 153, 173, 185, 288, 311 Perianal, 205, 228, 311 Pericardium, 311, 333 Perinatal, 83, 90, 105, 112, 200, 311 Perineal, 201, 311 Perineum, 311, 312 Periodontal disease, 157, 312 Perioperative, 197, 312 Perioperative Care, 197, 312 Peripheral blood, 93, 291, 312, 317 Peripheral Nerves, 295, 312 Peripheral Nervous System, 269, 274, 306, 312, 332, 339 Peripheral stem cells, 283, 312 Peripheral Vascular Disease, 171, 312 Peristalsis, 155, 312 Peritoneal, 17, 199, 201, 251, 292, 312 Peritoneal Cavity, 251, 292, 312 Peritoneum, 300, 312, 325 Peritonitis, 9, 38, 90, 106, 312 Peroxide, 139, 180, 187, 312 Phagocyte, 22, 309, 312 Phagocytosis, 14, 313 Pharmaceutical Preparations, 154, 260, 276, 280, 313 Pharmacodynamic, 64, 125, 313 Pharmacokinetic, 124, 313 Pharmacologic, 6, 16, 22, 100, 104, 248, 251, 313, 335, 338 Pharyngitis, 313, 326 Pharynx, 101, 290, 304, 313 Phenotype, 8, 19, 28, 46, 49, 88, 265, 313 Phenyl, 154, 155, 169, 172, 313 Phenylalanine, 313, 337 Phorbol, 46, 313, 319 Phosphodiesterase, 141, 313 Phospholipases, 313, 328 Phospholipids, 8, 151, 277, 296, 313, 319 Phosphorus, 257, 313 Phosphorylase, 179, 257, 313 Phosphorylated, 150, 263, 301, 313 Phosphorylates, 8, 313, 319 Phosphorylating, 172, 313 Phosphorylation, 7, 8, 17, 37, 47, 50, 55, 150, 171, 301, 313, 320 Photocoagulation, 263, 313 Physical Examination, 124, 201, 281, 314 Physiologic, 14, 15, 27, 42, 58, 98, 144, 184, 200, 245, 254, 314, 319, 323, 324
358
Sepsis
Physiology, 49, 58, 112, 197, 273, 280, 284, 306, 314 Pigment, 254, 314 Pituitary Gland, 138, 266, 314 Placenta, 250, 276, 314, 318, 321 Plague, 13, 314, 336 Plant Diseases, 274, 314 Plants, 146, 246, 255, 258, 268, 269, 282, 295, 302, 307, 314, 326, 330, 335, 336 Plaque, 157, 314 Plasma cells, 249, 302, 303, 314 Plasma protein, 10, 153, 173, 184, 246, 274, 314, 320, 328 Plasma Volume, 116, 301, 314 Plasmapheresis, 130, 314 Plasmid, 54, 314, 339 Plasmin, 314, 315 Plasminogen, 147, 314, 315, 331 Plasminogen Activators, 314, 315 Platelet Activation, 315, 328 Platelet Aggregation, 155, 187, 248, 306, 315 Platelet Count, 191, 315 Platelet Factor 4, 292, 315 Platelets, 128, 253, 257, 306, 310, 315, 334 Platinum, 296, 315 Pneumonia, 20, 34, 47, 61, 87, 89, 103, 126, 128, 139, 168, 266, 315 Poisoning, 47, 226, 257, 292, 305, 315, 327 Polyethylene, 93, 208, 315 Polymerase, 315, 318, 324 Polymers, 7, 181, 315, 320, 331 Polymethyl Methacrylate, 110, 315 Polymorphic, 33, 316 Polymorphism, 12, 22, 34, 94, 138, 171, 316 Polymyxin, 14, 83, 84, 264, 316 Polypeptide, 140, 145, 150, 174, 176, 247, 264, 278, 287, 311, 314, 316, 318, 339, 341 Polysaccharide, 25, 40, 70, 245, 249, 260, 316, 320 Porosity, 184, 316 Porphyrins, 300, 316 Portal Hypertension, 200, 316 Portal Vein, 316 Positive pressure ventilation, 113, 316 Posterior, 247, 251, 309, 310, 316, 326 Postmenopausal, 26, 308, 316 Postnatal, 14, 48, 316, 330 Postoperative, 5, 193, 196, 201, 279, 303, 316 Postoperative Complications, 196, 316 Postoperative Period, 5, 316
