ACIDOSIS 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., 1960Acidosis: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00013-X 1. Acidosis-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 acidosis. 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 ACIDOSIS ................................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Acidosis ......................................................................................... 7 E-Journals: PubMed Central ....................................................................................................... 62 The National Library of Medicine: PubMed ................................................................................ 69 CHAPTER 2. NUTRITION AND ACIDOSIS ....................................................................................... 115 Overview.................................................................................................................................... 115 Finding Nutrition Studies on Acidosis...................................................................................... 115 Federal Resources on Nutrition ................................................................................................. 119 Additional Web Resources ......................................................................................................... 119 CHAPTER 3. ALTERNATIVE MEDICINE AND ACIDOSIS ................................................................. 121 Overview.................................................................................................................................... 121 National Center for Complementary and Alternative Medicine................................................ 121 Additional Web Resources ......................................................................................................... 131 General References ..................................................................................................................... 132 CHAPTER 4. DISSERTATIONS ON ACIDOSIS................................................................................... 133 Overview.................................................................................................................................... 133 Dissertations on Acidosis........................................................................................................... 133 Keeping Current ........................................................................................................................ 133 CHAPTER 5. PATENTS ON ACIDOSIS ............................................................................................. 135 Overview.................................................................................................................................... 135 Patents on Acidosis.................................................................................................................... 135 Patent Applications on Acidosis ................................................................................................ 161 Keeping Current ........................................................................................................................ 172 CHAPTER 6. BOOKS ON ACIDOSIS ................................................................................................. 173 Overview.................................................................................................................................... 173 Book Summaries: Federal Agencies............................................................................................ 173 Book Summaries: Online Booksellers......................................................................................... 181 Chapters on Acidosis.................................................................................................................. 181 CHAPTER 7. MULTIMEDIA ON ACIDOSIS ...................................................................................... 183 Overview.................................................................................................................................... 183 Video Recordings ....................................................................................................................... 183 CHAPTER 8. PERIODICALS AND NEWS ON ACIDOSIS ................................................................... 185 Overview.................................................................................................................................... 185 News Services and Press Releases.............................................................................................. 185 Newsletter Articles .................................................................................................................... 187 Academic Periodicals covering Acidosis .................................................................................... 189 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 191 Overview.................................................................................................................................... 191 U.S. Pharmacopeia..................................................................................................................... 191 Commercial Databases ............................................................................................................... 192 Researching Orphan Drugs ....................................................................................................... 192 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 197 Overview.................................................................................................................................... 197 NIH Guidelines.......................................................................................................................... 197 NIH Databases........................................................................................................................... 199 Other Commercial Databases..................................................................................................... 201 APPENDIX B. PATIENT RESOURCES ............................................................................................... 203 Overview.................................................................................................................................... 203
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Patient Guideline Sources.......................................................................................................... 203 Associations and Acidosis .......................................................................................................... 206 Finding Associations.................................................................................................................. 206 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 209 Overview.................................................................................................................................... 209 Preparation................................................................................................................................. 209 Finding a Local Medical Library................................................................................................ 209 Medical Libraries in the U.S. and Canada ................................................................................. 209 ONLINE GLOSSARIES................................................................................................................ 215 Online Dictionary Directories ................................................................................................... 216 ACIDOSIS DICTIONARY........................................................................................................... 217 INDEX .............................................................................................................................................. 309
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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 acidosis is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about acidosis, 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 acidosis, 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 acidosis. 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 acidosis, 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 acidosis. 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 ACIDOSIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on acidosis.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and acidosis, 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 “acidosis” (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: •
Hepatic Failure and Lactic Acidosis Due to Fialuridine (FIAU), an Investigational Nucleoside Analogue for Chronic Hepatitis B Source: New England Journal of Medicine. 333(17): 1099-1105. October 26, 1995. Summary: In this article, the authors describe severe and unexpected multisystem toxicity that occurred during a study of the antiviral nucleoside analogue fialuridine (FIAU) as therapy for chronic hepatitis B virus infection. Fifteen patients with chronic hepatitis B were randomly assigned to receive fialuridine at a dose of either 0.10 or 0.25 mg per kilogram of body weight per day for 24 weeks. They were monitored every 1 to 2 weeks by means of a physical examination, blood tests, and testing for hepatitis B virus markers. During the 13th week, lactic acidosis and liver failure suddenly developed in 1 patient. The study was terminated on an emergency basis, and all treatment with fialuridine was discontinued. Seven patients were found to have severe
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hepatotoxicity, with progressive lactic acidosis, worsening jaundice, and deteriorating hepatic synthetic function, despite the discontinuation of fialuridine. Of these seven patients, five died and two survived after liver transplantation. The authors conclude that the toxic reaction was probably caused by widespread mitochondrial damage and may occur infrequently with other nucleoside analogues. 5 figures. 1 table. 43 references. (AA-M). •
Renal Tubular Acidosis: Pathophysiology and Diagnosis Source: Archives of Internal Medicine. 156(15): 1629-1636. August 12-26, 1996. Summary: In this article, the authors review the pathophysiology and diagnosis of renal tubular acidosis (RTA). They review the literature on this topic and then present a case that illustrates the diagnostic difficulties that may be encountered in a patient with suspected RTA. The principles of renal acid excretion are then discussed. The diagnostic tests available are covered in regard to both their general principles and to interpretation of the results in the context of the various RTA subtypes. Finally, a schematic approach to the diagnosis of RTA is presented to illustrate that only a few relatively simple tests are required to diagnose RTA and to differentiate the pathophysiological subtypes.
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Alkali Therapy in Renal Tubular Acidosis: Who Needs it? Source: JASN. Journal of the American Society of Nephrology. 13 (8): 2186-2188. August 2002. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-6423. Summary: Renal tubular acidosis (RTA) is a renal (kidney) tubule disorder that causes acidosis by restricting the reduction of urinary pH and thereby the titration of urinary buffers and the excretion of acid. The acidosis of type 1 RTA (classic) results in osteoporosis and other disorders of bone demineralization. Alkali (base pH) therapy has been given to children with RTA to heal osteopenia and to encourage normal growth. This article considers the use and indications of alkali therapy in adults with RTA. The authors review recent studies in this area, including studies investigating the impact of high net acid dietary load. The authors also consider the therapeutic potential of alkali in the increasingly large number of elderly people who are likely to be impaired by RTA. The authors conclude that with the scope of its recognized expression so expanded, the frequency of its consequent occurrence so increasing, and the potential societal benefits of its treatment so enormous (and so inexpensively achieved), RTA may be coming of age as a disorder of public health importance. 41 references.
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Inherited Renal Tubular Acidosis Source: Current Opinion in Nephrology and Hypertension. 9(5): 541-546. September 2000. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-3030 or (301) 223-2300. Fax (301) 223-2400. Website: www.currentopinion.com. Summary: The past few years have witnessed great progress in determining the molecular basis of inherited renal tubular acidosis (RTA). This article summarizes the current understanding of the genetic causes of primary inherited RTA. The authors also evaluated the ability of known functional and biochemical properties of the mutant
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proteins to explain the pathophysiology of associated renal acidification defects. Molecular genetic study has demonstrated that inherited RTA is associated with mutations in genes, with expression restricted almost uniquely to the kidney. Consistent with the physiologically defined importance of multiple gene products in urinary acidification, heritable renal tubular acidosis is genetically heterogeneous. Autosomal dominant distal renal tubular acidosis has been association with a small number of mutations, although the pathophysiologic mechanisms behind these mutations remains unclear. Rarely, autosomal recessive distal RTA is caused by homozygosity or compound heterozygosity for the loss of function mutation. A larger proportion, often accompanied by hearing loss, is associated with a different gene mutation. Another gene mutation has been recently identified in proximal renal tubular acidosis with corneal calcification. The authors conclude that although these mutations have been discovered during investigation of the genetic causes of inherited renal acidification defects, studies of these naturally occurring mutations will advance the understanding of the normal urinary acidification process, as well as of acid base transport processes in other organ systems. 2 figures. 1 table. 33 references. •
Hereditary Distal Renal Tubular Acidosis: New Understandings Source: in Coggins, C.H.; Hancock, E.W., Eds. Annual Review of Medicine: Selected Topics in the Clinical Sciences, Volume 52. Palo Alto, CA: Annual Reviews Inc. 2001. p. 471-484. Contact: Available from Annual Reviews Inc. 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303-0139. (800) 523-8635. Fax: (415) 855-9815. PRICE: $47. ISBN: 0824305450. Summary: The primary or hereditary form of distal renal tubular acidosis (dRTA), although rare, has received increased attention recently because of dramatic advances in the understanding of its genetic basis. This review article discusses several recent important studies that have begun to unravel the genetic defects causing different types of primary or hereditary dRTA (the authors do not discuss acquired dRTA). The final regulation of renal acid excretion is effected by various acid and base transporters localized in specialized cells in the cortical collecting and outer medullary collecting tubules. Inherited defects in two of the key acid or base transporters involved in distal acidification, as well as mutation in the cytosolic carbonic anhydrase gene, can cause dRTA. The syndrome is inherited in both autosomal dominant and recessive patterns; patients with recessive dRTA present with either acute illness or growth failure at a young age, sometimes accompanied by deafness, whereas dominant dRTA is usually a milder disease and involves no hearing loss. Hypokalemia (low levels of potassium in the blood), metabolic acidosis, nephrocalcinosis (calcium phosphate in the tubules of the kidney, resulting in kidney insufficiency), and renal calculi (kidney stones) are seen in both autosomal recessiave and dominant dRTA but tend to be more severe and more common in autosomal recessive dRTA. Growth retardation is also much more common and severe in recessive dRTA, probably because the recessive form occurs earlier in life and causes severe metabolic acidosis. The severity of the acidosis manifesting at an early age is the key determinant of delayed growth. 2 figures. 1 table. 64 references.
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Diabetic Ketoacidosis Source: Practical Diabetology. 10(3): 1-5, 8. May-June 1991. Summary: This article describes the pathophysiology and therapy of diabetic ketoacidosis (DKA), from initial presentation to discharge. Topics covered include the role of insulin, increased production of free fatty acids, increased hepatic production of
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glucose and ketoacids, dehydration, the diagnosis of DKA, interpretation of the diagnostic tests used to confirm DKA, treating DKA (replacing fluids, insulin, and potassium), monitoring the patient during therapy, and other clinical and laboratory considerations. The author also mentions potential complications of DKA, including hypoglycemia, hypokalemia, insulin resistance and prolonged DKA, hypoxemia, obtundation and brain edema, lactic acidosis, and hypercholermic acidosis. 1 figure. 3 tables. •
Value of Calcium Carbonate in Treating Acidosis, Phosphate Retention, and Hypocalcemia Source: Nephrology News and Issues. 5(7): 16, 18-19, 32. July 1991. Summary: This article discusses the value of calcium carbonate in treating acidosis, phosphate retention, and hypocalcemia. The author notes that calcium carbonate is easily available in high and varied dosage forms and is inexpensive. Topics include indications for calcium carbonate in the renal patient, guidelines for the use of calcium carbonate, and complications arising from the use of calcium carbonate, including hypercalcemia and constipation. The author suggests that continued problems with high serum calcium and phosphorus in some patients using calcium salts may necessitate the intermittent use of aluminum binders. 43 references.
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Treatment Strategies for Diabetic Ketoacidosis in Children and Adolescents With Insulin-Dependent Diabetes Mellitus Source: Clinical Diabetes. 11(5): 102-106. September-October 1993. Summary: This article reviews the current thinking on treatment strategies for diabetic ketoacidosis (DKA) in children and adolescents with insulin-dependent diabetes mellitus (IDDM). Topics include a brief review of DKA and how it happens; rehydrating patients; replenishing potassium; lowering the glucose level; correcting acidosis; treating other DKA symptoms; avoiding cerebral edema; continuing insulin therapy; and monitoring patients. 2 tables. 11 references.
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Diabetic Ketoacidosis and Hyperosmolar Nonketotic State: Gaining Control Over Extreme Hyperglycemic Complications Source: Postgraduate Medicine. 99(6): 143-148, 150, 152. June 1996. Summary: This continuing education article focuses on the evaluation and management of diabetic ketoacidosis and hyperosmolar nonketotic state in adults. The distinctions between these conditions are clearly defined, and the authors stress that accurate recognition is important for proper treatment. Topics include the differences between insulin-dependent and noninsulin-dependent diabetes (IDDM and NIDDM, respectively); assessment considerations; factors related to decompensated hyperglycemic states; characteristic findings in diabetic ketoacidosis and in hyperosmolar nonketotic state; treatment modalities; and recommendations for followup of treatment. The authors contend that the two conditions may represent variants of decompensated hyperglycemia that differ only by the magnitude of dehydration and the severity of acidosis. 4 tables. 21 references. (AA-M).
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Federally Funded Research on Acidosis The U.S. Government supports a variety of research studies relating to acidosis. 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 acidosis. 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 acidosis. The following is typical of the type of information found when searching the CRISP database for acidosis: •
Project Title: A CHEMICALLY SYNTHETIC ANTI-TOXIC VACCINE AGAINST MALARI Principal Investigator & Institution: Schofield, Louis; Walter and Eliza Hall Inst Medical Res of Medical Research Victoria, Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 31-AUG-2003 Summary: (Adapted from the Applicant's Abstract): Plasmodium falciparum is a global health problem because of the morbidity and mortality associated with infection. Much of this morbidity and mortality is believed to arise from the actions of a malaria toxin. The toxin initiates a systemic inflammatory cascade involving cytokine excess, which may result in disseminated intravascular coagulation, hepatic dysfunction, acute renal failure, multi-organ inflammation, hypoglycemia, lactic acidosis and death. The toxin may further contribute to organ-specific and cerebral disease syndromes by hyperactivation of the vascular endothelium. Clinical immunity to malaria is acquired considerably earlier than anti-parasite immunity, and it is possible that this is mediated by anti-toxin mechanisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: A ROLE OF ACID-SENSING ION CHANNELS IN ISCHEMIA Principal Investigator & Institution: Simon, Roger P.; Director, Neurobiology Research; Emanuel Hospital and Health Center Portland, or 972083950 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2003 Summary: (provided by applicant): Ischemic injury causes an immediate and marked fall in brain pH, the consequences of which are multiple and complex and incompletely understood. The recent discovery of proton-gated cation channels (acid-sensing ion channels, ASIC) in the brain offers a novel opportunity to explore hitherto unknown aspects of biology relevant to understanding the response of the brain to ischemia. The ASIC system does respond during ischemia. Our preliminary data show up-regulation of the brain-specific ASIC2a subunit following ischemia and co-localization of another
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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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ASIC subunit to brain mitochondria, a major site of perturbation during ischemic necrosis and apoptosis. In patch-clamping experiments, cultured neocortical cells showed an acid-evoked current matching that of ASIC1a, whose properties changed after in vitro ischemia, and neuronal (PC12) cells displayed an acid-evoked current that was blocked with an ASIC subunit-specific antagonist. We therefore propose to 1) characterize the expression of all ASIC subunits after focal and global ischemia; 2) identify and compare ASIC subunit-protein interactions in normal and ischemic brain; 3) describe the sub-cellular location of the ASIC subunits; and 4) assess electrophysiologically the effect of ischemia on ASIC function and the effect of ASIC activity on the outcome of ischemic injury. These novel studies are likely to offer new understanding of the biology of brain ischemia and offer new targets for therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALDOLASE-MEDIATED REGULATION OF V-ATPASE Principal Investigator & Institution: Lu, Ming; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Vacuolar H+ATPases (V-ATPases or H+ATPases) are highly conserved proton pumps that couple hydrolysis of ATP to proton transport out of the cytosol. They are essential for renal acid-base homeostasis, for sorting of newly synthesized proteins in the Golgi, and for acidification and normal function of the yeast vacuole. Although a central question in the field is how V-ATPase is regulated under physiological conditions, until recently little was known about the underlying mechanisms. The glycolytic enzyme aldolase has been identified to interact with three subunits of V-ATPase by our lab. This represents the first example of physical association between the ATP-generating glycolytic pathway and an ATP-hydrolyzing ion pump. Deletion of the aldolase gene in yeast cells results in complete disassembly of and a dramatic reduction in V-ATPase. These abnormalities can be fully restored by aldolase complementation. Our data suggest that disruption of the interaction between aldolase and V-ATPase results in malfunction of V-ATPase, which leads to renal tubular acidosis found in patients with hereditary fructose intolerance, an autosomal recessive disorder caused by mutations in an isoform of aldolase. In this proposal, we will carry out molecular genetic analysis in yeast cells to examine the structural basis and regulation of the interaction between aldolase and V-ATPase, and test the hypothesis that aldolase mediates V-ATPase assembly, function and stability. The specific aims of this proposal are: 1) to generate aldolase and V-ATPase subunit mutants that lack binding for a specific interaction but retain aldolase enzymatic activity and/or binding to other V-ATPase subunits; 2) to express the aldolase and V-ATPase subunit mutants in yeast deletion mutant strains lacking either aldolase or a single subunit of V-ATPase, and examine the effects on V-ATPase assembly, function and stability; 3) to examine the parameters required for aldolase to bind intact V-ATPase and disassembled V-ATPase sectors. These studies will provide important insight into the molecular basis for metabolic control of proton transport. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ATP SYNTHESIS IN MITOCHONDRIAL DISORDERS Principal Investigator & Institution: Manfredi, Giovanni; Assistant Professor of Neuroscience; Neurology and Neuroscience; Weill Medical College of Cornell Univ New York, Ny 10021
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Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: Mitochondria are the main sources of energy in the cell. They contain their own DNA (mtDNA), whose genes encode components of the respiratory chain/oxidative phosphorylation system. They are essential for the normal functioning of all cells in the body, and are absolutely critical for the function of those tissues that are highly dependent on aerobic metabolism, especially muscle and brain. Since 1988, both mtDNA point mutations and mtDNA rearrangements (i.e. large-scale deletions and duplications) have been associated with a heterogeneous group of sporadic, mendelian, and maternally-inherited mitochondrial encephalomyopathies. These mutations generally cause an impairment of the respiratory chain, with a reduction in ATP synthesis. However, very little is known about how affected cells cope with the reduced ATP production: for example, which ATP-dependent cellular functions are preserved and which are down-regulated or abolished. Understanding ATP distribution inside mutant, as well as normal, cells would be extremely important for the interpretation of the biochemical and clinical phenotype of mitochondrial disorders. This Career Development Award Application proposes to investigate the effect of mtDNA abnormalities, on the intracellular ATP pool in different cell compartments, with particular emphasis on the mitochondria, the cytoplasmic membrane, and the nucleus. We plan to study the ATP content in cytoplasmic hybrids of human mtDNAless cyss ( rho o cells ) repopulated with mitochondria derived from patients tissues, by targeting a recombinant firefly luciferase to different cell compartments. Utilizing a similar experimental approach, we will also attempt a novel genetic strategy for treatment of point mutations in the mtDNA ATPase6 gene, that are responsible for a maternally- inherited form of Leigh syndrome (MILS): to recode the ATPase 6 gene to contain the universal genetic code by in vitro mutagenesis, to fuse a mitochondrial targeting sequence to the recoded sequence, and then to transfer this construct into the nucleus, in order to express the gene from nuclear DNA and target it back to mitochondrial ( allotopic expression). Allotopic expression of the recoded wild-type genes should partially restore the APT synthetic function in mutant cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ATPASES IN MICROVASCULAR ENDOTHELIAL CELLS AND DIABETES Principal Investigator & Institution: Martinez-Zaguilan, Raul; Physiology; Texas Tech University Health Scis Center Health Sciences Center Lubbock, Tx 79430 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-JUL-2004 Summary: Angiogenesis is important for vascular remodeling and is strictly controlled under normal conditions. In pathological states such as cancer and diabetes, angiogenesis is altered. The process of angiogenesis requires growth and invasion/migration of endothelial cells through extracellular matrix proteins. Microvascular endothelial cells are exposed to an acid and anoxic environment, conditions that are unfavorable for growth and survival. Thus it is paradoxical that microvascular endothelial cells grow under these conditions. It is known that the extracellular environment of tumors is acidic and anoxic, yet these cells grow and survive in this hostile environment. A vacuolar type proton ATPase (pmV-ATPase) has been identified in highly invasive and metastatic tumor cells. The cells utilize pmVATPase to maintain an aalkaline cytosolic pH permissive for growth. Because microvascular endothelial cells also invade and migrate through extracellular matrix proteins, it is hypothesized that microvascular endothelial cells exhibit pmV-ATPase that is greater at the invading/leading edge of the cells, and that pmV-ATPase activity is
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exacerbated by chronic acidosis. It is also hypothesized that pmV-ATPase is decreased in microvascular endothelial cells from diabetic models where angiogenesis is impaired. To test these hypothesis, pmV-ATPase will first be analyzed in microvascular endothelial cells by evaluating the role of pmV-ATPase for pHcyt regulation using timeresolved fluorescence spectroscopy and ion substituion/pharmacological approaches. The presence of this pump's activity at the plams membrane will be analyzed by immunocytochemistry, immunogold electron microscopy and Western blot analyses of subcellular fractions. The relevance of pmV-ATPase at the leading edge of the cell will be understood by studying pHcyt regulation in single cells from leading to lagging edge using line scanning laser confocal resolution respectively. The physiological relevance of pmV-ATPase will be evaluated using in vitro invations mibration assays, in vitro angiogenesis models and the wounded monolayer model. This will be done in the presence and absence of V-ATPse inhibitors. The relevance of pmV-ATPase in angiogenesis and diabetes will be understood by using microvascular endothelial cells from a spontaneous model of diabetes with inborn defects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BICARBONATE TRANSPORT BY THE MATURING RENAL TUBULE Principal Investigator & Institution: Schwartz, George J.; Professor; Pediatrics; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-JUL-1990; Project End 30-JUN-2004 Summary: (Adapted from the Applicant's Abstract): Membrane-bound carbonic anhydrase (CA) is essential for HCO transport in the proximal tubule and collecting duct. Clinically, problems in neonatal renal acidification may be due to delayed membrane CA expression. Membrane CA includes CA isoform IV, which is anchored to the luminal membrane via a glycosylphosphatidylinositol (GPI) linkage. However, two anti-CA IV peptide antibodies show that CA IV is expressed on both apical and basolateral membranes of the proximal tubule, the latter not expected for a GPIanchored protein. Other membrane CA isoforms (CA XII, and XIV), could reside on the basolateral membrane and cross-react with these antibodies. The identity of the basolateral CA, the mechanisms for its targeting, and its regulation during acidosis and development will be examined in rabbit kidney. Aim 1 is to determine which CA isoform resides in the basolateral membrane of the proximal tubule. A PCR-based approach will be used to obtain cDNA probes for CAs XII, and XIV in rabbit. Peptides will be prepared from these sequences to test specificity of the CA IV antibodies and to generate CA XII- and XIV-specific antibodies. Another anti-CA IV peptide antibody (with no homology to CAs XII or XIV) will be made. The apical basolateral CAs will be compared and characterized. Aim 2 examines the targeting of membrane CAs. Membrane CA cDNAs will be FLAG-tagged and transiently transfected into immortalized mouse proximal tubule cells. The polarity of expressed membrane CAs will be examined and compared with the targeting of the C-terminus. This will establish whether GPI-linkage confers apical polarity and the C-terminal hydrophilic segment confers basolateral polarity to the membrane CA. The regulation of these CAs in response to metabolic acidosis and maturation will also be examined. Aim 3 investigates physiologic correlations. The presence of basolateral CA activity on HCO transport and cell pH will be examined in perfused proximal tubules. The regulation of basolateral CAs in response to acidosis and development will be studied. Finally, the mechanisms by which acidosis causes resistance to CA inhibition will be studied in outer medullary collecting ducts, which absorb HCO despite a luminal disequilibrium
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pH. The objective is to better understand the role of membrane carbonic anhydrases (CAs) in mediating renal acid-base transport. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOCHEMICAL DEFICIENCIES
GENETICS
OF
CARBONIC
ANHYDRASE
Principal Investigator & Institution: Sly, William S.; Chairman and Professor; Biochem and Molecular Biology; St. Louis University St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 30-NOV-2003 Summary: The twelve known carbonic anhydrases (CAs) and CA-related proteins (CARPs) play important roles in diverse physiological processes including respiration, bone resorption, renal acidification, gluconeogenesis, signal transduction, and formation of cerebrospinal fluid and gastric acid. The recently discovered CA IX and CA XII are related to oncogenesis and are over-expressed in certain cancers. The broad goal of this research is to study the functional genomics of this gene family to determine the importance of individual members to health and disease. We have five specific aims: 1. Complete studies characterizing the biochemical and molecular genetics of CA II deficiency. CA II deficiency is the basis for the human inborn error of metabolism producing osteopetrosis, renal tubular acidosis, and brain calcification, novel studies are also proposed on the CA II-deficient mouse. 2. Characterize the mouse doubly deficient for CA II and CA IV and determine what other CA in kidney compensates for CA IV deficiency. CA IV is the GPI-anchored membrane CA on surfaces of epithelial cells in kidney and gut and of capillary endothelial cells. The CA IV null mouse lacks the expected renal defect. 3. Characterize the CA VA gene knockout mouse, the newly discovered CA Vb, and candidates for CA V deficiency. CA VA is the mitochondrial CA thought to be involved in gluconeogenesis and ureagenesis. 4. Characterize CA IX and define its role in the regulation of cell proliferation and in oncogenesis. CA IX is a tumor-associated CA that is over-expressed in several cancers and expressed in normal stomach. 5. Characterize the properties and the functional genomics of CA XII. CA XII is a newly discovered, transmembrane CA that is over-expressed in several cancers and expressed in normal kidney and intestine. These studies should enhance our understanding of how thee individual carbonic anyhydrases contribute to normal physiology, how single CA deficiencies produce disease, and why the newly discovered CAs IX and XII are over-expressed in certain cancers, and should also suggest new targets for isozyme-specific CA inhibitors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CELL ADHESION MOLECULES IN CEREBRAL MALARIA. Principal Investigator & Institution: Van Der Heyde, Henri C.; Microbiology and Immunology; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, La 71103 Timing: Fiscal Year 2002; Project Start 01-JUL-1997; Project End 31-AUG-2002 Summary: (provided by the applicant): Despite decades of effort to conquer malaria, it remains a leading cause of death due to a single infectious agent. The advent of drugresistance by Plasmodium falciparum and insecticide resistance by the mosquito vector jointly makes development of therapy against malaria highly desirable. While a vaccine to prevent infection is a laudable goal, the development of therapy to control the pathological consequences of malaria may represent a more achievable solution. To develop such a therapy, we need a detailed understanding of the pathophysiology of malaria. Results from clinical studies of P. falciparum patients indicate that these
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Acidosis
individuals develop impaired consciousness with posturing (cerebral malaria), respiratory distress with lactic acidosis, anemia and (rarely) acute nephritis. Development of shock is, according to the WHO, a prognostic indicator of poor outcome. In addition, patients with P. falciparum have activated endothelium with increased expression on endothelium of a number of cell adhesion molecules (CAMs). Collectively these findings indicate that the processes of circulatory shock are occurring in patients with P. falciparum malaria. Recent work from our laboratory indicates that P. berghei-infected mice, a well-recognized model of cerebral malaria, also develop circulatory shock and respiratory distress with lactic acidosis. This model is therefore useful to mechanistically dissect the role of CAMs in the development of cerebral malaria and respiratory distress. We will use the recently developed dual radiolabel technique to assess CAM expression on endothelium and flow cytometry to assess CAM expression on T cells during P. berghei malaria. CAMs with increased expression during P. berghei malaria will be tested for their role in cerebral malaria and respiratory distress by using CAM0/0 and anti-CAM mAb-treated mice. Pro-inflammatory cytokines are often needed to increase CAM expression, so we will determine whether selected pro-inflammatory cytokines function in pathogenesis of malaria by regulating CAM expression. Our preliminary data indicate that both CAMs and pro-inflammatory cytokines are indeed required for pathogenesis of P. berghei malaria. We will test whether inhibition of an intracellular signaling pathway (specifically NF-?B) abrogates cerebral malaria and respiratory distress by preventing increased CAM expression and T cell adherence to endothelium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CELL CYCLE PROTEINS IN RENAL GROWTH, INJURY, AND REPAIR Principal Investigator & Institution: Preisig, Patricia A.; Professor; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-JUL-2005 Summary: Renal epithelial cells are normally quiescent, but can increase their growth rate. In some situations, such as following an acute renal injury, the cell growth is essential to repairing the damaged epithelium, and appears tightly regulated. In contrast, unregulated, and ultimately destructive, growth occurs in renal cancer, polycystic kidney disease, and the progressive loss of renal function associated with loss of renal mass, diabetes mellitus, and most forms of glomerular injury. The growth changes that occur involve both hyperplasia (resulting in an increase in cell number) and hypertrophy (resulting in an increase in cell size). Using in vitro systems, two mechanisms of renal epithelial cell hypertrophy have been characterized; One involves regulation of the cell cycle process (referred to as being cell cycle-dependent) and is mediated by growth factors and cytokines, and the other is independent of cell cycle processes and mediated by agents that alkalinize intravesicular compartments, such as NH4C1. Using in vivo renal growth models, we have shown that: 1) Compensatory renal growth following uninephrectomy is a hypertrophic growth process that involves primarily activation of cyclin D kinase, without an increase in BrdU incorporation, and is not affected by inhibiting ammoniagenesis, suggesting that a cell cycle-dependent mechanism is involved; 2) Diabetes-induced renal growth involves an initial hyperplastic growth phase associated with activation of both G, kinase and an increase in BrdU incorporation, followed by a hypertrophic growth phase associated with continued activation of cyclin D kinase, inhibition of cyclin E kinase, and inhibition of BrdU incorporation; 3) The renal growth associated with chronic hypokalemia can be
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reversed when ammoniagenesis is inhibition by an alkaline diet, suggesting a cell cycleindependent mechanism of growth; and 4) In transgenic mice in which the endothelin B receptor has been knocked out, uninephrectomy does not lead to hypertrophy. Aim 1 will continue to characterize the role of cell cycle proteins in compensatory renal growth. Aim 2 will focus of diabetes-induced hypertrophy. Studies will examine the regulation of the cell cycle proteins in the switch between a hyperplastic and hypertrophic growth pattern. Studies will be done in 3 models of diabetes mellitus: streptozotocin-induced type I, in Nod mice (type I), and in db/db mice (type II). Studies will also be done to determine the role of the endothelin B receptor in diabetes-induced renal growth. Aim 3 will determine the mechanisms involved in the activation of cyclin D kinase and inhibition of cyclin E kinase in cell cycle-dependent hypertrophy. Aim 4 will determine if the endothelin B receptor plays a role in chronic metabolic acidosis and chronic potassium deficiency, models of renal hypertrophy thought to be mediated by the cell cycle-independent mechanism. Together these studies will afford us the opportunity to determine if direct regulation of cell cycle processes provides an avenue for therapeutic advances that will either improve upon the beneficial effects or reduce the detrimental sequelae of renal injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CELLULAR MECHANISMS OF MEDULLARY SEROTONERGIC NEURONS DURING DEVELOPMENT Principal Investigator & Institution: Richerson, George B.; Associate Professor; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2003; Project Start 07-JUL-2003; Project End 31-MAR-2008 Summary: The overall goal of this program is to define the cause of SIDS. With the recent discovery of abnormal LSD binding in the medulla of SIDS infants, we have focused our efforts on the medullary serotonergic system, to define what specifically happens to serotonergic neurons to cause them to malfunction. The goal of Project 5 is to define the cellular properties of serotonergic neurons, as a means of providing a neurobiological explanation for the link between serotonin and SIDS. We have previously demonstrated that serotenergic neurons closely apposed to large arteries in the rat ventral medulla increase their firing rate in response to acidosis, and we have proposed that they are chemoreceptors that stimulete breathing, arousal and other CNS changes to restore pH homeostasis: We now plan to use a rat model to determine whether the cellular properties of serotonergic neurons can explain the three risk factors in the Triple Risk Model for SIDS. We wiil use a combination of multielectrode arrays and patch clamp recordings from serotonergic neurons in culture and in brain slices. We will: 1) Study how different subsets of serotonergic neuron respond to acidosis, hypoxia, temperature and glucose. 2) Examine how muscarinic receptor activation leads to enhancement of chemoreception. 3) Define the changes in chemosensitity of serotonergic neurons as they undergo development. 4) Determine the effects of acute and chronic (during pregnancy) nicotine exposure on the function of serotonergic neurons. 5) Compare the cellular properties of serotonergic neurons from rats with those of piglets and mice, and determine whether serotonergic neurons from these species, as well as human infants, are closely associated with large arteries of the ventral medulla. These experiments will provide information critical to a full understanding of the role of serotonergic neurons in brain function, and will lead to specific testable hypotheses about how their malfunction or maldevelopment could lead to death during sleep. URimately, the results of these experiments may provide important insights that could lead to diagnostic and therapeutic tests for those infants at highest risk of SIDS.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CEREBRAL ISCHEMIA IN THE FEMALE Principal Investigator & Institution: Hurn, Patricia D.; Professor and Vice Chairman for Research; Anesthesiology/Crit Care Med; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-FEB-1995; Project End 31-JAN-2004 Summary: In this animal research protocol, the investigators propose to ascertain the cerebral blood flow and metabolic effects of the presumed neuroprotective female hormones during and following global cerebral ischemia. Specifically, the proposed study will determine the effect of global cerebral ischemia on cerebral blood flow (CBF), energy metabolism, and pial vessel reactivity in female animals compared to their male counterparts. The investigators also will evaluate whether or not the female hormone, beta- estradiol, plays an important role in recovery mechanisms from ischemia. Unneutered males also will be studied to determine if there are important gender-specific recovery responses during ischemia/reperfusion and if any therapeutic benefit from reproductive steroid administration is limited to females. The proposed experiments will explore two specific mechanisms of ischemic injury in vivo; specifically, 1) acidosis leading to depressed recovery of energy metabolism, loss of pH regulation, and related iron- catalyzed oxidant injury; and 2) microvascular endothelial dysfunction. To study these variables, the investigators will use magnetic resonance (MR) spectroscopy and intravital microscopy to determine if estradiol acts via specific cellular mechanisms. Four Specific Aims are presented. In Specific Aim #1, the investigators will test the hypothesis that ischemic acidosis is less in females, with consequently more complete recovery of brain energy phosphates compared to males; and that chronic estrogen therapy further improves post-ischemic recovery of energy metabolism and intracellular pH. Specific Aim #2 will examine the effect of pre-ischemic hyperglycemia and its consequent exaggerated tissue acidosis on metabolic recovery, testing the hypothesis that the anti- oxidant activity of estradiol decreases vulnerability to hyperglycemiamediated reperfusion injury. Intravital microscopy will be employed in Specific Aim #3 to determine if post-ischemic pial vessel reactivity to endothelium-dependent pharmacologic agents is impaired in females and estradiol-treated animals. Finally, Specific Aim #4 will test the hypothesis that chronic estradiol therapy increases brain cGMP, nitric oxide synthase activity and pial vessel responsivity to NO-mediated agents in a dose-dependent manner. The information derived from these experiments should contribute to our understanding of vascular function in females at decreased risk for cerebrovascular disease relative to males and of the role of estrogen as potential neuroprotective therapy for patients of either sex. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CHARACTERIZATION OF A NEW FAMILY OF PROTEIN KINASES Principal Investigator & Institution: Popov, Kirill M.; Assistant Professor; Molecular Biology and Biochem; University of Missouri Kansas City Kansas City, Mo 64110 Timing: Fiscal Year 2002; Project Start 01-JUL-1995; Project End 30-JUN-2004 Summary: (From the application abstract:) The mitochondrial pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate, the reaction that determines the metabolic fate of carbohydrates. The enzymatic activity of the mammalian PDC is regulated by reversible phosphorylation. The specific kinase (pyruvate dehydrogenase kinase or PDK) converts it to an inactive form that can be
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reactivated only by a specific phosphatase. The hyperphosphorylation of PDC observed in diabetes, ischemia, and metabolic acidosis directly contributes to the morbidity and mortality associated with these conditions. It is generally believed that the hyperphosphorylation is due, in part, to enhanced kinase activity. Recently this laboratory provided the first data indicating that, in humans and other mammals there are multiple isoenzymes of PDK. The physiological significance of multiple isoenzymes is currently unknown. The results available thus far strongly suggest that the isoenzymes are functionally different. The isoenzyme PDK2 is likely to be responsible for the * short-term regulation of PDC activity. The inducible isoenzyme PDK4, in contrast, may be mainly responsible for long-term control. Its over-expression in diabetes is likely a leading cause of the hyperphosphorylation of PDC that, in turn, contributes to hyperglycemia. This proposal is aimed to further elucidate the structure, function, regulation and physiological significance of the multiple isoenzymes of PDK. Its major goals are: 1) to determine the three dimensional structure of pyruvate dehydrogenase kinase; 2) to elucidate the molecular basis for catalysis and substrate recognition by pyruvate dehydrogenase kinase; 3) to further define the molecular mechanisms responsible for regulation of pyruvate dehydrogenase kinase activity; 4) to characterize the molecular interactions between isozymes, as well as between isozymes and pyruvate dehydrogenase complex under normal conditions, as well as under starvation and diabetes. These goals will be achieved though a combination of structure/functional analysis, biochemical characterization, as well as more physiologically oriented studies of isozymes under conditions such as starvation and diabetes. This will allow us to understand how this structurally unique protein kinase functions. It will also allow us to take the first step towards the design of isoenzymespecific drugs that may alleviate some of the symptoms and prevent complications associated with diabetes, ischemia and acidosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNDROME
CLONIDINE
TREATMENT
FOR
NEONATAL
ABSTINENCE
Principal Investigator & Institution: Gauda, Estelle B.; Associate Professor; Pediatrics; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2006 Summary: (provided by applicant): In the United States, as many as 20,000 babies a year are born to opioid ("narcotic") addicted mothers. Like their mothers, these infants are opioid dependent. Following birth, the infant is removed from its opioid source, inducing a withdrawal syndrome in these infants. Withdrawal symptoms in newborns include vomiting, diarrhea, poor feeding, tachycardia, hypertension, diaphoresis, restlessness, insomnia, irritability, tremors, clonus, hyperphagia with poor growth and acidosis, reversible neurologic abnormalities, and even seizures. This complex of signs and symptoms is referred to as neonatal abstinence syndrome (NAS). Reinstitution of opioids followed by a slow tapering protocol is currently the standard of care, necessitating prolonged hospitalization from weeks to months. Clonidine is a nonnarcotic central alpha2-adrenergic receptor agonist that blocks the effects of overexcitation of the sympathetic nervous system and is an approved treatment for opioid withdrawal in adults. We currently have a physician sponsored IND (#63,781) to study the effect of clonidine as adjunct therapy to opioids for the treatment of NAS. This proposal will test the hypothesis that combination therapy of clonidine and opioids is 1) safe and efficacious, 2) allows reduced amount of opioid drug use, and 3) results in shorter time of treatment and hospitalization. This will be accomplished in a