Postprandial, 197, 316 Postsynaptic, 316, 328 Post-translational, 12, 49, 145, 316 Potassium, 90, 144, 301, 316 Potentiates, 19, 291, 316 Potentiating, 254, 317 Potentiation, 19, 317, 328 Practice Guidelines, 222, 228, 317 Precursor, 145, 156, 186, 250, 271, 272, 274, 275, 307, 313, 315, 317, 318, 320, 337, 338 Predisposition, 20, 33, 121, 317 Pregnancy Tests, 281, 317 Preleukemia, 303, 317, 329 Preoperative, 190, 197, 317 Presumptive, 165, 317 Presynaptic, 306, 317 Prevalence, 67, 185, 317 Priapism, 187, 317 Primary Biliary Cirrhosis, 72, 317 Primary endpoint, 128, 317 Primary Sclerosing Cholangitis, 195, 317 Private Practice, 116, 317 Probe, 12, 35, 147, 317 Procaine, 295, 318 Proctectomy, 201, 318 Proctitis, 205, 318 Prodrug, 318 Proestrus, 25, 318 Progesterone, 318, 331 Prognostic factor, 196, 318 Progression, 56, 156, 162, 165, 199, 248, 318 Progressive, 30, 191, 260, 263, 266, 269, 271, 276, 283, 294, 302, 305, 308, 315, 318, 324, 337 Progressive disease, 191, 318 Projection, 269, 307, 318 Prolactin, 25, 318 Proliferating Cell Nuclear Antigen, 27, 318 Promoter, 22, 29, 51, 94, 174, 175, 318 Promotor, 318, 324 Prone, 93, 318 Prophase, 255, 303, 318, 333, 334 Prophylaxis, 68, 84, 162, 180, 191, 318, 338 Proportional, 308, 310, 318, 332 Prospective study, 5, 79, 318 Prostaglandin, 28, 39, 118, 150, 154, 155, 319 Prostaglandins A, 290, 319 Prostate, 160, 201, 254, 319, 337
359
Protease, 44, 45, 48, 59, 108, 143, 144, 264, 319 Protease Inhibitors, 59, 143, 144, 319 Protein Binding, 181, 319 Protein C, 15, 17, 25, 30, 44, 82, 144, 246, 247, 250, 252, 263, 296, 303, 319, 336, 337 Protein Isoforms, 247, 319 Protein Kinase C, 301, 319 Protein Kinases, 182, 301, 319 Protein S, 12, 15, 30, 41, 50, 98, 254, 281, 320, 325 Protein Subunits, 15, 320 Protein-Serine-Threonine Kinases, 301, 320 Proteinuria, 157, 302, 320 Proteoglycans, 253, 277, 320 Proteolytic, 145, 246, 264, 275, 278, 314, 315, 320 Prothrombin, 27, 44, 241, 310, 320, 334 Prothrombin Time, 27, 320 Protocol, 59, 320 Protons, 246, 287, 293, 320, 322 Protozoa, 148, 254, 300, 320, 330 Protozoal, 320 Protozoan, 137, 177, 260, 281, 298, 320, 336 Proximal, 201, 271, 317, 320 Psoriasis, 141, 150, 152, 160, 164, 178, 180, 211, 212, 320 Psychiatry, 320, 339 Psychic, 299, 321 Psychogenic, 321, 338 Psychology, 271, 321 Public Health, 13, 20, 191, 222, 321 Public Policy, 221, 321 Publishing, 4, 62, 196, 321 Puerperium, 307, 321 Pulmonary Artery, 106, 255, 321, 340 Pulmonary Edema, 17, 294, 321 Pulmonary Gas Exchange, 54, 321 Pulmonary hypertension, 169, 321 Pulse, 52, 302, 321 Purifying, 135, 151, 269, 321 Purines, 150, 321, 327, 341 Purpura, 64, 144, 321 Purulent, 198, 274, 321, 338 Putrefaction, 280, 321 Pyelonephritis, 72, 203, 321 Pyrimidines, 150, 321, 327 Pyrogens, 143, 322 Pyruvate Decarboxylase, 171, 322 Q Quality of Life, 201, 322