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Acidosis
randomized, placebo controlled double blind clinical trial comparing diluted tincture of opium (DTO) combined with a placebo (control) vs. DTO combined with clonidine. Additional sub-studies include determination of 1) pharmacokinetics and pharmacodynamics of DTO and clonidine in the enrolled cohort and 2) further safety evaluation by evaluating developmental outcome on the Bayley Scale of Infant Development (BSID) at 6 and 12 months of age. Pharmacokinetics will be determined by measuring serum concentrations of clonidine and morphine and analyzing volume of distribution, elimination half-life and clearance. These results will have important clinical implications and may change the standards of care not only for management of infants with severe NAS, but also for the management of infants and children, after long-term iatrogenic opioid exposure for instance following prolonged analgesia for mechanical ventilation or multiple operations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTROL OF BREATHING DURING PHYSIOLOGIC CONDITIONS Principal Investigator & Institution: Forster, Hubert V.; Professor; Physiology; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-JUN-1986; Project End 31-MAY-2005 Summary: Several theories on the neural control of breathing that were based on data from reduced preparations were not supported by our recent findings in awake and asleep goats on the effects of rostral medullary neuronal dysfunction and/or carotid body denervation (CBD). Some findings mimicked the altered breathing found in obstructive sleep apnea (OSA) and congenital central hypoventilation syndrome (CCHS). The mechanisms that mediated these effects are not established, but one likely mechanism is through intracranial chemoreceptors for years thought to exist only near the ventral medullary surface (including the retrotrapezoid nucleus RTN)). However, findings in reduced preparations of chemoreceptors at widespread brain sites have raised questions related to the location and role of chemoreceptors that affect breathing in awake and asleep states and whether brain chemoreceptor sensitivity is altered by CBD. One recently identified site of chemoreception is the medullary raphe nuclei (MRN) whose role in the control of breathing during awake and asleep states remains speculative. Accordingly, to study chemosensitivity and the role of the RTN and MRN in the control of breathing, we will implant microtubules into these nuclei of goats to: a) create a focal acidosis by dialysis of mock cerebrospinal fluid with different PCO2's, or b) induce neuronal dysfunction through injection of glutamate or serotonin receptor antagonists or agonists, or a neurotoxin. Major hypotheses are: 1) focal acidosis (equivalent to that breathing 7 percent inspired CO2, delta brain pH approximately -.05) in the RTN will increase breathing in awake, but not asleep states, while acidosis in the MRN will increase breathing in asleep, but not awake states, 2) at RTN sites where focal acidosis increases breathing, neuronal dysfunction will attenuate whole body CO2 sensitivity, but not alter rest and exercise breathing, 3) neuronal dysfunction in the MRN will attenuate CO2 sensitivity and rest and exercise breathing, 4) during the first 10 days after CBD, the effect of RTN and MRN focal acidosis will be attenuated but 15 plus days after CBD, the effect of focal acidosis will be accentuated. and 5) at most RTN and MRN sites, the acute effects of neurotoxic lesions will be hypoventilation (rest and exercise) and attenuated CO2 sensitivity; the acute effects of these lesions will be greater in CBD than in intact goats, but recovery after lesioning will be greater in intact than in CBD goats. Our unique studies are important because hypotheses generated largely from reduced preparations will be tested in awake and asleep states to enhance the understanding of medullary chemoreceptor contribution to the control of breathing and
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how abnormalities in this contribution may underlie diseases such as OSA, CCHS, and the Sudden Infant Death Syndrome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTROL OF RENAL GLUTAMINASE INDUCTION DURING ACIDOSIS Principal Investigator & Institution: Curthoys, Norman P.; Professor and Chairman; Biochem and Molecular Biology; Colorado State University-Fort Collins Fort Collins, Co 80523 Timing: Fiscal Year 2002; Project Start 01-OCT-1989; Project End 31-MAR-2006 Summary: During chronic metabolic acidosis, increased renal ammoniagenesis and gluconeogenesis from glutamine are sustained, in part, by a cell specific increase in expression of the mitochondrial glutaminase (GA) that results from the selective stabilization of the GA mRNA. Previous experiments identified an 8-base AU- sequence within the 3'- non-translated region of the GA mRNA that functions as a pH-response element (pHRE) when introduced into a chimeric reporter mRNA. This sequence was used as an affinity ligand to purify and identify zeta-crystallin/NADPH; quinone reductase as the pHRE-binding protein. The functional characterization of the pHRE was carried out in LLC-PK1-FBPase+ cells, a porcine proximal tubule-like cell line that expresses multiple forms of GA mRNAs. The corresponding porcine GA cDNAs were cloned and sequenced. Only the 4.5-kb GA mRNA contains pHREs that are identical to the sequence identified in the rat GA mRNA and only this form of GA mRNA is stabilized and increased by incubating the cells in acidic medium (Ph=6.9, 10 mM HCO3). Thus this cell lines provides a system to further characterized the molecular mechanism of GA mRNA stabilization and the associated signal transduction pathway. Finally, the 4.50kb GA mRNA is the ortholog of a newly identified isoform of the human kidney-type GA that is generated by alternative splicing of exons within the GA gene. This isoform contains a unique C-terminal domain of unknown function. The specific aims of the proposed research are: to express and characterize the isoforms of the kidney-type GA; to characterize the mechanism of GA mRNA turnover; to characterize the role of zeta-crystallin/NADPH; quinone reductase in the stabilization of the GA mRNA; and to identify the signal transduction pathway that leads to enhanced binding of zeta-crystallin/NADPH; quinone reductase to the pHRE. The results of the proposed experiments should significantly increase the understanding of the molecular mechanism that regulates this essential adaptive response and may provide insight to improve the clinical treatment of chronic acidosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORE--LABORATORY OF INTEGRATED KIDNEY FUNCTION Principal Investigator & Institution: Wang, Tong; Research Scientist; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-DEC-2003; Project End 30-NOV-2008 Summary: Recently, the use of genetically altered animal models became an important tool to examine the contributions of individual channels, transporters and proteins to the maintenance of physiological function and pathophysiology of disease. We are now able to perform renal clearances and in vivo and in vitro tubular microperfusion studies in mice. These techniques will be used to gain insight into the physiological role of specific transporter proteins to tubule and overall renal function. To facilitate the goal of the Program Project to extend our fundamental knowledge about cellular and molecular
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Acidosis
mechanisms regulating renal tubular function in normal and diseased states, we propose to continue the Small Animal Physiology Core, with the following specific aims: (1) Provide a variety of rat and mouse animal models, such as adrenalectomy and hormone replacement, metabolic or respiratory acidosis and chronic diuretic treatment (furosemide, thiazide). (2) Provide a metabolic measurement of plasma and urine electrolytes and examine the dietary modulations in different animal models, including knockout and mutant mice provided by each PI. (3) Perform renal clearance experiments in rats and mice to examine renal phenotypes in mutant animals and to assess the physiological roles of ion channels, proteins and transporters, such as ENaC, ROMK, CFTR and NKCC2. (4) Measure arterial blood pH, pCO2 and HCO3- and urine pH and HCO3- to evaluate the acid-base status in these animals. (5) Perform in situ microperfusion of the proximal tubule and loop of Henle of rat and mouse to assess segmental tubular function and measure electrolyte content of nanoliter sized samples (Na+, K+, Cl-, total CO2, Ca2+ and Mg2+) of tubular fluid collected from these different sites. (6) Perform in vitro microperfusion of isolated proximal tubule and collecting tubule to examine the electrolyte transport in these segments. (7) Measure tubular absorption of proteins such as albumin to investigate endocytosis-related tubular functions. This core will be utilized by most of the PPG projects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CSF AND THE CENTRAL CHEMICAL CONTROL OF BREATHING Principal Investigator & Institution: Nattie, Eugene E.; Professor of Physiology; Physiology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 01-DEC-1981; Project End 31-MAY-2004 Summary: Appropriate breathing requires 1) feedback concerning the level of CO2 from central chemoreceptors, and 2) a tonic 'drive', partly from CO2, and partly from other sources including the rostral ventrolateral medulla (RVLM). Recent work established that 1) central chemoreception is present at many brainstem locations, and 2) the retrotrapezoid nucleus (RTN) is a key RVLM site that provides both chemoreception and a tonic drive to breathe. We ask: Why are there so many central chemoreceptor sites? How do they work? What is the physiological role of the RTN in the control of breathing? We will evaluate chemoreceptor and RTN function during sleep and wakefulness in a chronic unanesthetized rat model using a microdialysis probe to deliver substances to the RTN (or other site). The probe tip is 1 mm in length and 240 mum in diameter, a volume of 45 nl. It allows repeated application of neuroactive substances at the same site in the same animal with continuous measurement of ventilation and oxygen consumption (whole body plethysmograph), arousal state (EEG, nuchal EMG), body temperature and blood pressure (telemetry), and, in some cases, blood gases and pH. Approximately 2/3 of the experiments use this model; 1/3 an anesthetized, ventilated rat with phrenic activity as the measure of respiratory output. For studies of chemoreception physiology, we produce focal tissue acidosis by CO2 microdialysis in both models. For studies of mechanism, we alter neural function by injection/dialysis within the focal region of acidosis in the anesthetized rat. For studies of the RTN, we inhibit neurons reversibly by dialysis with muscimol, a GABA-A receptor agonist, in the chronic model. Central chemoreceptor physiology is significant; CO2 is a key component of the respiratory control system and CO2 retention in disease causes morbidity. Chemoreception and RTN function vary with arousal state, and thus are likely to be important in sleep disordered breathing, and the RTN is hypothesized to be an animal homologue for the arcuate nucleus, described as abnormal in SIDS victims. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EFFECTS OF ACID ON BONE Principal Investigator & Institution: Bushinsky, David A.; Professor of Medicine and Physiology; Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: Metabolic acidosis, present during many clinical disorders, has significant effects on bone. The proposed studies are designed to test hypotheses relating to the effects of increases in proton concentration ([H+]), acidosis, on the ionic composition of bone mineral and on bone cell function. We propose to study how acidosis affects mass spectroscopy and to study how acidosis alters signal transduction pathways and bone cell expression. With the microprobe we obtain sensitive, mass resolved images and spectra of the ionic composition of bone mineral. We propose three Specific Aims: 1) To test the hypothesis that there are specific changes in bone ion composition with respect to time and location after exposure to acidosis. To pursue this aim we will test the hypothesis that in vivo acidosis initially causes a preferential loss of mid-cortical bicarbonate, Na and K due to physicochemical dissolution, with subsequent additional loss of phosphate due to cell-mediated resorption. We will test the hypothesis that the magnitude of H+ buffering by bone increases with age as the carbonate content increase and the phosphate content decreases and that there are labile pools of Ca and K preferentially released during in vivo acidosis. We will test the hypothesis that mice deficient in osteopontin (OP), matrix gla protein (MGP) or c-src have altered basal bone ion composition and an altered osseous response (Jca and JH) to acidosis. 2) To test the hypothesis that the mechanism of acid-induced cell-mediated bone resorption involves activation of signal transduction pathways such as protein kinase A (PKA), protein kinase C (PKC) and/or mitogen-activated protein kinase (MAPK) by using specific inhibitors of PKA and PKC and measurements of PKA, PKC and MAPK during acidosis. 3) To test the hypothesis that metabolic acidosis selectively inhibits osteoblastic extracellular matrix gene expression via distinct transcriptional mechanisms, by testing acidosis effects on OP and MGP RNA transcription initiation. We will identify sequences in the mouse OP and MGP genes which are capable of conferring pH dependence to a reporter gene. These Specific Aims are interrelated as the effects of acidosis at the level of the gene lead to alterations in bone cell function which subsequently alter bone mineral. Our long term goal is to develop a model to describe how acidosis affects bone in order to devise therapy to preserve mineral while maintaining the H+ buffering properties of bone. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EFFECTS OF ACIDOSIS ON EXERCISE INDUCED MUSCLE PROTEIN SYNTHESIS Principal Investigator & Institution: Johansen, Kirsten L.; Assistant Professor; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EFFECTS OF BIER BLOCK W/ BRETYLIUM ON RHYTHMIC FOREARM EXERCISE Principal Investigator & Institution: Sinoway, Lawrence I.; Professor of Medicine; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390
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Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: The goals of this study are to determine if the withdrawal of sympathetic tone leads to greater blood flow to exercising muscle. We will also determine if this greater flow leads to less muscle acidosis and less sympathetic discharge. We will also determine if in subjects with heart failure, the effects of sympathetic withdrawal are greater than they are in age matched controls. We hypothesize that in heart failure, sympathetic blockade will increase limb flow, reduce muscle acidosis, and attenuate the muscle reflex response to exercise. During the last GCRC period, we have perfected the bretylium bier block procedure. We have studied the effect of this block on limb blood flow during forearm exercise sympathetic discharge, and muscle metabolism. Sympathetic blockade produced a two-fold increase in forearm blood flow and vascular conductance. (P<0.05) both at rest and during hand grip contractions. Hemoglobin saturation was increased 30% at rest following sympathetic blockade but was not different from the control trial during contractions. Similarly, exercise venous plasma lactate, potassium and hydrogen ion concentration were not different following sympathetic blockade. Separate nuclear magnetiic resonance studies indicated that intracellular acidosis was not affected by sympathetic blockade. The data suggest that forearm oxygen uptake and lactate production were both increased two-fold during the bretylium trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EXPRESSION OF TRPV1 AND VARIANT TRPV1 IN THE KIDNEY Principal Investigator & Institution: Cohen, David M.; Associate Professor of Medicine; Medicine; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): TRPV1 is a cation channel that was originally cloned as the capsaicin (or "hot pepper") receptor. TRPV1 is expressed in the peripheral nervous system where it serves to sense and integrate a large number of noxious stimuli such as heat, protons, and lipid mediators. Very recent data indicate that TRPV1 is also expressed in some epithelial cells (e.g., those of the colon, lung, and bladder) and plays a vital role in sensing noxious stressors including wall tension and cellular acidosis. Based upon Northern analysis and RNase protection assays, others have postulated the existence of novel splice variants of TRPV1 expressed only in the kidney. To date, convincing splice variants have not been described in any tissue. In the course of identifying a rat kidney TRPV1 clone, we discovered several novel splice variants of TRPV1 predicted to encode proteins with either small or large C-terminal deletions. These variants were not found in central or peripheral nervous system. In other models, including the related TRPC4 channel, splice variants have encoded dominant negativeacting channel subunits. In addition, we noted anti-TRPV1 immunoreactivity in lysates prepared from renal epithelial MDCK cells; furthermore, this immunoreactivity could be downregulated by protracted treatment with the TRPV1 agonist, capsaicin. Moreover, MDCK cells exhibited robust calcium transients in response to TRPV1 agonists. In aggregate, these data suggested an intact TRPV1 system in kidney tubule cells with unique regulatory features (i.e., splice variants). As such, the first objective is to identify the anatomic and subcellular localization of TRPV1 and of the novel kidneyspecific TRPV1 splice variants in the mammalian kidney, through a combination of immunoblotting, immunohistochemistry, RNase protection, and in situ hybridization techniques. The second objective is to describe the functional significance of variant TRPV1 expression in the kidney, via fura-2-based calcium imaging, protein interaction strategies, and electrophysiological methods. The long-term objectives are to establish
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the sensory role of TRPV1 in the kidney (through a combination of anatomic and functional studies), and to determine whether one of these unique kidney-specific splice products encodes either a channel with unique properties, or an inhibitor or modulator of TRPV1 function. In addition, such a reagent might have potential therapeutic utility with respect to this important pathway mediating nociception. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC CONTROL OF VACUOLAR H+-ATPASE EXPRESSION Principal Investigator & Institution: Lee, Beth S.; Assistant Professor; Physiology and Cell Biology; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-JAN-1997; Project End 30-JUN-2006 Summary: (provided by applicant): The vacuolar proton-translocating ATPase, or VATPase, is a multi-subunit complex that uses energy from ATP hydrolysis to transport protons across cellular membranes. In most eukaryotes, V-ATPases reside solely in membranes of the endocytic network, where they serve to acidify endosomes, lysosomes, the trans-Golgi, and other vacuolar compartments. However, some specialized cell types, including kidney epithelia, osteoclasts, macrophages, and neurons, express the V-ATPase at high levels and in specialized subcellular compartments, where the enzyme is critical for such diverse functions as urinary acidification, bone resorption, regulation of intracellular pH, and regulated vesicular uptake of neurotransmitters. The variety of functions performed by V-ATPases among mammalian cells is attributable to expression of multiple subunit isoforms, differences in overall expression levels, and the capacity for regulated targeting to specialized membrane compartments. Inappropriate expression of V-ATPase in humans has been shown to lead to serious disease states, including renal tubular acidosis, deafness, and osteopetrosis. The genetic controls that regulate V-ATPase expression must be varied and diverse to meet the specific proton-transport needs of many specialized cell types, as well as its constitutive role in the endocytic network. These include both transcriptional and post-transcriptonal mechansims, as well as intracellular targeting of both V-ATPase mRNA and proteins. The long-term goal of this project is to understand the mechanisms by which V-ATPases are expressed at appropriate levels and in appropriate membrane compartments. To this end, the specific aims are directed toward (1) examining mechanisms by which V-ATPase mRNA stability is regulated in protonsecreting cells such as macrophages and kidney epithelia; (2) examining determinants within V-ATPase mRNAs that mediate intracellular trafficking in specialized cell types; and (3) defining genetic elements that control expression of a uniquely regulated VATPase subunit involved in intracellular trafficking. These aims will be achieved through experiments in which V-ATPase mRNAs are genetically manipulated in cell culture models; the effects of these manipulations of V-ATPase expression and cell function will be determined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENETIC CORRECTION OF MATERNALLY INHERITED DISEASES Principal Investigator & Institution: Guan, Min-Xin; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): The objective of this proposed research is to define the role of mitochondrial leucyl-tRNA synthetase and elongation factor TU (EFTU) in the pathogenesis of mutations in the tRNALeu (UUR) that are commonly related to
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human diseases. This second goal of this study is to explore a way to therapeutically intervene for maternally inherited disease by over-expression of these two proteins in the cybrids carrying pathogenic mutations in the tRNA Leu (UUR). A variety of mitochondrial DNA (mtDNA) mutation have been found to be associated with many clinical abnormalities, including neuromuscular disorders. Of the 100 pathogenic point mutations in mtDNA, >70 occur in tRNA genes. Of these, the most common mutation is the A to G transition at position 3243 (A3243G) in the tRNALeu (UUR) gene, which causes mitochondrial encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS) and other disorders. Mitochondria with this mutated tRNA exhibited a reduced ATP production, which results from quantitative deficiencies in mitochondrial protein synthesis. We hypothesize that the over-expression of human mitochondrial leucyl-tRNA synthetase and EFTU in the disease cell model of the A3243G mutation in the tRNALeu (UUR) gene will correct the mitochondrial translational defects, consequently increasing the level of ATP production. This application proposes two specific aims: 1). Construction of the stably transfected cell lines through transferring human mitochondrial leucyl-tRNA synthetase and EFTU cDNAs into the cybrid cell lines carrying the A3243G mutation and wild type mtDNA. 2). These stably transfected cell lines will be evaluated for the correction of mitochondrial dysfunction by using biochemical and metabolic assays. Success of this protection will define the role of the mitochondrial leucyl-tRNA synthetase and EFTU in the pathogenesis of mutations in the tRNALeu(UUR) gene associated with human diseases. This should provide new insights into the molecular mechanism of maternally inherited disorders. In particular, success in the aim of correcting the biochemical defect associated with A3243G mutation in the tRNA Leu (UUR) gene by overexpressing mitochondrial leucyl-tRNA synthetase, will open the way to therapeutic interventions for maternally inherited diseases. In the long term, fundamental experimental approaches and knowledge, which results from this proposed work would be applicable to many other tRNA gene mutations, associated diseases in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GLUTARYL-COA DEHYDROGENASE AND NEUROLOGIC DISEASE Principal Investigator & Institution: Frerman, Frank E.; Professor of Pediatrics and Of; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 10-DEC-1999; Project End 30-NOV-2003 Summary: Defects in the flavoprotein, glutaryl-CoA dehydrogenase (GCD), cause glutaric aciduria type I (GA1), an autosomal recessively inherited neurometabolic disorder. GCD catalyzes the alpha, beta dehydrogenation of glutaryl-CoA by a mechanism which is common along acyl-CoA dehydrogenases. GCD also catalyzes the decarboxylation of the enzyme- bound intermediate, glutaconyl-CoA, to crotonyl-CoA and CO2. Decarboxylation of glutaconyl-CoA requires oxidation of the dehydrogenase flavin and protonation of the proposed crotonyl-CoA anion (-CH2=-CH=-CH=COSCoA). In patients with defects in GCD, the onset of neurological symptoms in GA1 patients usually follows a viral injection early in life. Over 50 missense mutations have been identified that may affect oxidation and decarboxylation of glutaryl-CoA. These mutations may also affect assembly or stability of the tetramer, the oxidation-reduction potential of the dehydrogenase flavin or reoxidation of the dehydrogenase flavin by electron transfer flavoprotein (ETF). The proposed research has the following specific aims. [1] A number of mutant alleles will be expressed and the defective proteins characterized by kinetic and redox methods to access the basis of the enzymatic defects.