Quinoxaline, 152, 322 R Race, 301, 322 Radiation, 27, 44, 149, 203, 277, 278, 279, 292, 293, 300, 322, 328, 341 Radiation therapy, 203, 277, 292, 322 Radical cystectomy, 201, 322 Radicular, 322 Radiculopathy, 205, 322 Radioactive, 287, 289, 292, 293, 302, 307, 308, 322 Radiography, 281, 322 Radiolabeled, 322 Radiologist, 195, 322 Radiotherapy, 256, 322 Randomized, 73, 83, 85, 106, 117, 127, 128, 129, 272, 322 Reactive Oxygen Species, 18, 27, 30, 31, 35, 322 Reagent, 181, 323 Recombinant, 47, 56, 70, 76, 79, 82, 85, 106, 110, 130, 138, 142, 150, 175, 210, 323, 339 Recombination, 27, 281, 323 Rectal, 5, 199, 201, 205, 323 Rectovaginal Fistula, 201, 323 Rectum, 4, 199, 202 Recurrence, 228, 323 Red blood cells, 52, 276, 285, 309, 323, 326 Reductase, 250, 300, 323 Refer, 1, 256, 264, 274, 279, 286, 296, 298, 302, 304, 306, 307, 316, 323, 335 Reflux, 110, 323 Refraction, 304, 323, 329 Refractive Power, 304, 323 Refractory, 16, 32, 185, 272, 323 Regeneration, 27, 197, 323 Regimen, 6, 13, 155, 191, 272, 323 Regional lymph node, 259, 323 Regression Analysis, 43, 323 Rehydration, 197, 323 Remission, 323 Renal failure, 3, 16, 39, 41, 66, 190, 210, 324, 337 Renal Replacement Therapy, 96, 324 Reperfusion, 35, 45, 147, 149, 152, 156, 180, 187, 304, 324 Reperfusion Injury, 147, 152, 156, 180, 187, 324 Repressor, 19, 56, 308, 324 Research Design, 42, 50, 324 Resection, 27, 324 Resolving, 86, 324
360
Sepsis
Resorption, 180, 324 Respiration, 18, 113, 167, 258, 278, 302, 324, 325 Respirator, 299, 316, 324, 339 Respiratory distress syndrome, 17, 43, 56, 65, 125, 130, 145, 146, 152, 153, 158, 173, 180, 198 Respiratory failure, 32, 190, 324, 339 Respiratory Physiology, 324, 339 Respiratory System, 302, 324, 339 Response Elements, 22, 324 Response rate, 191, 324 Restoration, 304, 323, 324, 325, 341 Resuscitation, 29, 94, 107, 155, 325 Retina, 266, 270, 295, 298, 304, 325, 326, 338 Retinal, 265, 270, 308, 325 Retinopathy, 157, 270, 325 Retroperitoneal, 4, 198, 325 Retrospective, 84, 110, 325 Retrospective study, 84, 110, 325 Retroviral vector, 281, 325 Rhabdomyolysis, 84, 325 Rheumatism, 288, 325 Rheumatoid, 87, 116, 141, 150, 156, 160, 175, 178, 180, 182, 212, 261, 309, 325 Rheumatoid arthritis, 87, 116, 141, 150, 156, 160, 175, 178, 180, 182, 212, 261, 325 Rhinitis, 160, 180, 325, 328 Riboflavin, 169, 325 Ribose, 149, 244, 268, 325, 338 Ribosome, 50, 325, 336 Rigidity, 314, 325 Risk factor, 6, 58, 68, 109, 198, 296, 318, 325 Ristocetin, 325, 339 Rod, 252, 274, 326 Rubber, 5, 243, 326 Rubella, 190, 326 S Saline, 39, 94, 256, 326 Salivary, 268, 270, 310, 326 Salivary glands, 268, 270, 326 Saponins, 326, 331 Sarcoma, 160, 205, 278, 326 Sarcomere, 37, 326 Scarlet Fever, 190, 326 Schizoid, 326, 341 Schizophrenia, 326, 341 Schizotypal Personality Disorder, 326, 341 Sclera, 265, 266, 326, 338 Scleroderma, 277, 326