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[2] We will investigate the coupling of glutaryl-CoA oxidation with decarboxylation/protonation of the enzyme bound intermediate, glutaconyl-CoA, using site directed mutations hypothesized to uncouple these steps in catalysis. The crystal structure of GCD with a bound glutaryl-CoA analog and with the reaction intermediate, glutaconyl-CoA, will be determined to provide insight into the decarboxylation reaction. [3] We will investigate the decarboxylation of glutaconyl-CoA directly and define the roles of specific amino acids in the reaction. The participation of the 2'-hydroxyl of the ribityl side chain of the FAD prosthetic group in stabilization of decarboxylation/protonation intermediates will also be determined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: H,K,ATPASE FUNCTION IN POTASSIUM HOMEOSTASIS Principal Investigator & Institution: Wingo, Charles S.; Professor of Medicine and Physiology; Medicine; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 01-AUG-1996; Project End 31-JUL-2004 Summary: The long-range goal of this research is to examine the role of H,K-ATPases in potassium homeostasis and to determine how these ion-motive pumps are regulated by ion channels. H,K-ATPases are important for renal potassium conservation, but it is now apparent that the kidney possesses several different H,K-ATPase enzymatic activities which likely reflect the presence of multiple gene products. Experiments in Specific Aim 1 will determine the molecular identities of the H,K-ATPase subunit isoforms that are responsible for specific enzymatic activities, and for potassium and proton flux in discrete nephron segments, by the study of animals with targeted gene disruption of the H,K-ATPase HK-alpha-1, HK-alpha-2, or HK-beta genes. Experiments in Specific Aim 2 will examine whether knockout of HK-alpha-1, HK-alpha-2, or HK-beta subunits affects the normal anatomy of the kidney or the morphological response to potassium depletion. Experiments in Specific Aim 3 will characterize fully the newly discovered potassium-permeable ion channels that are present at the apical membrane of the inner stripe of the outer medullary collecting duct (OMCD), and the cell types that contain these channels. These channels exhibit novel properties since they appear to be stimulated by cellular acidification whereas most potassium channels are inhibited by acidosis. The proposed experiments are intended to establish the contribution of each of these genes to an important adaptive response (potassium depletion), the compensatory renal response to the disruption of these genes, and whether these genes are involved in the normal morphology of the kidney or its response to potassium depletion. Since accruing evidence indicates that modest potassium depletion causes or contributes to systemic arterial hypertension, and may contribute to chronic renal insufficiency, these studies area expected to contribute to our understanding of the role of potassium depletion as a risk factor for both renal and cardiovascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: H/HCO3 TRANSPORT IN THE COLLECTING DUCT Principal Investigator & Institution: Weiner, I. David.; Associate Professor; Medicine; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2003; Project Start 01-AUG-1993; Project End 31-MAY-2007 Summary: (provided by applicant): Ammonia metabolism is critical for normal health. Inappropriate ammonia metabolism in the kidney leads to metabolic acidosis and in the liver leads to ammonia encephalopathy. In the central nervous system increased extracellular ammonia alters neuronal function and can lead to encephalopathy.
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Accordingly, understanding the cellular and molecular mechanisms of ammonia metabolism, which includes ammonia transport, is important. Recent studies have identified a novel family of ammonium ion (NH4+)-specific transporters. These proteins were first identified in yeast and in plants, and homologues are present throughout nature. In model systems, such as yeast, plants and bacteria, these are intrinsic membrane proteins that mediate high-affinity, ammonium-specific transport and whose expression is physiologically regulated. Two of these proteins, RhBG and RhCG are expressed in the connecting segment and the collecting duct of the kidney, and exhibit polarized expression. These observations lead us to postulate that RhBG and RhCG are integral membrane, physiologically-regulated ammonium-ion transporters that play critical roles in renal ammonia metabolism. The broad, long-term objectives of this project are to define the roles of RhBG and RhCG in mammalian renal physiology. To do so, the Specific Aims of the current proposal are to: (1) Define the regulation of mouse renal RhBG and RhCG expression and vesicular trafficking in response to specific clinical conditions associated with altered renal ammonia metabolism; (2) Determine the mechanism of extracellular ammonia-stimulated changes in RhBG- and RhCG-mediated ion transport; and, (3) identify the specific ion-transport characteristics of RhBG and RhCG. We will utilize in vivo animal models of altered renal ammonia metabolism, metabolic acidosis and alkalosis and hypokalemia, to define the regulation of RhBG and RhCG expression and cellular localization, a cultured collecting duct cell line, mIMCD-3, for in vitro studies examining the cellular mechanisms underlying regulation of RhBG and RhCG-mediated transport, and heterologous expression systems in which to define the specific ion transport characteristics of RhBG and RhCG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HMG-COA CYCLE CONTROL IN NORMAL AND DIABETIC LIVER Principal Investigator & Institution: Miziorko, Henry M.; Professor; Biochemistry; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-APR-1978; Project End 30-JUN-2005 Summary: This program's long term objective is an understanding, at the molecular level, of the mechanisms which control metabolic flux through ketogenesis and the related early steps in cholesterogenesis. Disturbances in the ketogenic pathway can lead to developmental abnormalities as well as ketoacidosis; two inborn errors of metabolism, that have serious medical consequences, mapped within the ketogenic pathway. Likewise, impaired control of cholesterogenesis can produce hypercholesterolemia and the array of problems derived from vascular deposition of excess cholesterol. Enzymes under investigation include hydroxymethylglutaryl-CoA (HMG-CoA) synthase and HMG-CoA lyase will be investigated to elucidate structure/function correlations that account for the catalytic activity and regulatory properties. For each of these, the investigators have developed recombinant proteins and initiated extensive steps in characterizing these proteins. For HMG-CoA synthase, site directed mutagenesis has implicated several active site amino aids in catalysis. Several aims address functional assignments for these and any other residues identified as important to the reaction chemistry. The assignments of roles for these residues will be pursued using mechanistic and physical biochemistry approaches. Expression and functional assignment of prokaryotic proteins that are homologous to animal HMG-CoA synthase will also be explored. Any suitable candidates will be screened in crystallization trials aimed at securing the first diffraction quality crystals for this protein. In the case of HMG-CoA lyase, directed mutagenesis work has implicated amino acids involved in regulation and catalysis. Specific aims to be pursued include
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extension of this approach to new targets implicated by protein chemistry, sequence homology, or mapping of point mutations that result in human HMG-CoA lyase deficiency. The mutants which appear to be a mechanistically informative will be characterized using mechanistic and physical approaches similar to those previously employed in this laboratory to identify catalytic or regulatory residues. The significance of thiol/disulfide exchange, in vitro regulation of peroxisomal HMG-CoA lyase, and in vivo regulation of mitochondrial HMG-CoA lyase will be tested. Crystalization trials will be extended in an attempt to secure diffraction quality crystals of prokaryotic or eukaryotic HMG-CoA lyase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INTERDISCIPLINARY STUDY OF ACID-MEDITATED TUMOR INVASION Principal Investigator & Institution: Gatenby, Robert A.; Radiology; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2006 Summary: (provided by applicant): The proposed study investigates a novel, conceptually simple mechanism for cancer invasion developed by the investigators. Its goal is a fuller understanding of the structure and dynamics of the tumor-host interface through an interdisciplinary approach with continuous interaction between laboratory experiments and the formulation and analysis of mathematical models. This work was initiated by extensive evidence that tumor metabolism is consistently different from normal tissue with increased reliance on glycolytic pathways for energy production. The investigators hypothesized that excess H+ ions excreted by tumor cells would diffuse into the tumor-host interface and adjacent normal tissue creating an acidic microenvironment favorable for tumor invasion because: 1. Normal cells are significantly less tolerant to acidic pile than are tumor cells 2.acidic pHe promotes release of proteolytic enzymes breaking down extracellular matrix facilitating tumor invasion 3. acid pHe increases release of IL8 and VEGF promoting angiogenesis. This hypothesis is formalized through mathematical models using both coupled partial differential equations and a modified cellular automata approach. Critical parameter values in these models such as H+ production and diffusion coefficient have been determine experimentally. This has allowed the mathematical models to produce detailed predictions of the peritumoral acid gradient and the resulting morphology of the tumor-host interface. These predictions have been investigated using a dorsal skin fold chamber technique. Preliminary data measuring pHe using fluorescence ratio imaging (FRIM) has confirmed a gradient of H+ ions extending from the tumor edge into adjacent normal tissue. Using dye exclusion techniques loss of viability has been demonstrated in peritumoral normal cells exposed to the acidic environment - a key component of the hypothesis. The proposed study will extend the experimental observations by comparing the peritumoral pHe gradients and the resulting changes in the peritumoral normal tissue and tumor growth dynamics in the MCF7/s and MDAmb-435 tumor lines which have markedly different acid production rates and in-vivo behavior. The mathematical models will be further refined as additional parameter values can be determined. Perturbations that produce slowing or reversal of the traveling wave solution to the state equations (ie tumor growth) will be explored to predict possible new treatment strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INTRACELLULAR CHEMORECEPTORS
PH
RESPONSES
OF
CENTRAL
Principal Investigator & Institution: Putnam, Robert W.; Professor; Physiology and Biophysics; Wright State University Colonel Glenn Hwy Dayton, Oh 45435 Timing: Fiscal Year 2002; Project Start 01-JUL-1997; Project End 31-JUL-2005 Summary: Increased CO2 (hypercapnia) is a major stimulus for increased respiration and blood pressure. This pathway for cardiorespiratory control involves specialized central neurons, called chemosensitive neurons, that sense hypercapnia, but the cellular mechanisms that transduce hypercapnia into an increased neuronal firing rate are not well understood. Our work will involve the study of individual neurons from at least two chemosensitive brainstem areas (locus coeruleus and either nucleus tractus solitarius or ventrolateral medulla) and at least one nonchemosensitive area (either inferior olive or hypoglossal nucleus) using slices from neonatal rat brains. Simultaneous measurements of neuronal membrane potential (Vm) and intracellular pH (pHi) will be achieved using perforated patch recordings or whole cell recordings (WCR) combined with pH- sensitive fluorescent dyes and fluorescence imaging microscopy. Our first aim is to identify the signal pathways that transduce hypercapnia into an increased firing rate. It will consist of 4 separate aims: i) study the roles of molecular CO2, external pH (pHO) and pHi as the proximate signal of chemoreception by exposing neurons to solutions that vary in each of these parameters; ii) examine the phenomenon of "washout", whereby the Vm response to hypercapnia is lost during WCR measurements, to see if additional signal molecules (e.g. Cai, polyamines or carbonic anhydrase) are also involved in chemoreception; iii) study the "hypoxia paradox" (hypoxia-induced acidification does not appear to increase firing rate in chemosensitive neurons) to see if it is due to the lack of additional signal molecules; and iv) study the changes in the Vm and pHi response to hypercapnia in chemosensitive neurons from rats with reduced chemosensitivity (induced by chronic exposure to hypercapnia). Our second aim is to study the effects of the signals, identified in Aim 1, on various K+ channels and determine the role of each of these channels in modifying the shape of the action potential and neuronal firing rate. Three K+ channels will be studied: i) inward rectifying K+ channels, important in determining the slope of the interspike depolarization and thereby the firing rate of the neuron; ii) Ca2+-activated K+ channels, important in determining the shape of the action potential and the magnitude of the after hyperpolarization; and iii) TWIK-related acid sensitive K+ channels (TASK), important in determining the resting Vm. This work should indicate the precise nature of the proximate signal of chemosensitivity, elucidate the way in which hypercapnic stimuli affect various K+ channels and give insight into how these effects are integrated to result in the final neuronal response. Further, by comparing the findings in neurons from 2 chemosensitive areas, our findings should help clarify why there are numerous chemosensitive regions in the brainstem. These studies will contribute to our understanding of respiratory diseases thought to be due in part to central chemoreceptor dysfunction, such as sudden infant death syndrome (SIDS) and central alveolar hypoventilation syndromes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MAP DYSFUNCTION
KINASES
AND
H202
INDUCED
MYOCARDIAL
Principal Investigator & Institution: Lucchesi, Pamela A.; Professor; Physiology and Biophysics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-JUL-1999; Project End 30-JUN-2003
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Summary: Reperfusion of the myocardium following an ischemic episode is associated with profound contractile and metabolic dysfunction, referred to as myocardial stunning. Reperfusion also increases the activity of the Na+/H+ exchanger (NHE), which restores intracellular pH (pHi) towards normal following ischemia-induced acidosis. However, activation of NHE also produces undesirable secondary effects leading to the exacerbation of tissue injury, a phenomenon termed the "pH paradox". Increased generation of oxygen free radicals (OFR) plays an important role in reperfusion-induced myocardial stunning and NHE activation. An in vitro model for studying the effects of OFRs on cultured neonatal rat ventricular myocytes (NRVM) has been defined, in which low concentrations of H2O2 (similar to those generated during reperfusion) cause contractile dysfunction, Ca2+ overload, and NHE activation. There is considerable interest in identifying signaling events that link H2O2 to myocardial dysfunction. H2O2 and hypoxia activate members of the mitogen activated protein kinase (MAPK) family, including p38, c-jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinases (ERK1/2). Low doses of H2O2 decrease myocyte contractility and stimulate NHE activity in an ERK1/2-dependent manner. Preliminary data indicate that exposure of cardiac myocytes to H2O2 induces myofilament disassembly, Ca2+ overload, and the activation of the nonreceptor tyrosine kinase src. The hypothesis of this proposal is that the MAPK family modulates NHE activity, Ca2+ overload and contractile dysfunction induced by H2O2. In Aim 1, experiments with synthetic inhibitors and antisense oligonucleotides will determine whether MAP kinase inhibition blocks H2O2-induced phosphorylation of NHE, since phosphorylation of the exchanger protein is associated with its activation. NHE activation will be measured by fluorimetric imaging of intracellular pH and by examining the phosphorylation state of the NHE protein in vitro and in vivo. In Aim 2, the link between H2O2-induced contractile dysfunction, Ca2+ overload and MAPK activation will be investigated using pharmacological inhibitors and antisense oligonucleotides against p38, JNK, and ERK MAPKs. Contractile dysfunction will be defined as a decrease in myocyte contractility (using video edge detection), and by immunocytochemistry to measure myofibrillar assembly. In Aim 3, a studies using immunecomplex kinase assays, immunoprecipitation and Western blot analysis will identify regulatory components upstream of MAPKs that are activated by H2O2. This aim will focus on src, protein kinase C, and the Ras superfamily of monomeric GTP-binding proteins. The proposed investigations are fundamentally important to the development of therapeutic strategies targeted to signaling pathways involved in oxidant-induced injury and may have important clinical implications in the treatment myocardial ischemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM OF RENAL ACID/BASE HOMEOSTASIS Principal Investigator & Institution: Dubose, Thomas D.; Chief, Division of Nephrology; Internal Medicine; University of Kansas Medical Center Msn 1039 Kansas City, Ks 66160 Timing: Fiscal Year 2002; Project Start 01-JUL-1981; Project End 31-AUG-2002 Summary: Abundant evidence has established a pivotal role for an H+, K+- ATPase in renal K+ homeostasis and acid-base balance. The regulatory response of the H+, K+ATPases to chronic hypokalemia and chronic acidosis has been localized to the outer medullary and inner medullary collecting ducts (OMCD and IMCD). Two, and perhaps more, alpha-subunit isoforms have been localized to the mammalian kidney, but uncertainties remain with respect to participation of specific alpha isoforms in segmental K+ and acid-base homeostasis. Transport studies have been forced to rely on the effect of "specific" inhibitors of the H+, K+-ATPase (such as Sch 28080) to identify
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that component of bicarbonate and/or K+ absorption attributable to this transporter. Since the H+, K+-ATPases exhibit differing sensitivities to ouabain and Sch 28080, it is not known with certainty if modulations in transport and the well established response to chronic metabolic acidosis and hypokalemia are the result of modulation in function of HKalpha1, HKalpha2, HKalpha4, or yet to be identified isoforms. This study is designed to elucidate the pathophysiologic factors which regulate at both molecular and functional levels, at H+, K+-ATPases in collecting duct segments, and in medullary collecting cells in culture. By transfecting mOMCD1, and mIMCD-3 cells with anti-sense HKalpah1, HKalpha2, and HKalpha4, we will define which isoform is responsible for the well-accepted adaptive response to chronic hypokalemia. We will then define the molecular equivalent of the H+, K+-ATPase enzymatic activity characterized as type III, which is upregulated by chronic K+ depletion. This approach will required the synthesis and screening of a subtraction cDNA library. Thirdly, we will determine if aldosterone or endothelin regulate H+, K+-ATPase function in mOMCD1 and mIMCD-3 cells in culture, and if so, we will delineate the alpha, H+, K+-ATPase iosoform responsible. Finally, we will define the contribution of the H+, K+-ATPases to net acid secretion in the OMCDis perfused in vitro during metabolic alkalosis without K+ depletion. Metabolic alkalosis with and without hypokalemia will then be simulated in mOMCD1, cells in culture to delineate whether hypokalemia or alkalemia per se upregulates the alpha H+, K+-ATPase, and if so, which alpha H+, K+-ATPase isoform responds specifically to each condition. These studies will help to elucidate the means by which K+ depletion can maintain metabolic alkalosis. The H+, K+- ATPase remains a candidate gene for abnormal structure and function in inherited and acquired forms of distal renal tubular acidosis. To understand this group of disorders more completely, fundamental studies which elucidate the molecular regulation of this family of transporters will be necessary to further our understanding of the pathophysiology of this disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM OF RENAL TUBULAR ANION TRANSPORT Principal Investigator & Institution: Aronson, Peter S.; Professor; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: The principal focus of this project continues to be the mechanisms of anion transport in the proximal tubule. Studies during the past decade have supported a model by which transcellular CI-absorption in the proximal tubule involves uphill CIuptake across the luminal membrane by exchange with formate and oxalate. Recycling of formate occurs by H/+- couple formate transport in parallel with Na/+-H/+ exchange, whereas next project period we propose to investigate two aspects of proximal tubule anion transport. First, we plan to complete the cDNA cloning and carry out the physiological characterization of a novel transporter that is likely to play a role in mediating apical membrane anion transport. Specifically, we will isolate, clone and sequence cDNAs encoding the transporter, determine anion specificity and transport modes by functional expression in Xenopus oocytes; general specific antibodies, and determine cell and membrane sites of expression; determine whether different isoforms of the transporter exist; examine structure-function relationships by use of chimeric constructs; and estimate the contribution of the transporter to integrated tubule function in microperfusion studies in mice with targeted disruption of the transporter gene. Second, in collaboration with Gerhard Giebisch (project#1), we propose to continue studies of the mechanisms of regulation of transcellular NaHCO/3 and NaCI
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reabsorption in the proximal tubule. Specifically, we will measure the activities of both anion exchanges (CI-formate and CI-oxalate) and recycling pathways (H+-coupled formate transport, Na/+- sulfate co-transport, oxalate-sulfate exchange) in renal brush border vesicles isolated from rats subjects to conditions that regulate proximal NaHCO/3 and NaCI reabsorption (eg. metabolic acidosis, hypokalemic alkalosis, furosemide-induced volume contraction). Activities of these pathways in membrane vesicles will be correlated with rates of transtubular HCO/3- and CI- reabsorption in the intact tubule under similar conditions. We will thereby test the hypothesis that activities of luminal membrane anion transporters are appropriate altered tot permit independent regulation of proximal tubule NaHCO/3 and NaCI reabsorption. The proposed project will provide new information on the molecular mechanisms and regulation of renal CItransport, and is therefore of relevance for understanding clinical disorders of NaCI balance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS OF CELL DEATH IN LIVER CELLS Principal Investigator & Institution: Herman, Brian A.; Professor and Chair; Cellular & Structural Biology; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 01-JUL-1999; Project End 30-JUN-2004 Summary: Basic information concerning the mechanisms responsible for hypoxic cell death is lacking. The overall goal of the proposed project is to define the cellular mechanisms which are responsible for the onset of irreversible injury and cell death using isolated rat hepatocytes as a model system. Cell viability, cytosolic free calcium and pH, mitochondrial membrane potential, lysosomal distribution and integrity, cytoskeletal status, plasma membrane distribution and integrity, and cell surface morphology will be evaluated in single individual hepatocytes during hypoxia by quantitative digitized video microscopy (DVM). DVM will allow the direct observation of the dynamics of organelles and molecules in living cells, providing new information about the roles of these components in cellular function. The onset of irreversible cell injury and cell death and the progression or recovery from injury during reoxygenation will be determined with respect to these cellular functions. Since increased cytosolic free calcium, cell swelling, decreased energy supply, proteolysis and reactive oxygen species have all been hypothesized to play a role in cell death during hypoxia or following reoxygenation, pharmacologic stabilization regimes utilizing calcium antagonists, anaerobic substrates, osmotic agents, protease inhibitors, and scavengers of free oxygen radicals will be assessed with regard to their ability to delay or prevent the onset of irreversible injury and cell death. The role of the cytoskeleton in hypoxic injury will be examined using agents which modulate cytoskeletal structure and function. Additionally, cytoskeletal structure during hypoxia will be visualized using immunocytochemistry in combination with light and electron microscopy. Parallel experiments with suspensions of hepatocytes will also be carried out using conventional biochemical techniques. This project will provide fundamental, new information regarding mechanisms responsible for the onset of hypoxic cell death. This information will be important for the development of treatment modalities effective in the preservation of cells and tissue during hypoxic episodes. 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 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
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Project Title: MEMBRANE TRANSPORT OF NH3 AND NH4+ Principal Investigator & Institution: Nakhoul, Nazih L.; Medicine; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Renal production and excretion of NH3/NH4+ play a vital role in acid/base homeostasis and regulation of systemic pH. The classical model of NH3/NH4+ transport proposes that: 1) NH3 crosses cell membranes solely by nonionic diffusion through the lipid phase of the membrane and 2) NH4+ transport occurs via channels (e.g., K+ channels) or transporters (e.g. Na/K/2CI co-transport or Na-H exchange), mostly as a substitute for K+. Recent studies report new characteristics of NH3/NH4+ transport and regulation that were not previously recognized. A new class of recently cloned membrane proteins, belonging to the Rh antigen family, may function as transporters of NH4+. Other studies indicate that NH3 transport may be facilitated by
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the presence of water channels (AQP). In addition, NH3 was reported to act as a signaling molecule and recent studies proposed that the Rh proteins may actually be gas channels for NH3 and even CO2. The main objectives of this proposal are to investigate the characteristics of AQPs and Rh glycoproteins with respect to NH3 and NH4+ transport. Specifically we will address the following aims: 1) Transport of NH3 through carrier proteins and the role of AQPs. 2) Characterization of transport properties of Rh glycoproteins. These studies will involve expression of cloned genes (Rh and AQPs) in oocytes to study their transport characteristics. Measurements of intracellular pH and other ions will be obtained by microelectrodes and pH sensitive dyes. Studies will also be conducted on cells in culture and the isolated perfused tubule preparation. Because of the importance of NH3/NH4+ in regulating pH, these studies have significant physiological implications. The possibility that a gas, such as NH3, could be transported through an AQP or another carrier protein, is unique and suggest that its transport could be regulated. NH4+-specific transporters, as Rh glycoproteins may be, have never been described in mammalian cells before. These are new properties of NH3/NH4+ transport that will help explain the role of NH3 and NH4+ in acidosis and their effect on transport of other ions a well. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: METABOLIC REGULATION OF MUSCLE BLOOD FLOW Principal Investigator & Institution: Hester, Robert L.; Physiology and Biophysics; University of Mississippi Medical Center 2500 N State St Jackson, Ms 39216 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: The blood flow to the peripheral circulation is regulated to maintain a balance between the delivery of nutrients and the metabolic demands of the tissue. Blood flow increases to a metabolically active tissue. This increased blood flow is the result of an increase in arteriolar diameter of terminal arterioles and larger upstream vessels. The terminal arterioles appear to determine distribution of flow while the upstream or "feed" vessels are more important in regulating total tissue flow. With an increase in metabolism there is the release of vasoactive metabolites from the tissue. Although vasoactive metabolites are known to affect the diameters of terminal arterioles the mechanisms by which metabolic factors regulate the diameter of upstream arterioles is uncertain. Recent studies from our lab and others have indicated an important role for the venular-arteriolar diffusion of vasoactive substances. The studies outlined in this proposal will test the following working hypothesis. In response to mismatches in blood flow and tissue metabolism, decreases in PO2 and/or increases in PCO2 and H+ are directly or indirectly sensed by the venular endothelial cells, resulting in the release of vasoactive metabolites of arachidonic acid which regulate the tone of adjacent arterioles. The proposed studies will test this hypothesis utilizing recently developed in situ microcirculatory techniques in which we are able to selectively remove the venular endothelium and assess the impact on blood flow regulation. The proposed studies will test two specific hypotheses: 1) The venular endothelium releases a metabolite of arachidonic acid that diffuses from the venule to the arteriole to cause an arteriolar dilation in response to an increase in tissue metabolic rate. 2) The venular endothelium responds to hypoxia, hypercapnia, and acidosis, directly, or indirectly to initiate the release of one or more vasoactive factors from the venular endothelial cells. These studies should provide new and important information relevant to our understanding the importance of venular-arteriolar diffusion of endothelial derived factors in the regulation of blood flow. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MICROENVIRONMENT OF THE RETINA Principal Investigator & Institution: Linsenmeier, Robert A.; Professor; Biomedical Engineering; Northwestern University 633 Clark Street Evanston, Il 60208 Timing: Fiscal Year 2002; Project Start 01-JUL-1983; Project End 31-JUL-2007 Summary: (provided by applicant): The long-term objectives of this work are to understand aspects of the retinal microenvironment related to oxygen and pH, and how these relate to energy metabolism and function of the mammalian retina in vivo. While this work will be done in animals, it is particularly relevant to blinding diseases that affect the relationships between the circulation and retinal neurons in humans. During the next project period, our main interests are in diabetic retinopathy, retinal detachment, and retinal arterial occlusive disease. However, the results will also provide fundamental information that may be relevant to other types of retinal dysfunction. The proposed work will be done primarily on intact anesthetized cats, since their retina provides a good model for much of the human retina. The techniques are primarily to use oxygen and pH sensitive microelectrodes to map out retinal oxygen levels, pH and electrical activity (the electroretinogram) with high spatial and temporal resolution, as we have done previously under other experimental conditions. Following the measurements, mathematical modeling of diffusion will be used to extract metabolic parameters that are not apparent from the measurements alone, and to perform simulations of situations that may not be amenable to experimentation. Some measurements of retinal histology will also be made. The project has 5 specific aims. 1) We will study intraretinal oxygenation following photocoagulation, because the mechanism by which photocoagulation blocks neovascularization is still unclear. 2) We will use information about oxygenation after photocoagulation from specific aim 1 to create an appropriate two-dimensional diffusion model of this situation, with the hope of providing a better rationale for the density and size of lesions designed to treat retinopathy. 3) We will study retinal oxygenation in the detached retina in order to understand the basis for the protective effect of hyperoxia in retinal detachment, which has been shown recently in cats. 4) We will study pH after retinal arterial occlusion, to understand the potential role of acidosis in damaging the retina. 5) We will investigate the influence of anesthesia on the metabolic measurements we make, and will study metabolic differences between the cat and primate retinas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MITOCHONDRIAL DNA ANALYSIS IN CYCLIC VOMITING SYNDROME Principal Investigator & Institution: Boles, Richard G.; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 900276062 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: (from applicants abstract): Cyclic vomiting syndrome (CVS) is a disabling condition characterized by multiple severe and distinct episodes of nausea, vomiting, lethargy and variable other symptoms separated by asymptomatic intervals. Although CVS is generally believed to be a (predominantly) childhood variant of migraine, its etiology and pathogenesis are poorly understood. Several features of CVS, including a maternal bias in inheritance, suggest that mitochondrial DNA (mtDNA) sequence variations/mutations may be involved in its etiology. A significant subset of children with CVS have additional neuromuscular disease manifestations including cognitive dysfunction and epilepsy. Maternal inheritance of migraine and/or various neuromuscular disorders and lactic acidosis are present in ten children with CVS
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followed by the investigators, strongly suggesting that mtDNA mutations are involved in at least some cases. An inherited complex mtDNA rearrangement was found in one. Preliminary results using temporal temperature gradient gel electrophoresis (TTGE) found heteroplasmic sequence variations in the mtDNA D-loop in 2 additional CVS cases. TTGE is a novel mutation detection assay which was developed for use with mtDNA by the PI and collaborators. TTGE is sensitive and cost effective relative to other methods and for the first time permits the screening of large groups of patients for mutations throughout the entire mtDNA. Since mtDNA sequence variations are postulated to be more likely involved among CVS sufferers with additional neuromuscular disease manifestations, in the first sub-study 50 of these individuals will be screened by TTGE for all sequence variations throughout the mtDNA. The incidence of CVS cases caused by mtDNA sequence variations will be determined in a second substudy in which the mtDNA in an unbiased group of 100 CVS sufferers will be screened. All sequence variations found in CVS sufferers will be compared against those found upon an identical screening of 100 control individuals, and any of interest will be sequenced. Pathogenicity of suspected mutations will be determined in rho negative cybrids. An extensive amount of clinical and laboratory data will be collected in all patients, allowing for the comparison of CVS sufferers with and without mtDNA mutations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MITOCHONDRIAL DYSFUNCTION IN PEDIATRIC HEAD INJURY Principal Investigator & Institution: Robertson, Courtney L.; Assistant Professor; Pediatrics; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Following traumatic brain injury (TBI), the immature rat brain experiences many secondary insults that lead to delayed cell death. Although considerable evidence indicates that mitochondria are primary mediators of ischemic and excitotoxic neural cell death and survival, relatively little is known regarding mitochondrial involvement in adult TBI, and nothing has been reported for models of pediatric TBI. Limited studies of the immature rat brain have demonstrated vulnerability to many known mediators of mitochondrial injury, including elevated intracellular calcium and oxidative stress. Mitochondrial alterations can also trigger the cascade of caspase activities that mediate apoptosis, a process of programmed cell death that appears particularly important in TBI. The working hypothesis for the proposed study is that the response of brain mitochondria to metabolic acidosis, elevated calcium, oxidative stress, and pro-apoptotic proteins plays an integral role in the neurochemical, histologic, and neurologic outcome following pediatric TBI. We will test the following mechanistic hypotheses using a clinically relevant model of pediatric TBI: 1) Mitochondrial injury early after TBI increases the sensitivity of mitochondria to cellular factors that promote apoptotic or necrotic cell death cascades. 2) Cerebral lactic acidosis after TBI promotes cytochrome c release, mediated by mitochondrial swelling due to activation of the membrane permeability transition. 3) Oxidative stress following TBI contributes to mitochondrial dysfunction, cell death and neurologic injury. This study will help define the molecular mechanisms by which mitochondria are injured after TBI in immature animals. This may identify novel targets for neuroprotection following TBI in infants and children. This proposal is intended to provide for the research experience and career development of the applicant, specifically involving the mechanisms of, and therapeutic strategies for, the treatment of acute brain injury. The Departments of Anesthesiology and Pediatrics, and the Brain Injury and Neuroprotection Research
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Group at the University of Maryland will provide a rich environment for the study of experimental brain injury, and have a strong commitment to fostering meaningful and contemporary research in this field. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MITOCHONDRIAL METABOLITES
NUCLEOTIDE
CARRIERS
OF
NRTI
Principal Investigator & Institution: Gulick, Tod S.; Asst. Biochemist/Asst. Professor of Medi; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Nucleoside reverse transcriptase inhibitors (NRTI) are critical components of highly active anti-viral therapies. Phosphorylated derivatives (NRTI-P) mimic the cellular dNTP substrates for HIV RT, but produce chain termination, thereby limiting retroviral amplification. NRTIs produce reversible side effects that resemble those of patients with mitochondrial (mito) genetic disorders, including cardiomyopathy, myopathy, neuropathy and lactic acidosis, and these correlate with NRTI-induced loss of mito DNA in various tissues. Toxicity has been attributed to inhibition of DNA polymerase g, interfering with mito DNA maintenance. Alternative or additional mechanisms of mito damage may also be at play. Regardless of mechanism, NRTI toxicity is dependent on import into mito. We have isolated novel human genes and cDNAs that encode orphan members of the mito metabolite carrier family (OMC). Five carry a signature specific to nucleotide (nt) carriers, including a putative adenine nt transporter (ANT), two putative CoA transporters, and a nonspecific exchanger of nucleotides (OMC27). We have shown that purified OMC27 and its yeast ortholog transport NRTI-P's AZT-TP and -DP, ddl-TP, and ddC-TP in proteoliposome radiochemical flux assays. Disruption of the orthologous yeast gene protects against AZT-induced mito dysfunction. This project examines the role of OMC27 in NRTI-mediated toxicity, with goals of understanding mechanisms by which NRTIs gain entry to the matrix, and identifying nucleoside analogs with known antiviral activity that offer potential for improved therapeutic index by virture of mito exclusion and reduced mito toxicity. We will test the hypotheses that OMC27 (and yeast ortholog) are highly affinity transporters of NRTI-P, that this represents the primary pathway for mito uptake of NRTI-P; that OMC27 expression is critical to NRTI-induced mito failure; and that a useful therapeutic index for NRTIs may be evident from the ratio of NRTI anti-viral to MC-mediated uptake activities; using complementary in vitro, yeast and mammalian cell, and in vivo mouse studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MODULATION OF ELECTROGENIC SODIUM BICARBONATE TRANSPORT Principal Investigator & Institution: Kurtz, Ira; Professor; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Sodium bicarbonate cotransporters contribute to intracellular pH (pHi) regulation and the transepithelial transport of sodium and bicarbonate in several tissues. The recent cloning, functional expression, and immunolocalization of electrogenic and electroneutral sodium bicarbonate cotransport (NBC) proteins provides an opportunity to investigate the molecular mechanisms responsible for modulating their function. The electrogenic sodium bicarbonate
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cotransporter kNBC1 is the main pathway for proximal tubule basolateral bicarbonate effiux. Loss of function mutations in the NBC1 gene cause a severe form of autosomal recessive proximal renal tubular acidosis. There is currently a paucity of information regarding both the structural motifs responsible for the electrogenicity of kNBC 1, and the biologically important protein interactions that modulate its function. In recent studies, we have demonstrated that PKA-dependent phosphorylation of the C-terminal Ser982 residue altered the electrogenicity of kNBC1 by shifting its HCO3-:Na + stoichiometry from 3:1 to 2:1. In the region adjacent to Ser982, structural analysis reveals a charged region with aspartic acid residues that could potentially play an important role in this regard. We hypothesized that the phosphorylation state of Ser982 determines whether this negatively charged region in the kNBC1 C-terminus will interact electrostatically either with one bicarbonate binding site in the transporter (2:1 mode), or a putative binding protein (3:1 mode). On this basis we screened a human kidney cDNA library in a yeast two-hybrid assay using the C-terminus of kNBC 1 as bait, and isolated the enzyme aspartoacylase. Aspartoacylase has several N-terminal basic residues which could mediate its interaction electrostatically with the C-terminus of kNBC1. Aspartoacylase was localized to the basolateral membrane of proximal tubule cells, and co-immunoprecipitated with kNBC 1 from kidney. PKA-dependent phosphorylation of kNBC1-Ser982 prevented the interaction between the proteins. Furthermore, the function of kNBC1 was significantly greater in cells co-transfected with kNBC 1 and aspartoacylase in the presence of N-acetylaspartate. We will use the mPCT cell line as a model system for achieving the goals of this proposal. Successful completion of this project will enhance our understanding of the mechanisms responsible for regulating H+/base transporters. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR PHYSIOLOGY OF BAND 3 LIKE PROTEINS OF KIDNEY Principal Investigator & Institution: Alper, Seth L.; Professor; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 15-JAN-1991; Project End 31-MAR-2003 Summary: (Adapted from the Applicant's Abstract): The AE anion exchanger gene family encodes complex polytopic transmembrane polypeptides that contribute to regulation of intracellular pH (pHi), cell [Cl-], and cell volume through their mediation of electroneutral Cl-/HCO3- exchange. AE-mediated Cl-/HCO3- exchange in polarized epithelia also regulates secretion and reabsorption of proton equivalents and of Cl-. AEmediated Cl-/HCO3-exchange is thought to be of widespread physiological importance in many cell types. AE1 deficiencies have been particularly associated with hereditary syndromes of spherocytic anemia and of distal renal tubular acidosis. Deficiencies of AE2 or AE3 activity have yet to be defined. Deficiency of a different Cl-/HCO3exchange activity leads to congenital chloride diarrhea. This competitive continuation grant application proposes to extend past and current experiments by pursuit of the following Specific Aims: 1. Further define structural loci of the regulatory differences among AE isoforms, especially AE1 and AE2. 2. Study natural variants of the AE genes and a different class of anion exchanger for clues about ion translocation pathways and mechanisms. These will include: a. AE1 mutations that cosegregate and likely contribute to heritable distal renal tubular acidosis b. AE polypeptides of genetically related fish that live in river or in soda lake environments c. a more distantly related member of the bicarbonate-transporter superfamily cloned from yeast d. the unrelated sulfate transporter DRA that when mutated results in congenital chloride diarrhea. 3. Further