Sclerosis, 141, 156, 160, 164, 178, 180, 303, 326 Sclerotherapy, 4, 326 Screening, 24, 43, 88, 111, 135, 157, 166, 181, 227, 263, 310, 327 Sebaceous, 269, 327 Sebaceous gland, 269, 327 Secondary tumor, 300, 327 Secretion, 5, 49, 53, 54, 155, 266, 286, 291, 292, 294, 301, 302, 327 Secretory, 246, 302, 327 Segregation, 252, 323, 327 Sella, 314, 327 Semen, 319, 327 Seminal vesicles, 201, 327 Senile, 308, 327 Sensibility, 247, 327 Sensory loss, 322, 327 Septic, 3, 6, 7, 8, 11, 16, 19, 23, 24, 29, 30, 32, 33, 35, 36, 39, 50, 51, 52, 55, 62, 63, 64, 65, 66, 67, 68, 69, 70, 116, 118, 123, 124, 129, 130, 137, 140, 142, 143, 152, 153, 155, 156, 158, 159, 161, 162, 163, 164, 165, 166, 169, 170, 171, 173, 175, 177, 180, 181, 182, 183, 185, 192, 193, 198, 201, 208, 209, 228, 237 Septicaemia, 327, 328 Sequela, 183, 327 Sequence Analysis, 12, 327 Sequencing, 12, 21, 62, 69, 71, 327 Serine, 8, 59, 144, 172, 273, 301, 319, 320, 327, 336 Serine Endopeptidases, 273, 327 Serologic, 288, 328 Serotonin, 306, 328 Serotypes, 135, 328 Serous, 274, 328 Serum Albumin, 41, 328 Side effect, 125, 165, 183, 212, 213, 215, 245, 254, 328, 335 Sigmoid, 5, 328 Sigmoid Colon, 328 Signal Transduction, 26, 33, 42, 49, 52, 99, 257, 259, 328 Skeletal, 36, 41, 48, 50, 248, 267, 268, 302, 304, 325, 328, 336 Skeleton, 243, 293, 319, 328 Skin Aging, 157, 328 Skin graft, 328, 330 Skull, 267, 328, 333 Small intestine, 143, 144, 261, 262, 265, 271, 281, 286, 288, 292, 304, 329, 336
361
Smoldering leukemia, 303, 329 Smooth muscle, 24, 185, 187, 248, 251, 257, 265, 286, 287, 302, 329, 332 Social Environment, 322, 329 Sodium, 144, 256, 301, 329, 332 Soft tissue, 58, 256, 277, 278, 328, 329 Solid tumor, 157, 248, 255, 329 Solvent, 253, 276, 282, 308, 329 Soma, 329 Somatic, 42, 162, 244, 286, 299, 301, 312, 329 Somatic cells, 162, 299, 301, 329 Sorbitol, 286, 329 Sound wave, 322, 329 Spasticity, 252, 268, 329 Specialist, 110, 229, 270, 329 Specificity, 10, 42, 176, 196, 245, 273, 317, 329 Spectrum, 65, 69, 103, 139, 259, 288, 329 Sphincter, 228, 330 Spinal cord, 251, 252, 260, 261, 262, 271, 280, 299, 305, 309, 312, 317, 322, 330 Spinal Cord Injuries, 322, 330 Spinal Nerve Roots, 322, 330 Spinal tap, 296, 330 Spirochete, 297, 330, 333 Spleen, 53, 54, 268, 297, 330 Splenectomy, 98, 330 Splenomegaly, 290, 330 Spondylitis, 180, 330 Spontaneous Abortion, 86, 330 Spores, 263, 330 Stabilization, 17, 330 Staging, 100, 208, 330 Standard therapy, 16, 330 Staphylococcal Infections, 47, 330 Staphylococcal Scalded Skin Syndrome, 190, 330 Steatosis, 25, 330 Stem Cells, 43, 246, 312, 330 Stenosis, 199, 330, 331 Stents, 81, 330 Sterile, 39, 331 Steroid, 67, 108, 196, 250, 253, 267, 326, 331 Steroid therapy, 67, 331 Stimulus, 10, 58, 102, 182, 183, 184, 266, 272, 276, 292, 293, 331, 334 Stoma, 202, 331 Stool, 202, 264, 265, 289, 294, 331 Strand, 27, 315, 331 Streptococcal, 68, 84, 90, 97, 113, 114, 139, 331
Streptococcal Infections, 97, 331 Streptococci, 61, 170, 326, 331 Streptococcus, 9, 19, 64, 69, 77, 80, 87, 91, 101, 153, 173, 277, 331 Streptokinase, 4, 147, 331 Stricture, 195, 202, 203, 330, 331 Stroke, 132, 152, 180, 187, 220, 258, 331 Stroke Volume, 258, 331 Stroma, 310, 331 Stump, 5, 331 Styrene, 326, 331 Subacute, 168, 290, 331 Subarachnoid, 284, 331 Subclinical, 290, 331 Subcutaneous, 272, 280, 310, 332 Subspecies, 57, 329, 332 Substance P, 123, 300, 