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compare and define the mechanisms of electroneutral and electrogenic anion exchange mediated by AE1 E699Q and likely mediated by AE2 E1007Q. 4. Apply directed mutagenesis to define the residues of AE1 and AE2 that contribute to binding and transport of substrate anions and to deduce constraints on secondary and tertiary structure of AE polypeptides. 5. Define aspects of transcriptional and translational regulation of AE gene products in kidney of mutant and parental mouse strains and in cultured kidney cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR PHYSIOLOGY OF RENAL K-CI COTRANSPORTERS Principal Investigator & Institution: Mount, David B.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2004; Project Start 01-MAY-2000; Project End 30-JUN-2008 Summary: (provided by applicant): Coupled K+-CI- co-transport is mediated by the KCC proteins, encoded by four members of the SLC 12 cation-chloride cotransporter gene family. Genetics, physiology, and the characterization of knockout mice have implicated the KCCs in the pathogenesis of disorders as diverse as hypertension, epilepsy, renal tubular acidosis, neuropathic pain, and sickle cell anemia. In the renal proximal tubule, isotonic swelling induced by apical Na absorption activates basolateral K+ -Cl- cotransport mediated by KCC3 and KCC4, implicating these transporters in proximal re-absorption of filtered Na+-Cl- and other solutes. Indeed, in addition to reduced fluid transport, KCC3-deficient mice exhibit defects in the absorption of bicarbonate, suggesting that loss of KCC3 causes generalized proximal tubular defects. Furthermore, given the demonstrated role of KCC3 in regulatory volume decrease (RVD), the response to oxidant stress, and a severe neurodegenerative syndrome, we propose that KCC3 is required to maintain cellular integrity in response to ischemic volume increase ("IVI"), such that loss of KCC3 predisposes to ischemic tubular necrosis. The role and regulation of K+-Cl - cotransport in the proximal tubule is thus the focus of this competing renewal. We propose in Aim 1 to finish characterizing the renal phenotype of our existing mouse strain with germline deletion of the KCC3 (Slc12a6) gene, in addition to creating and characterizing a mouse strain with KCC3 deletion that is limited to the renal proximal tubule. These animal studies will encompass immunohistochemistry, renal physiology, and assessment of the response to renal ischemia/reperfusion injury. Whereas neuronal-specific KCC2 is unique in mediating constitutive K+-Cl - cotransport, the other three KCCs are quiescent in the absence of cell swelling. Using a chimeric approach, we have localized the molecular determinants of constitutive isotonic activity to a KCC2-specific expansion in the C-terminal cytoplasmic domain. Given t he role o f s welling-activated K +-Cl- cotransport in proximal tubular salt and solute transport we will characterize the molecular determinants of swelling activation, using chimeras between K CC4 and t he s wellinginhibited N a-K-2Cl cotransporter N KCC2. T he effect o f c ell volume o n phosphorylation status and membrane trafficking will also be studied in Aim 2, using KCC4 and several N-terminal variants of KCC3. These studies will begin in Xenopus oocytes but will ultimately be extended to the opossum kidney (OK) cell line and/or other epithelial cell lines. In Aim 3 we will focus on the role of conserved cysteines in the mechanism and regulation of K+-Cl - cotransport, building on data from both activating and inactivating mutations of conserved transmembrane cysteines. Various cysteinedepleted mutants will also be used to distinguish the cytoplasmic and membraneassociated mechanisms in the activation and inactivation of the KCCs by nitric oxide (NO) and related cysteine-reactive compounds.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MRI AGENTS THAT REPORT THE EXTRACELLULAR PH OF TUMORS Principal Investigator & Institution: Mudigonda, Dhurjati S.; Macrocyclics Suite 120 Dallas, Tx 75252 Timing: Fiscal Year 2003; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): In this project, we will develop new gadoliniumbased contrast agents that are exquisitely sensitive to pH and establish their feasibility in determining extracellular pH in vivo using a standard clinical MRI protocol. Extracellular pH is clearly an important parameter to know in neoplastic tissues because it has been shown that acidosis can modulate the cytotoxicity of some anticancer drugs, influence thermal radio-sensitization and enhance the killing effects of heat. We recently demonstrated that a simple gadolinium complex containing a single, slowly exchanging, inner-sphere water molecule senses pH via catalytic exchange of bound water protons. This unique chemical feature offers a major advantage over other known gadolinium complexes because proton relaxivity is not limited by molecular exchange of the bound water. This means that complexes with water relaxivity values higher than previously achieved can be made by attaching existing small molecule pH sensitive agent to polymers of increasing size. We have licensed this technology from the University of Texas at Dallas and through the current funding mechanism intend to create even more pH responsive MRI agents, demonstrate their utility in vivo in animal models, and make them commercially to the biomedical research community. PROPOSED COMMERCIAL APPLICATION: Magnetic resonance imaging is widely used to detect tumors in humans, yet little physiological information is gained in a normal MRI exam. We plan to develop new pH sensitive contrast agents that can be safely injected into patients to determine the extracellular pH of tumors using a standard imaging protocol. We believe this could become a standard protopcol in clinical oncology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEONATAL PROXIMAL TUBULE ACIDIFICATION Principal Investigator & Institution: Baum, Michel G.; Professor; Pediatrics; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-FEB-1991; Project End 30-JUN-2006 Summary: (provided by applicant): There are clinically important differences between the neonatal and adult kidney. The neonatal kidney has a lower glomerular filtration rate and immature tubules compared to the adult. Tubular immaturity predisposes neonates to develop fluid and electrolyte disorders. The adult proximal tubule reabsorbs 80 percent of the filtered bicarbonate and 60 percent of the filtered NaCl. Most of proximal tubule acidification in the mature proximal tubule is due to the apical Na+/H+ exchanger (NHE3). The Na+/H+ exchanger in parallel with a Cl-/base exchanger also mediates transcellular NaCl transport. Half of NaCl transport in the mature segment is passive and paracellular. Neonatal proximal tubules have almost an undetectable level of NHE3. This proposal will examine what produces the developmental increase in NHE3 and in proximal tubule NaCl transport. There is a 100-fold increase in corticosterone level and a 10-fold increase in thyroid hormone level during the first three weeks of life in the rat. We have recently demonstrated that this rise in glucocorticoids mediates most, but not all, of the increase in NHE3. The first aim will examine the mechanisms whereby glucocorticoids increase NHE3. The second aim will
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examine if the maturation of NHE3 is totally prevented in a novel animal model, a hypothyroid glucocorticoid deficient neonatal rat. In addition to the developmental changes in active transport, we have recently demonstrated that there are significant differences in the paracellular pathway in immature tubules, which impact the passive component of NaCl transport. Whereas one half of NaCl transport is paracellular in the adult proximal tubule, there is essentially no passive NaCl transport in the neonatal segment. The third aim will characterize the physiologic and molecular characteristics of the neonatal and adult proximal tubule paracellular pathway to determine why there is no passive NaCl transport in the neonatal proximal tubule. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEUROLOGIC AIDS RESEARCH CONSORTIUM Principal Investigator & Institution: Clifford, David B.; Professor; Neurology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-MAY-1997; Project End 31-JUL-2008 Summary: The Neurologic AIDS Research Consortium (NARC) will maintain an effective collaborative clinical study group dedicated to the study of HIV-associated neurologic disease. Projects are identified by investigators, designed with review by internal and external experts and implemented. This proposal includes completion of currently active studies, and initiation of new areas of investigation relevant to the neurologic complications associated with HIV infection. The specific projects to be undertaken include: 1. Complete and analyze A5090 testing the safety and efficacy of transdermal selegiline for HIV- associated motor cognitive disorder; 2. Monitor the incidence, prevalence and natural history of HIV related neuropathy and neuropsychologic disorders and validate brief screens for detection of central and peripheral nervous system dysfunction in the Adult Longitudinal Linked Retroviral Treatment (ALLRT) Cohort of the AIDS Clinical Trial Group; 3. Complete and analyze longitudinal physiologic and morphologic characterization of distal sensory neuropathy in HIV over a one year period of observation; 4. Complete and analyze our study of the virologic, immunologic and pharmacologic manifestations of HIV in CSF compartment during anti-retroviral treatment; 5. Perform a study of Acetyl L-carnitine for treatment of dideoxynucleoside induced painful neuropathy in HIV infection; 6. Develop and implement a study to measure the safety, tolerability and analgesic properties of Prosaptide for HIV-associated painful peripheral neuropathy; and 7. Characterize the newly described acute neuromuscular disorder associated with lactic acidosis seen in treated HIV patients. Major studies will be developed and operated cooperatively with the AIDS Clinical Trial Group (ACTG). The NARC will continue to develop a broad agenda for clinical study of neuroAIDS complications following these studies, directed by the Principal Investigator, Executive Steering committee and the NINDS appointed Data and Safety Monitoring Board (DSMB). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NOVEL ASSAY FOR ETHYLENE GLYCOL TOXICITY Principal Investigator & Institution: Kloepfer, Hans G.; Micronix, Inc. 14950 Greyhound Ct, Ste 307 Carmel, in 46032 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-MAY-2003 Summary: (Applicant's abstract) Poisoning from ethylene glycol is a potentially lethal medical emergency but can be treated effectively when recognized early. Conversely, when diagnosis is late, the outcome is usually poor. The major pathogenic factor is
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metabolic acidosis from glycolic acid (glycolate). Because laboratory testing for ethylene glycol and glycolate is severely restricted, timely diagnosis depends on comparatively nonspecific physical signs and laboratory tests. Lack of access to specific testing and need for differentiation from conditions featuring similar symptoms constitute a unique medical dilemma. Recognizing these deficiencies we propose to develop novel, specific enzymic assays for ethylene glycol and glycolate. Two product configurations are perceived: 1) aqueous reagents for existing clinical analyzers (serum, quantitative); 2) a dry-chemistry, dual-analyte point-of-care testrip method (whole blood, semiquantitative).The POC method is a dual-analyte test tab device for the simultaneous estimation of ethylene glycol and glycolate from approximately two (2) microliters of whole blood without centrifugation or any other form of sample or reagent handling. To make such a level of miniaturization and simplicity feasible, we have developed a capillary fill sampling technique permitting specimen dosing, plasma separation, and red cell removal in one wholly integrated step. Because of rapid metabolism of (flontoxic) ethylene glycol and the longer half life of (toxic) glycolate, the latter provides better prognostic information and improved clinical sensitivity, especially late postingestion. Thus, rapid and simultaneous availability of test results for both analytes expands the window of diagnostic/therapeutic opportunity. Socioeconomic benefits are: 1) reducing expensive gas chromatographic screening, confirmatory and other testing; 2) averting late or unnecessary treatment; 3) cutting intensive care and hospital stay; 4) abating long term morbidity (renal dialysis). PROPOSED COMMERCIAL APPLICATION: Most current gas chromatographic screening and confirmatory methods for ethylene glycol require derivatization, sample pretreatment and special columns. Direct methods are fraught with analytical problems such as peak overlap and trailing. Cases have been reported where other compounds were identified as ethylene glycol with serious consequences. All methods require specialized equipment unavailable in most laboratories, are technically demanding, time consuming, and relatively insensitive. For these reasons access to timely and reliable testing for ethylene glycol is extremely limited. Testing for the clinically more sensitive and relevant toxic metabolite glycolic acid is essentially non-existant. Not a single routine clinical analyzer currently exists offering either an ethylene glycol or glycolate method. The proposed products would solve these problems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL NON-HEART-BEATING DONOR KIDNEY STORAGE MEDIUM Principal Investigator & Institution: Chen, Sumi C.; Principal Investigator; Chen Laboratories, Inc. 13704 Killarney Court Phoenix, Md 21131 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-OCT-2002 Summary: Donor kidney cannot meet current demand for kidney transplantation, the most effective for end stage renal failure. Non-heart-beating (NHB) donor kidneys are under-utilized because current technology does not allow NHB donor organs to withstand unavoidable extended periods of warm and cold ischemia. Chen Medium (CM), a novel physiological preservation solution, is highly effective for human donor cornea storage and preservation. CM contains beta-hydroxybutyrate, a unique nonlactate-generating high-energy metabolite that enables tissues to generate high levels of ATP while suppressing intracellular acidosis. NHB donor organs undergo unique metabolic compromise, many aspects of which could be prevented by nicotinamide. Nicotinamide, an NAD+ precursor that is safe for humans, is idea for MHB donor organ preservation because it scavenges free radicals, preserves NDA+ levels through
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inhibition of poly(ADP-ribose) polymerase-mediated NAD+ catabolism, and inhibits both inducible nitric oxide synthase and expression of leukocyte-attracting molecules on human endothelial cells after injury. We propose to use physiological, biochemical and histological criteria with the isolated perfused pig kidney model to demonstrate that CM with nicotinamide is superior to UW and EC solutions for NHB donor organ preservation. Our aim is to advance transplant technology to allow effective utilization of under-utilized NHD donor organs. PROPOSED COMMERCIAL APPLICATIONS: The proposed research, if successful, will have potential commercial application. That is, CM will be able to be marked as a non-heart-beating kidney preservation medium. This is an Orphan product with a market size estimated about $20 million a year in the US and about $6-10 million for the foreign markers combined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NRTI-INDUCED MITOCHONDRIAL CARDIOMYOPATHY Principal Investigator & Institution: Wallace, Kendall B.; Professor; Biochem/Mole Biol/Biophysics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Cardiovascular disease is a growing complication of HIV. Although there is an increased incidence associated with the infection itself, it is further complicated by the antiviral therapy prescribed to treat the disease. The cornerstone of the HAART drug regimen for treating HIV are nucleoside analog reverse transcriptase inhibitors (NRTIs), which inhibit viral RNA-dependent DNA polymerases. However, these drugs are also recognized by host cell DNA polymerases including Polg, which is responsible for replicating the mitochondrial genome. As a result, the NRTIs inhibit mtDNA replication and biogenesis leading to mitochondrial depletion, which is manifested as a dose-limiting lactic acidosis and life-threatening cardiomyopathy. Although there is considerable evidence implicating mitochondrial depletion in the pathogenesis of NRTI toxicity, little is known regarding the bioenergetic characteristics responsible for the mitochondrial phenotype. The purpose of this investigation is identify which NRTIs induce mitochondrial cardiomyopathy in animal models at relevant doses and to fully characterize the mitochondrial bioenergetic deficits that underlie the metabolic disorder. We propose that the loss of coordinated expression of the nuclear and mitochondrial genomes leads to the assembly of poorly coupled electron transport chains, resulting in a loss of efficiency of oxidative phosphorylation accompanied by the catalytic liberation of highly reactive oxygen free radicals. Mitochondrial cardiomyopathy likely reflects both bioenergetic failure and increased oxidative damage owing to this interference with mitochondrial biogenesis. The results of this investigation will provide valuable insight into distinguishing which NRTIs are cardiotoxic and identifying the underlying mechanisms in the pathogenesis of cardiac injury. This information will be essential to predicting possible interactions between components of the HAART drug regimen and for developing reliable biomarkers and/or new treatment strategies designed to minimize the cardiomyopathy and thus improve the clinical success of HIV pharmacotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OSTEOCLAST ACTIVATION IN UREMIC BONE DISEASE Principal Investigator & Institution: Holliday, Lexie S.; Orthopaedics & Rehabilitation; University of Florida Gainesville, Fl 32611
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Timing: Fiscal Year 2002; Project Start 17-SEP-2001; Project End 30-JUN-2006 Summary: (Adapted from the Applicant's Abstract): Vacuolar V-ATPases (V-ATPases) have an essential role in the endocytic pathways of eukaryotic cells. In some cell types, like osteoclasts and certain renal epithelial cells, V-ATPases are expressed at high levels and are required for the specialized functions of the cells. In osteoclasts and renal epithelial cells, V-ATPases are stored in vesicles or tubules in the cytoplasm until the cell encounters an activating signal. V-ATPases are then transported to specialized domains of the plasma membrane. Although this transport is a crucial means by which VATPases are regulated, until recently little was known about the underlying mechanisms. A specific interaction between V-ATPases and filamentous actin (F-actin) has been identified by our lab. This represents the first example of a direct interaction between an ion pump and microfilaments. This grant will test the hypothesis that interaction between V-ATPase and F-actin accounts for the transport of V-ATPases in osteoclasts and other cells. The binding interaction between V-ATPase and F-actin is mediated by the B-subunit of V-ATPase; the B-subunit thus represents a new and unique member of the family of actin binding proteins. The interaction between actin and V-ATPase can be reconstituted using bacterially-expressed fusion proteins representing the N-terminal domains of B-subunits. This grant will continue characterization of the binding interaction between V-ATPase and actin using molecular and biochemical techniques with the goal of understanding the binding interaction in great detail. With this information, mutated molecular constructs of the B-subunit will be created which are able to integrate with other VATPase subunits to support proton pumping activity, but which lack the capacity to bind actin. These constructs will be expressed in an osteoclast cell culture model to test the physiologic importance of the binding interaction between V-ATPase and F-actin. The specific aims are: I. To obtain detailed molecular information about the F-actin binding site on the B-subunit, and generate mutant B subunits that lack actin binding but retain catalytic activity. II. To study effects of V-ATPase-F-actin binding on F-actin organization and V-ATPase enzymatic function. III. To test the importance of the binding interaction in osteoclast cell culture models. Because V-ATPases are crucial enzymes to the lives of all cells, and have been implicated in clinical disorders including osteoporosis and renal tubular acidosis, understanding their regulation will be of great importance for both basic and clinical science. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PATHOGENESIS OF RETINOPATHY OF PREMATURITY Principal Investigator & Institution: Holmes, Jonathan M.; Professor and Chairman; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: (Adapted from the applicant's abstract): Retinopathy of prematurity (ROP) is a blinding disease of premature infants resulting from development of abnormal blood vessels in the immature retina. It has been well established that excess oxygen is an important causative factor in the pathogenesis of ROP. Nevertheless, despite the more careful use of oxygen, the incidence of ROP is increasing in the United States. In addition, current treatments for severe ROP fail to prevent blindness in a large proportion of infants. Therefore, further research into the pathogenesis of ROP is critical to increase our understanding of the disease and to develop new methods of prevention and treatment. Infants who never experience hyperoxia (e.g., those with congenital heart disease) may also develop ROP. For these infants in particular, and for premature neonates in general, systemic acidosis has been implicated as a risk factor in the
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development of ROP. A new neonatal animal model has been developed that allows study of metabolic acidosis and retinal neovascularization. The investigator has confirmed that metabolic acidosis alone leads to preretinal neovascularization in the retina of immature animals, and has termed this model "metabolic acidosis-induced retinopathy" (MAIR). Using this model, the investigator proposes to characterize the effect of acidosis on the immature retina and investigate biochemical and molecular mechanisms. These studies may lead to new avenues of prevention and treatment of ROP. The primary hypothesis for this series of experiments is that: "acidosis is a risk factor for ROP in human neonates." This leads to the following secondary hypotheses that will be tested in the MAIR model, which is that: (1) a dose-response relationship exists between the extent of metabolic acidosis and the severity of retinopathy in the neonatal rat model; (2) neovascularization in the acidotic model is mediated by downregulation followed by up-regulation of one or more growth factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and insulin-like growth factor 1 (IGF-1); and (3) the retinopathy can be prevented by reversal of acidosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PATHWAYS OF APOPTOSIS IN HYPOXIC CARDIAC MYOCYTES Principal Investigator & Institution: Webster, Keith A.; Professor; Molecular and Cellular Pharm; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2003; Project Start 01-APR-1990; Project End 31-MAR-2007 Summary: (provided by applicant): C-Jun N-terminal kinase (JNK) is activated by reoxygenation or reperfusion in all models of myocardial ischemia in vitro and in vivo. JNK can exert strong modulation over cell survival and may determine the extent of myocardial cell loss during reperfusion. Controversy has existed over the role of activated JNK in different models of reperfusion with some groups describing proapoptosis and others protection. We present new data demonstrating that JNK functions are metabolically regulated that may resolve this controversy; JNK is protective when intracellular [ATP] is high and pro-apoptotic when [ATP] is low. As such JNK acts as a metabolic sensor in determining cell fate. We hypothesize that the targets that promote survival are different from those that promote death. In aim 1 of this proposal we will use the JNK functional switch as a tool to identify the phospho-proteins that mediate these different effects on hypoxic cardiac myocytes. Hypoxia and acidosis are integral features of ischemic heart disease. This combination is one of the strongest stimuli to activate programmed death of cardiac myocytes in culture. The pathway involves the Bcl-2 family protein BNIP3 that is strongly induced by hypoxia. Hypoxic cardiac myocytes containing induced BNIP3 do not undergo programmed death until the environment becomes acidic. We hypothesize that BNIP3 is induced and activated by hypoxia and acidosis respectively. Experiments are proposed to determine the mechanism and whether there are secondary effects of acidosis on mitochondrial signaling. Because we have established the role of BNIP3 in cultured cardiac myocytes, a major goal is to determine whether the same pathway promotes cell death during ischemia and infarction in vivo. The signals for JNK activation by reoxygenation have not been determined but are thought to involve reactive oxygen species (ROS). Our preliminary data suggest that coupled mitochondrial electron transport and membrane potential, but not ROS are essential components of this signaling pathway. We hypothesize that the pathway involves calcium loading activated by the mitochondrial membrane potential, coupled with myofilament calcium transients. Calcium is proposed to activate the kinase Pyk2 followed by Rac-1 and TAK- 1 and then JNK. Experiments proposed to test this hypothesis include measurements of membrane potential and