325, 327, 332 Substrate, 176, 197, 275, 332 Substrate Specificity, 176, 332 Superoxide, 6, 28, 35, 39, 65, 81, 139, 144, 173, 187, 332 Superoxide Dismutase, 6, 28, 139, 332 Supplementation, 117, 129, 332 Suppositories, 280, 332 Suppression, 8, 28, 52, 56, 60, 143, 144, 191, 266, 332 Suppressive, 155, 332 Suppurative, 199, 274, 280, 332 Supraspinal, 252, 332 Surface Plasmon Resonance, 7, 332 Surfactant, 5, 43, 332 Survival Rate, 26, 27, 29, 332 Sweat, 146, 269, 286, 332 Sweat Glands, 269, 332 Sympathomimetic, 271, 275, 307, 333 Symphysis, 261, 319, 333 Symptomatic, 4, 199, 310, 333 Symptomatic treatment, 199, 333 Synaptic, 306, 328, 333 Synergistic, 26, 70, 318, 333 Syphilis, 190, 333 Systemic disease, 51, 135, 200, 327, 333 Systemic lupus erythematosus, 4, 160, 261, 333 Systemic therapy, 261, 333 Systolic, 287, 333 T Tachycardia, 5, 240, 252, 333 Tachypnea, 137, 177, 240, 252, 333 Taurine, 253, 261, 262, 333 Teichoic Acids, 283, 333 Teicoplanin, 127, 333
362
Sepsis
Telomere, 28, 333 Temporal, 75, 284, 298, 333 Teratogenic, 246, 270, 333 Testicular, 250, 333 Testis, 276, 333, 334 Tetravalent, 164, 334 Thalidomide, 64, 84, 334 Theophylline, 321, 334 Therapeutics, 7, 53, 73, 82, 151, 161, 163, 193, 195, 215, 334 Thermal, 38, 60, 271, 306, 334 Thorax, 243, 296, 334 Threonine, 301, 319, 320, 327, 334 Threshold, 16, 54, 287, 334 Thrombin, 17, 44, 45, 48, 61, 145, 165, 183, 278, 315, 319, 320, 334 Thrombocytes, 315, 334 Thrombocytopenia, 128, 334 Thrombolytic, 315, 331, 334 Thrombolytic Therapy, 331, 334 Thrombomodulin, 44, 319, 334 Thromboplastin, 171, 320, 334 Thrombosis, 45, 58, 71, 72, 106, 145, 152, 184, 200, 253, 291, 320, 326, 331, 334 Thrombus, 165, 166, 266, 290, 303, 304, 315, 334 Thymus, 46, 57, 288, 297, 334 Thyroid, 293, 334, 335, 337 Thyroxine, 246, 313, 335 Ticks, 297, 335 Tidal Volume, 32, 335 Tissue Extracts, 59, 335 Tolerance, 11, 19, 49, 136, 163, 208, 244, 282, 335 Tomography, 5, 335 Tone, 32, 329, 335 Tonicity, 285, 335 Tonsillitis, 326, 335 Tonus, 335 Tooth Preparation, 244, 335 Topical, 29, 61, 153, 173, 212, 214, 276, 287, 335 Torsion, 290, 335 Toxemia, 137, 166, 177, 185, 335 Toxicity, 8, 14, 23, 128, 177, 191, 212, 271, 299, 325, 335 Toxicology, 222, 335 Toxin, 137, 146, 274, 335 Trachea, 256, 313, 334, 335 Transcription Factors, 23, 27, 28, 31, 324, 335 Transduction, 26, 34, 42, 49, 52, 328, 336
Transfection, 19, 26, 52, 254, 281, 336 Transfer Factor, 288, 336 Transfusion, 63, 70, 128, 336 Translation, 15, 27, 50, 174, 336 Translational, 12, 49, 51, 58, 145, 336 Translocate, 53, 336 Translocation, 26, 186, 336 Transmitter, 243, 251, 271, 293, 299, 307, 336 Transplantation, 26, 48, 68, 129, 195, 196, 288, 294, 298, 336 Trees, 326, 336 Triad, 145, 336 Trichomoniasis, 300, 336 Trisomy, 148, 336 Tropomyosin, 303, 336 Troponin, 303, 336 Trypsin, 140, 275, 336, 341 Tuberculosis, 87, 212, 265, 297, 336 Tularemia, 13, 336 Tumor marker, 254, 336 Tumor Necrosis Factor, 23, 61, 66, 99, 142, 153, 164, 172, 174, 180, 184, 212, 334, 337 