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intracellular calcium during hypoxia and reoxygenation and relating these to Pyk2 and JNK. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
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: PH REGULATION IN HEART CELLS Principal Investigator & Institution: Spitzer, Kenneth W.; Cardiovascular Res & Trng Inst; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2003; Project Start 01-JUL-1989; Project End 30-JUN-2008 Summary: (provided by applicant): The broad, long-term goal of this work is to establish a comprehensive understanding of the role of pH in cardiac function at the cellular level. Changes in intracellular pH (pHi) and extracellular pH have profound
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effects on electrical activity, excitation-contraction coupling and contraction in the heart, which accounts in part for the arrhythmias and contractile dysfunction elicited by myocardial ischemia. Compared to the information available for ventricular muscle, much less is known concerning pHi regulation, the effects of pH on Ca 2+ handling, and intra- and intercellular H+ diffusion in cardiac myocytes that lack transverse tubules (Purkinje and atrial). The protocols described in this project focus primarily on these two cell types and are designed to help fill this gap using fluorescence imaging and patch pipette techniques. The specific aims include: 1. Characterize the effect of intracellular acidosis on excitation-contraction coupling in atria/and Purkinje myocytes. The goal here is to determine the effects of acidosis on Ca 2+ current (L and T type), the spatiotemporal profile of the Ca2+ transient, Ca 2+ handling by the sarcoplasmic reticulum and intracellular Ca 2+ diffusion in these cell types. The response of [Ca2+]i to spatially confined changes in pHi will also be studied. 2. Characterize the electrogenic properties of Na-HCO3 cotransport in ventricular, atrial and Purkinje myocytes. The objective here is to test the hypothesis that Na-HCO3 cotransport is electrogenic in these cell types. 3.Characterize the properties of pH_ regulatory systems in cardiac Purkinje myocytes. The objective here is to determine the kinetic properties and pH-dependence of Na-H exchange (NHE), Na-HCO3 cotransport (NBC) and HCO3-CI exchange (AE) in isolated Purkinje myocytes and to test the hypothesis that CI-OH exchange (CHE) is operational in this cell type. 4. Characterize intra- and intercellular H+ diffusion in atrial and Purkinje cells. The goal here is to determine the intracellular H+ diffusion coefficient within single cells and the junctional permeability H+ coefficient between pairs of electrically coupled myocytes and to test the hypothesis that both parameters are modulated by carbonic anhydrase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RECEPTOR
PHARMACOGENETICS
OF
THE
HUMAN
PROSTACYCLIN
Principal Investigator & Institution: Hwa, John; Pharmacology and Toxicology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Prostacyclin (PGI2), a derivative of arachidonic acid, plays an important role promoting vascular smooth muscle relaxation and preventing platelet aggregation. The actions are mediated through a poorly understood seven transmembrane domain spanning G-protein coupled receptor (GPCR), the prostacyclin receptor (IP). The clinical importance of this receptor stems from its involvement in cardiovascular diseases such as myocardial infarction, stroke, atherosclerosis, and hypertension. The potential use of prostacyclin in the treatment of pulmonary hypertension, and cancers (colon, breast and lung), is currently being intensely investigated. We have recently discovered eleven human prostacyclin receptor polymorphisms. Furthermore preliminary in vitro studies have revealed abnormal function in one of these polymorphisms (R212H). This has led to the hypothesis that such polymorphisms may play a critical role in cardiovascular disease. Through three Specific Aims the goal of this proposal is to understand the pharmacogenetic importance of hIP polymorphisms and in so doing to determine distinct features of this receptor, which enable it to bind a 20-carbon fatty acid (eicosanoid) and couple it to signal transduction pathways, leading to cardiovascular disease. Genomic screening and sequencing will be used to comprehensively search for new polymorphisms and assess association with clinical cardiovascular disease (Specific Aim #1). Novel polymorphisms found will be tested in vitro using site-directed mutagenesis, and structure-function
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studies (Specific Aim #2). Specific Aim #3 will focus on downstream signal transduction pathways in human vascular smooth muscle cells to determine mechanisms for cardiovascular defects. In addition to this proposed collaboration between the Pharmacology, Medicine (Statistics), Vascular Surgery, Cardiology and Pathology Departments here at Dartmouth, strong groups in protein structure-function and signal transduction, will be critical resources for addressing these Specific Aims. Achievement of these aims, should not only improve our understanding of the molecular genetics and structure-function of the prostacyclin receptor, but may also provide the critical biochemical understanding to explain interindividual differences in progress of cardiovascular disease and variable responses associated with prostacyclin analogue treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHYSIOLOGICAL ROLE OF CIC-2 CI CHANNELS IN HEART Principal Investigator & Institution: Duan, Dayue; Pharmacology; University of Nevada Reno 204 Ross Hall Mailstop 325 Reno, Nv 89557 Timing: Fiscal Year 2002; Project Start 20-JUL-2002; Project End 30-JUN-2006 Summary: (provided by applicant): Activation of chloride (Cl-) currents in the heart can cause important changes in action potential characteristics, which may increase the dispersion of electrophysiological properties and provide the substrate for the occurrence of arrhythmias. In mammalian myocardial cells the P.I and his colleagues have recently discovered a novel volume-regulated Cl- inward rectifier channel (Cl.ir) (Circulation Research 86:e63-e71, 2000). Distinct from all cardiac Cl- channels described previously, Cl.ir is the only channel that exhibits inwardly rectifying current-voltage relationship. The molecular property and the potential physiological role of Cl.ir in the heart, however, are presently not known. The working hypotheses for this proposal are that 1) Cl.ir may be encoded by ClC-2 gene, a member of the large C1C Cl- channel family, since Cl. ir has many biophysical and pharmacological properties in common to those of CIC-2 channel when expressed in heterologous expression systems, and 2) ClC2 channels are important in the regulation of the electrical activity and cell volume adaptation in the heart. Three specific aims are proposed to address these hypotheses. Aim 1 will determine the molecular localization of ClC-2 and its correlation with functional Cl.ir distribution pattern in different regions in the heart and the cellular and subcellular (sarcolemmal or subsarcolemmal membrane) localization of ClC-2 channel protein. This information will also greatly facilitate our understanding of the physiological role of ClC-2 channels in heart since regulation of cardiac electrical activity is determined by the heterogeneity of ion channel distribution in different regions. Aim 2 will use combined molecular biological, electrophysiological, and pharmacological approaches to identify the molecular identity of cardiac Cl.ir channel. The results from the proposed experiments will determine whether ClC-2 is responsible for native Cl.ir channels and the resulting molecular clones will provide essential tools for the study of the basic features and the regulatory mechanism of native and recombinant ClC-2 channels at molecular, cellular, and single-channel levels. Aim 3 will characterize the contribution of CIC-2 Cl- channels to the modulation of cardiac electrical activity (including resting membrane potential, diastolic membrane potential, action potential duration and repolarization, automaticity, etc.) and the regulation of cell volume in the heart. Since activation of volume- and acidosis-regulated ClC-2 Cl- channels can produce significant effects on action potential duration and automaticity of both conducting and contractile cells, as shown in our new preliminary experimental data, these channels have important clinical significance for several heart diseases, such as
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arrhythmias, myocardial ischemia, hypertrophy, and congestive heart failure and represent new important targets for the development of new agents against these diseases. This project has significant potential of elucidating the normal physiological and possible pathophysiological role of the newly discovered cardiac ClC-2 channels in the heart. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHYSIOLOGY OF ELECTROGENIC NA/HCO3 COTRANSPORTERS Principal Investigator & Institution: Boron, Walter F.; Cellular/Molecular Physiology; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-JAN-1982; Project End 30-NOV-2006 Summary: A major task of the kidney tubule is to reabsorb filtered HCO-3 and generate "new" HCO-3, thereby preventing a fatal metabolic acidosis. About 80 percent of HCO-3 reabsorption and generation occurs in the proximal tubule (PT), which secretes H+ into the tubule lumen, titrating HCO-3 to CO2 + H2O. After entering the PT cell, the CO2 + H2O regenerate HCO-3, which exits across the basolateral membrane via the electrogenic Na/HCO3 cotransporter (NBCe1-A). Since the Pl's laboratory reported the expression cloning of this cotransporter nearly 5 yrs ago, both "pancreatic" (NBCe1-B) and "brain" (NBCe1-C) splice variants have been identified. These cotransporters play key roles in HCO-3 transport by other epithelia, and in pHi regulation by many cell types. NBCe1 is part of the Bicarbonate Transporter (BT) superfamily, along with the C1-HCO3 exchangers (AEs), two other Na+ -coupled HCO-3 transporters (the electroneutral NBC and the Na+ -driven C1-HCO3 exchanger), related proteins not yet fully characterized, and at least one new gene (known from human genome sequence). The major goal of this project is to elucidate the molecular physiology of electrogenic NBCs, particularly in the kidney. An ancillary goal is to elucidate the expression of other Na+ -coupled HCO-3 transporters in key renal cell types. The proposed work has three aims: (i) Develop molecular tools. We will obtain the cDNA for a new NBCe-related sequence identified in the genome, extend our panel of type-specific antibodies, and determine the localization of Na+ -coupled HCO-3 transporters in the kidney. (ii) Determine properties of wild- type electrogenic NBCs. Using heterologous expression in oocytes, we will determine the function of two cDNA clones likely to encode electrogenic NBCs. We will also determine the stoichiometry of the electro-genic NBCs; assess their dependence on Na+, HCO-3 and pH; ask whether they transport CO=3; characterize the interaction between NBCe1 and carbonic anhydrase II; and examine the action of PKA on NBCe1 in oocytes. (iii) Analyze structure-function relationships. We will determine the structural requirements for extra- and intracellular DIDS sensitivity, ask whether conserved putative DIDS-reaction motifs are involved in electrostatic trapping of HCO-3, assess naturally occurring human NBCe1 mutations, explore the topology of NBCe1, and-in collaboration with another laboratory-study the biochemistry of the isolated cytoplasmic N termini of NBCe1-A and -B. The proposed work should elucidate the role that the electrogenic Na/HCO3 cotransporter plays in renal function, both in health and disease. The results could have important implications for understanding the normal control of acid-base balance and renal-tubule acidosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PILOT STUDY--HEPATIC STEATOSIS Principal Investigator & Institution: Tien, Phyllis C.; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747
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Timing: Fiscal Year 2003; Project Start 15-MAR-2003; Project End 30-NOV-2007 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PILOT STUDY--REGIONAL BLOOD FLOW IN FRESH WATER TURTLES Principal Investigator & Institution: Crocker, Carlos E.; San Francisco State University 1600 Holloway Ave San Francisco, Ca 941321722 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006 Summary: The primary goal of this study is to increase understanding of the physiology of diving in North American freshwater turtles. This research will quantify how environmental hypoxia (severe < 50% oxygen saturation), and/or moderate hypoxia (75 - 50% saturation), which leads to hypoxic hypoxia, affects the cardiovascular system. Ischemic hypoxia can cause irreversible damage to tissues; the protection of brain and heart function during long-term submergence is critical to survival. Hypoxic hypoxia produces cardiac insufficiency and alters peripheral vascular resistance, and it is currently hypothesized that it results in significant changes in the regional distribution of cardiac output to the vital organs (e.g. brain, heart, liver), at the expense of non-vital tissues/organs (e.g. skeletal muscle, gastrointestinal tract). To test this hypothesis, experimental animals will be fitted with indwelling catheters and one or more surgically implanted ultrasonic flow probes, for the measurement of blood flow to specific organs/tissues during prolonged aquatic submergence. Periodic sampling from the indwelling arterial cannula will provide blood samples for analysis of physiologically important acid-base relevant ions, plasma stress hormone concentrations (primarily epinephrine and cortisol), blood gases (O2 and CO2) and pH. Overall, this research will show that systemic hypoxia, cold-induced metabolic depression, and the progressive metabolic acidosis associated with prolonged aquatic submergence results in preferential blood distribution that favors the vital organs over the 'less critical' tissue masses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PILOT--REGULATION OF RENAL PYRUVATE DEHYDROGENASE DURING ACIDOSIS Principal Investigator & Institution: Harris, Robert A.; Professor of Pharmacology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: The objective of this work is to establish the importance of regulation of the pyruvate dehydrogenase (PDH) complex in the kidney in maintenance of acid-base balance. Activity of the pyruvate dehydrogenase complex is regulated by covalent modification. Phosphorylation and inactivation of the complex is catalyzed by four pyruvate dehydrogenase kinase (PDK) isoenzymes; dephosphorylation by two pyruvate dehydrogenase phosphatase (PDP) isoenzymes. Unique regulatory properties of these isoenzymes and differences in their levels of expression in different cell types provide tissue specific control of the activity of the pyruvate dehydrogenase complex. The basis for this proposed work is our preliminary data indicating that two of the PDK isoenzymes, PDK2 and PDK4, are increased in the kidney by metabolic acidosis. We propose therefore that increased expression of these PDKs results in inactivation of pyruvate dehydrogenase complex, which promotes generation of new bicarbonate by
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the kidney. Our working hypothesis is that alterations in the expression of the PDK2 and PDK4 isoenzymes cause hyperphosphorylation and therefore inactivation of pyruvate dehydrogenase complex in kidney during metabolic acidosis. The hypothesis will be tested by: (a) determining the effects of acute and chronic metabolic acidosis and alkalosis on activity state of the PDH complex and the expression levels of its kinases and phosphatases in rat kidney; (b) determining whether the compensatory mechanism for metabolic acidosis is abnormal in the kidney of the PDK4 null mouse; and (c) establish factors and mechanisms that regulate expression of PDK2, PDK4, and PDP2 in the kidney. The findings are expected to provide new insight with respect to an important compensatory mechanism for life threatening metabolic acidosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTEIN NUTRITION IN EXPERIMENTAL UREMIA Principal Investigator & Institution: Mitch, William E.; Professor; Internal Medicine; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 01-SEP-1987; Project End 30-NOV-2005 Summary: Uremia is often associated with weight loss, reduced muscle mass and a low serum albumin. Our long-term goal is to identify cellular mechanisms causing protein malnutrition in uremia to improve treatment. In rats with chronic renal failure (CRF), we identified metabolic acidosis as a stimulus for accelerated muscle protein degradation. This proteolytic response was confirmed in patients and is now vigorously treated to improve their nutritional status but the mechanism(s) underlying muscle catabolism is unknown. Factors that we identified as activators of the ubiquitinproteasome (Ub-P'some) Proteolytic pathway in muscle are a low extracellular pH, glucocorticoids and a low insulin level. Important problems to be solved are: first, myofibrillar proteins are not degraded and adding actin blocks myosin degradation by the Ub-P'some system. Our Preliminary Results indicate that the protease, caspase 3, is induced by acidification and plays a role in the early stages of muscle cell proteolysis by degrading myofibrillar proteins and actin to a stage where degradation proceeds via the Ub-P'some pathway. A second problem is how to integrate multiple signals that can activate the Ub-P'some system. We propose that depressed phoshatidylinositol 3-kinase (PI 3-kinase) is a key step as: we find CRF reduces muscle PI 3-kinase activity and insulin (or IGF- 1) blocks caspase 3 activation in muscle cells. A third problem is to understand how signals that initiate muscle proteolysis invariably stimulate transcription of genes encoding components of the Ub-P'some pathway. Since clinical evidence suggests an important role for TNFalpha in causing muscle wasting in CRF, we will examine the opposing actions between glucocorticoids and a TNFalphainducible transcription factor, NF-kB, on transcription of the C3 proteasome subunit to understand the requirement for glucocorticoids in stimulating transcription in many catabolic conditions. Finally, we will examine how TNFalpha influences protein degradation in muscle of CRF rats and in cultured muscle cells. Our results will uncover cellular mechanisms regulating protein turnover in uremia and other catabolic conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REENTRANT WAVEFRONTS IN VENTRICULAR FIBRILLATION Principal Investigator & Institution: Chen, Peng-Shen; Director, Pacemaker and Icd Clinic; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024
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Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2002 Summary: Sudden cardiac death due to ventricular fibrillation (VF) is an important public health problem. However, our understanding of VF is limited. The broad, longterm objective of this research project is to elucidate the mechanisms of the generation and the maintenance of reentrant wavefronts in VF. The applicant has previously reported that the reentrant wavefronts are responsible for the generation VF in the canine model. In this grant application, the applicant proposes to study the reentrant wavefronts in VF both in vivo and in vitro. Computerized mapping studies will be performed in human patients and in dogs to document that reentrant wavefronts are present in Wiggers' stage II VF. Computerized mapping techniques and standard transmembrane microelectrode recording techniques will be used to study a novel in vitro model of sustained reentry. The following hypotheses will be tested: (1) Multiple reentrant wavefronts are present during Wiggers' stage II VF in humans, in normal healthy dogs, and in acutely ischemic dogs. (2) The reentrant wavefront circulates around an area of functional conduction block (the 'core' of reentry) formed by cells undergoing graded responses but not full action potentials. There is no anatomical barrier at the core of reentry. (3) In normal tissue, the cycle length of the reentrant wavefront is longer than the wavelength of the reentrant wavefront. Therefore, an excitable gap is present. (4) The size of the core and the duration of the excitable gap are both important in determining the generation and maintenance of reentry. (5) Perturbations that decrease the size of the core decrease the volume of tissue that is needed to support a reentrant wavefront. Therefore, the smaller the size of the core, the easier to induce multiple reentrant wavefronts and VF. (6) Perturbations that decrease the excitable gap can protect the reentrant wavefronts from termination by competing wavefronts. Therefore, the smaller the excitable gap, the longer the life-span of the reentrant wavefronts, and the easier for VF to sustain itself. (7) The size of the core and the excitable gap of the reentrant wavefronts are both decreased by ischemia, predisposing the heart to ventricular fibrillation in this setting. These studies will further our understanding of the basic mechanisms of the generation and maintenance of VF in humans, and lead to new insights into prevention and treatment of sudden cardiac death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF KIDNEY MEMBRANE ION CHANNELS Principal Investigator & Institution: Boulpaep, Emile L.; Professor; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: The proposed studies plan to characterize channels, in particular chloride channels, in cell membranes of proximal tubule cells, from kidneys of rabbit, salamander, or CFTR knockout mouse, using a combination of isolated perfused tubules, non-perfused renal tubules, and separated single cells that have preserved their epithelial polarity. Patch-clamp and optical techniques will be used. The specific aims are: 1. To test the hypothesis that the chloride channel in the basolateral membrane of the proximal tubule cells share many of the intrinsic properties of the cystic fibrosis transmembrane conductance regulator CI- channel, we will study the biophysics and kinetics of chloride channels in mammalian proximal tubule and the intracellular signal transduction pathways involved in their regulation. 2. To test whether the gating of the basolateral chloride channel in proximal tubule cells by hydrolytic and non-hydrolytic interactions of ATP is analogous to that of the CFTR CI-channel. 3. To test the hypothesis that the basolateral chloride channel in proximal tubule cells regulates