Tumour, 141, 280, 337 Type 2 diabetes, 198, 337 Typhoid fever, 190, 337 Tyrosine, 36, 49, 55, 57, 182, 259, 271, 337 U Ubiquitin, 36, 337 Ulcer, 134, 152, 311, 337, 339 Ulceration, 157, 311, 337 Ulcerative colitis, 141, 152, 155, 156, 180, 201, 202, 290, 317, 337 Ultrafiltration, 284, 337 Ultrasonography, 281, 337 Unconscious, 248, 269, 288, 337 Uracil, 150, 321, 337, 338 Uraemia, 310, 337 Urea, 294, 332, 337, 338 Uremia, 139, 294, 324, 338 Ureter, 203, 287, 294, 338 Urethra, 311, 319, 338 Uric, 246, 321, 338 Uridine Phosphorylase, 179, 338 Urinary, 4, 5, 110, 203, 252, 267, 268, 281, 289, 308, 337, 338, 341 Urinary Retention, 5, 338 Urinary tract, 4, 203, 252, 338 Urinary tract infection, 4, 252, 338 Urinate, 338
363
Urine, 4, 66, 73, 124, 238, 239, 241, 250, 252, 255, 265, 267, 271, 276, 287, 289, 294, 308, 320, 325, 338 Urogenital, 281, 338 Urokinase, 147, 338 Ursodeoxycholic Acid, 196, 338 Urticaria, 160, 248, 338 Uterus, 261, 309, 318, 338 Uvea, 274, 338 Uveitis, 160, 338 V Vaccination, 159, 338 Vaccine, 12, 25, 47, 51, 80, 134, 159, 160, 244, 320, 338 Vagina, 201, 257, 269, 323, 338 Vaginal, 61, 214, 338 Vaginitis, 257, 338 Vancomycin, 73, 214, 339 Varicella, 190, 339 Varicose, 326, 339 Varicose vein, 326, 339 Vascular Resistance, 32, 137, 177, 198, 339 Vasculitis, 310, 339 Vasoactive, 16, 17, 33, 39, 101, 125, 339 Vasoactive Intestinal Peptide, 125, 339 Vasoconstriction, 16, 39, 275, 339 Vasodilatation, 52, 339 Vasodilation, 32, 39, 51, 187, 278, 339 Vasodilator, 4, 16, 256, 271, 286, 304, 339 Vasopressor, 16, 32, 155, 339 Vector, 17, 56, 174, 336, 339 Vein, 124, 248, 251, 292, 307, 316, 339 Venereal, 333, 339 Venoms, 146, 268, 339 Venous, 112, 127, 130, 251, 253, 255, 285, 315, 320, 339 Venous blood, 255, 315, 339 Ventilation, 32, 324, 339 Ventilator, 32, 168, 299, 324, 339 Ventricle, 288, 301, 321, 333, 339, 340 Ventricular, 18, 304, 340 Venules, 255, 258, 274, 300, 340
Vertebrae, 292, 330, 340 Vesicular, 40, 286, 340 Veterinary Medicine, 221, 340 Vinca Alkaloids, 340 Vincristine, 191, 340 Viral, 26, 65, 145, 176, 187, 266, 290, 308, 336, 340 Viral Hepatitis, 26, 340 Viral vector, 27, 340 Viremia, 137, 177, 340 Virulence, 9, 12, 20, 25, 38, 40, 46, 47, 51, 54, 79, 113, 139, 251, 254, 335, 340 Virulent, 68, 340 Viscera, 198, 300, 329, 340 Visceral, 72, 312, 340 Viscosity, 149, 340 Vitreous Hemorrhage, 270, 340 Vitro, 6, 7, 8, 12, 14, 19, 23, 27, 31, 35, 36, 38, 40, 46, 47, 48, 49, 54, 61, 66, 69, 77, 138, 254, 281, 285, 289, 325, 340 Vivo, 6, 7, 8, 10, 17, 19, 24, 26, 27, 31, 33, 36, 38, 40, 42, 45, 46, 48, 52, 61, 62, 63, 69, 135, 142, 145, 167, 172 W Warts, 199, 340 Weight Gain, 94, 340 Windpipe, 313, 334, 341 Withdrawal, 96, 196, 341 Wound Healing, 116, 118, 119, 150, 157, 196, 291, 299, 341 X Xanthine, 37, 150, 186, 187, 246, 341 Xanthine Oxidase, 37, 186, 187, 246, 341 Xenograft, 248, 341 X-ray, 51, 124, 279, 307, 322, 341 Y Yeasts, 258, 279, 313, 341 Yolk Sac, 278, 341 Z Zoster, 180, 341 Zygote, 265, 341 Zymogen, 145, 319, 341
364
Sepsis