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transcellular chloride reabsorption by the proximal tubule, and that alterations of apical chloride uptake indirect modulate the function of the basolateral chloride channel. 4. To explore the alternative pathways for transcellular chloride movement in proximal tubules of a CFTR-knockout mouse. Although the kidney expresses CFTR, there appears to be no impaired ion transport in patients suffering from cystic fibrosis. We will use a CFTR-knockout mouse, in order to establish how chloride channels contribute to transcellular chloride movement, and whether there is a regulatory relationship between CFTR and other chloride pathways. 5. To test the hypothesis that epithelial polarity in dissociated cells is not maintained by intrinsic proteins associated with the tight junction, we will study a model of a proximal tubule cells, that maintains epithelial polarity for us to ten days, and examine the cytoskeletal interactions that are essential for preserving polarity. The overall scope of the project is to understand transepithelial solute movement by the kidney at the single cell membrane and single channel protein level and to contribute to the understanding of clinical disorders such as cystic fibrosis, hypertension, metabolic alkalosis, acidosis, and acute renal failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RENAL AND SYSTEMIC PH IMAGING BY CONTRAST-ENHANCED MRI Principal Investigator & Institution: Raghunand, Natarajan; Assistant Research Assistant; None; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAR-2005 Summary: (provided by applicant): This proposal seeks to develop a contrast-enhanced magnetic resonance imaging (MRI) method for imaging extracellular pH of tissues in vivo, with special emphasis on the kidneys. Perturbations of both renal and systemic pH may accompany diseases of the kidney such as renal tubular acidosis. The ability to image tissue pH, particularly renal pH, would be helpful to assess the extent and severity of such conditions, and also to non-invasively follow response to therapy in the affected tissue(s). GdDOTA-4AmP is a gadolinium-based MRI contrast agent with a pHdependent longitudinal water-proton relaxivity. As with all other Gd-based contrast agents, the enhancement in water-proton relaxation rate produced by GdDOTA-4AmP is also dependent on its local concentration. In order to measure pH in vivo using GdDOTA-4AmP, one needs an independent measure of its pharmacokinetics in the animal being imaged. We propose a dual-contrast-agent strategy to image pH, in which GdDOTA-4AmP and a pH insensitive analogue, GdDOTP, are sequentially injected into the animal 1 h apart, with T1-weighted MRI images being dynamically collected following both injections. In preliminary experiments in mice we have made the assumption that the pharmacokinetics of GdDOTP and GdDOTA-4AmP are identical in a given animal, based on the similar size and charge of the two molecules. We have calculated preliminary pH images of the kidneys and surrounding tissues which distinctly show regions of acid pH corresponding to the collecting ducts, and pH 7.0-7.4 in other regions of the kidneys, in control mice. pH images of an acetazolamide-treated mouse showed an increase of 0.5-1.0 pH units in all renal pixels, with an apparent decrease of pH in extra-renal pixels, as compared to control mice. The goal of this proposal is to refine this dual-contrast-agent strategy for pH imaging using GdDOTA4AmP and GdDOTP, and to characterize and minimize sources of error in the pH measurement. The specific aims of this proposal are three-fold: (i) To optimize the dualcontrast-agent technique for imaging renal pH; (ii) To optimize the dual-contrast-agent technique for imaging pH of non-renal tissues; (iii) To devise a compromise protocol for
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optimally imaging pH of renal and non-renal tissues in the same experiment, and apply it to measure dose vs. pH response in mice with acetazolamide-induced acidosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RENAL CONTRANSPORTER
NET
ACID
SECRETION
AND
THE
NA/K/2C1
Principal Investigator & Institution: Wall, Susan M.; Professor; Internal Medicine; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 01-APR-1993; Project End 31-JAN-2004 Summary: Two distinct genes (BSC-1 and BSC-2) encode the NA/+-K/+-2CI- cotransporter. BSC-1, or the "absorptive isoform", is kidney-specific and localizes to the apical membrane of the thick ascending limb. BSC-2, the "secretory" isoform, is widely distributed BSC-1 is responsible for the "single effect" of the countercurrent multiplier, and thereby generates an axial gradient in the medullary interstitium for ammonium and other solutes, facilitating net acid secretion and urinary concentration. In the thick ascending limb, NH/4 uptake by the Na/+-K/+-2CI-co-transporter (BSC-1) is highly regulated. Since BSC-2 localizes to the basolateral membrane of the rat alpha intercalated cell and since it is both an NH/4 amd a CO/transporter, it likely mediates net acid secretion. However, regulation of BSC-2 in the kidney and its role in net acid secretion are untested. Regulation of net CI- and H/+ secretion by the collecting duct requires transport of these ions to be regulated in parallel across the apical and the basolateral membrane of the collecting duct cell. With perturbations in acid-base balance such as chronic metabolic acidosis an increase in apical proton secretion is observed which results from up- regulation of the apical H/+-ATPase in parallel with the basolateral CI- HCO/3-exchanger. However, in the rat contribution of CI-/HCO/3exchange to transepithelial net acid and CI-secretion has not been established. Thus, another mechanism for net H/+ and/or CI-uptake across the basolateral membrane may be important in mediating or modulating transepithelial net acid secretion. We will determine the contribution of BSC-2 to transepithelial net acid and net CI-secretion. Moreover, we will determine if activity of the co-transporter is modulated in a fashion appropriate for correction of perturbations in acid-base balance. With the recent cloning of both isoforms of the co-transporter, the published structure has been exploited to raise antibodies against co-transporter peptides. These antibodies can be used to study the long term regulation of the co-transporter. Changes in protein immunoreactivity and mRNA can be correlated with changes in transport activity to determine the role of the co-transporter in acid-base homeostasis. Specific Aims are to determine the following in the rat OMCD: 1. If BSC-2 modulates net acid secretion through direct NH/4+ uptake. 2. If BSC-2 is a major contributor to transepithelial net CI- secretion. 4. To determine the mechanism of BSC-2 transport regulation. To answer these questions, isolated renal tubules perfused in vitro will be studied. Transport will be studied with microfluorimetry as well as pH sensitive fluorescent probes. Transporter immunoreactivity and message abundance will be studied using immunoblots, immunocytochemistry and RT PCR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RESTORATION REHABILITATION
OF
MUSCLE
FUNCTION
DURING
Principal Investigator & Institution: Vandenborne, Krista H.; Chair and Associate Professor; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104
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Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: The purpose of this study is to investigate the spatial distribution of brain lactate in children with lactic acidosis using 1H spectroscopic imaging. Brain lactic acidosis may occur in a number of very different conditions. Inborn errors of metabolism affecting the lactate-pyruvate metabolism or those leading to secondary lactic acid accumulation represent some of them. Data are acquired using either a hybrid of 1D, 4th order, transverse Hadamard Spectroscopic Imaging (HSI) and a 2D Chemical Shift Imaging (CSI) or a 2D CSI. With the hybrid technique multiple slices can be obtained, covering a greater volume of the brain. The volume of interest usually is 7x7x4 cm3. We apply this technique into the clinical setting. The patient population consists of children with the diagnosis of an inborn error of for instance the lactate metabolism, mitochondrial encephalopathies, primary lactic acidosis of unknown etiology. Data obtained in several patient studies revealed regional differences of brain lactate accumulation. The pattern of spatial distribution of lactate may identify different subsets of mitochondria which can be affected separately by different metabolic diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE EXCHANGERS
AND
REGULATION
OF
INTESTINAL
SODIUM/H+
Principal Investigator & Institution: Chang, Eugene B,.; Martin Boyer Professor of Medicine; Medicine; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-JUL-1986; Project End 31-MAR-2003 Summary: Intestinal epithelial cell Na-H exchanger (NHE) isoforms have very specialized functions, regulatory systems, cellular distribution, and regional patterns of expression which are inherently important in adapting to acute and chronic metabolic demands and changes in liminal Na load. Until now, the regulation of NHE isoforms has largely been studied in mutant, NHE-deficient, non-epithelial cells where some findings, particularly with the epithelial-specific NHE-2 and NHE-3 isoforms, substantially differ from NHE function and regulation in intact enterocytes. These isoforms are believed to be the major route for non-nutrient dependent Na absorption by the gut. Therefore, the goal of this proposal is to test the hypothesis that the role and regulation of intestinal epithelial NHE isoforms are unique and best studied in intestinal epithelial cells in vivo and in vitro. The first Specific Aim is to characterize the role of intestinal epithelial NHEs in mediating the adaptation of intestinal Na absorption following massive small bowel resection and chronic metabolic acidosis in the rat. Preliminary studies show striking isoform-, region-, and cell-specific changes in NHE function and expression in response to these conditions. Additional studies will be performed to define the cellular and molecular bases for these adaptive responses. Potential determinants of the adaptive changes in the NHE expression, i.e. alterations in Na luminal load or metabolic/hormonal perturbations, will be experimentally assessed. In Specific Aim #2, Caco-2/C2BBE (C2) intestinal epithelial cell monolayers will be used to examine specific mechanisms of NHE function, regulation, and expression in response to extracellular metabolic perturbations and stimuli. C2 cells spontaneously differentiate in culture, have endogenous NHE-1, but little apical NHE expression, and, when transfected with NHE-2 or NHE-3, demonstrate correct sorting and functional and regulatory characteristics of these proteins that correlate with observations made in native enterocytes. NHE isoform activities expressed in C2 cells can also be separately measured. The roles of protein phosphorylation, membrane recycling, post-translational modifications, and potential regulatory roles of NHE binding proteins in mediating NHE responses to hormonal stimuli, luminal Na load, metabolic acidosis, and states of
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cellular differentiation will be examined. These studies will provide important insights into the gut-specific cellular and molecular mechanisms for regulation of intestinal epithelial NHEs and into physiologically-relevant mechanisms mediating the Na absorptive response of the gut to acute and chronic metabolic perturbations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF ACID-SENSING ION CHANNELS IN GLAUCOMA Principal Investigator & Institution: Saugstad, Julie A.; Emanuel Hospital and Health Center Portland, or 972083950 Timing: Fiscal Year 2004; Project Start 01-DEC-2003; Project End 30-NOV-2006 Summary: (provided by applicant): Glaucoma comprises a group of ocular disorders that exhibit characteristic optic nerve degeneration (glaucomatous optic neuropathy, GON), associated with concomitant visual field loss, and often, increased intraocular pressure (lOP). In many individuals, reduction of lOP ameliorates vision loss, but many others continue to lose vision despite pressure lowering. There are no therapies that directly target and prevent GON. While the exact underlying mechanisms of GON are being elucidated, specific patho-physiological changes (such as mechanical trauma and ischemia) ultimately lead to the death of retinal ganglion cells and their axons. We have directed our attention to a newly discovered family of proteins; acid-sensing ion channels (ASICs), which appear to be significant in brain injury. The ASICs are protonactivated sodium selective cation channels comprised of six subtypes that are expressed throughout the nervous system. They respond to acidic and mechanical stimuli activating in response to acidosis and swelling, notable features of ischemic brain injury. Recent studies reveal that rabbit retinal neurons and gila express ASIC messenger RNA. Thus ASICs could respond to mechanical stimulation in the eye from increased intraocular pressure and/or ischemic changes within the retina and optic nerve, two mechanisms commonly implicated in the pathogenesis of GON. These findings make retinal ASICs attractive cellular mediators for investigation. Our preliminary studies support a role of ASICs in the retina: immunoblot analysis of the ASIC2a subtype reveals a dramatic increase in expression in the retina and optic nerve of glaucomatous human tissue relative to age-matched controls. Upregulation of brain ASIC2a may be important for cell survival as cells expressing ASIC2a are less responsive to injury. Our laboratory has shown that neurons that survive an ischemic insult have increased levels of ASIC2a protein, suggesting a neuroprotective role for ASIC2a. This prediction is supported by the observation that ASIC2a alters the ion channel activation properties when it is complexed with ASICla, a subtype that is implicated in cell injury. Cells expressing homomeric ASICla channels are injured by low pH and modeled ischemia, while heteromeric ASICla/2a channels are less vulnerable to injury. Physiological studies lend insight into this finding; the pH of half-maximal activation (pHo.s) for ASIC2a channels is 4.35, for ASICla channels is 6.2, whereas ASICla/ASIC2a heteromeric channels is 4.8. This could be significant in the context of injury, where intracellular calcium overload has been implicated as a primary mechanism of neuronal injury. The goal of these studies is to characterize fully the expression of ASIC2a in the retina and optic nerve of normal and glaucomatous tissue, and to determine whether ASIC2a enhances cell survival in response to injury and could potentially serve as a therapeutic target for the treatment or prevention of glaucoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SENSITIZATION TO THERMORADIOTHERAPY IN HUMAN XENOGRAFTS Principal Investigator & Institution: Leeper, Dennis B.; Professor; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 31-MAR-2007 Summary: Project 1 serves the program by testing the hypothesis that acute acidification by lactic acidosis will enhance thermosensitization and selectively sensitize melanoma xenografts to radiotherapy. Protocols were established for acute acidification to less than or equal too pH3 6.3 and oxygenation of melanoma has uniquely high activity of H+ linked monocarboxylate transporters (MCT, a.k.a. lactate symport) that are the major membrane proton exchange. Although thermosensitization by acidification was demonstrated, radiation must be combined with hyperthermia to achieve local control. Five specific aims will test the hypothesis and investigate mechanisms of melanoma acidification. Aim 1 will investigate inhibition of mitochondrial respiration by metaiobenzylguanidine (MIBG) on melanoma acidification and oxygenation for sensitization to thermoradiotherapy. Variation in glycolytic/respiratory ratio among frozen melanoma biopsy cell suspensions will indicate relative susceptibility to MIBG. Aim 2 will investigate inhibition of the MCT either by alpha-cyano-4-hydroxy-cinnamic acid (CNCn) or by Ionidamine on acidification of melanoma and sensitization to thermoradiotherapy. The activity of the plasma membrane MCT among stored melanoma biopsy cell suspensions will indicate relative susceptibility to CNCn or Ionidamine. Aim 3 will identify the utility of combining MIBG and CNCn as a cocktail to acidify and oxygenate all melanomas. Melanomas with high rates of respiration will be sensitive to MIBG, and those with high rates of glycolysis sensitive to CNCn. In each protocol excess glucose must be combined with inhibitors to fuel lactate production. Two different F2 melanomas xenografts in nude mice will be studied that differ in vascularity, radiation sensitivity and expression of heat shock proteins. Tumor growth delay will be compared with tibial bone marrow toxicity to establish therapeutic gain. Cellular radiation response parameters in vitro will be determined in Project 3. Project 1 provides mice with melanoma xenografts to Project 2, so that together with Core A, biological endpoints can be investigated to predict response of melanomas and normal tissues to treatment pH9, pHi, 23Nai, pO2, oxygen consumption, bioenergetics and blood flow. Aim 4 supports Project 3 to determine the effect of acute acidification on apoptosis and the relationship with hyperthermia-induced upregulation of hsp70 in DB1 xenografts grown up from cell stably transfected with the gene for enhanced green fluorescent protein (egfp) under control of the hsp70 promoter. Aim 5 with Project 3 supports Project 4 to confirm whether nucleolin translocation is a determinant of heat response in vivo by measuring nucleolin movement from the nucleolus into the nucleoplasm in DB-1 xenografts as a function of acidification during hyperthermia. Acute tumor acidification will have the clinical effect of increased tumor temperature with additional benefit from increased tumor oxygenation. These results will help direct a Phase I/II trial conducted by Dr. Douglas Fraker, Univ. of Penn. To demonstrate the effects of acidification of melanoma response to limb perfusion with melphalan at 42 degrees Centigrade. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SEVERE MALARIA IN AFRICAN CHILDREN: A CLINICAL NETWORK Principal Investigator & Institution: Taylor, Terrie E.; Distinguished University Professor; Internal Medicine; Michigan State University 301 Administration Bldg East Lansing, Mi 48824 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-JUL-2004 Summary: Malaria remains a major scourge in sub-Saharan Africa, killing 1-2 million children each year. Major advances in our understanding of disease pathogenesis have occurred, along with the emergence of drugs which kill the malaria parasite twice as rapidly quinine, the current drug of choice--- but the mortality rate for severe malaria has not changed. Between 15-40% of children with cerebral malaria, malaria-associated acidosis and/or severe anemia will die, and half of those deaths occur within 12 hours of arriving at a hospital. Five clinical centers with much experience of severe malaria in African children have joined together to form a clinical trials network (SMAC). Individually frustrated by our own attempts to demonstrate any impact of promising interventions on malaria mortality, we have decided that our fundamental goal, to lower the death rate associated with severe malaria in African children, would be best realized by conducting mortality-based multi-center studies. This approach is necessary because there are no surrogate markers for outcome deaths in any one site are rare We are proposing to evaluate fluid resuscitation in children with malaria complicated by acidosis, and pentoxifvrnne (PTX) as adjunct therapy in children with cerebral malaria. Both of these require pilot studies (1 year) prior to the larger clinical trials. Our network is also well-positioned to evaluate "disease associations" which may illuminate pathogenetic processes or reveal potential new targets. Because it is simple to assess and because there are plausible biological and parasitological implications, we would like to determine the predictive value of intraleukocvtic DiQment in children with P. falciparum infections. This study will be part of an ongoing network activity, describing the malaria experience in each site using standardized information collected prospectively and archived in a database. The statistical and administrative "cores" will facilitate the efforts of the network. Data will be entered at each site and transmitted to a central facility (at one of the five sites) for analysis. There will be an annual SMAC meeting, and the intervals between meetings will be punctuated by frequent visits between sites so that young investigators can standardize their observations and experience other settings. This capacity to conduct multi-center trials in severe pediatric malaria has not existed before. The statistical power of a large group can unearth even a small decrease in mortality associated with a particular intervention. Given the enormous toll of malaria, this could re resent a significant decline in the death rate across sub-Saharan Africa. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURE AND FUNCTION OF MITOCHONDRIAL PROTEIN KINASE Principal Investigator & Institution: Chuang, David T.; Associate Professor; Biochemistry; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 31-DEC-2007 Summary: (provided by applicant): The long-term goal of this project is to understand the structure and function of a novel family of mitochondrial protein kinases (mPKs). The mPK members consist of branched-chain alpha-ketoacid dehydrogenase kinase (BCK) and the four isoforms of pyruvate dehydrogenase kinase. They are molecular
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switches that down-regulate the oxidation of alpha-ketoacids and pyruvate. Elevated levels of these metabolites are implicated in disease states such as insulin-resistant Type II diabetes, branched-chain ketoaciduria, and primary lactic acidosis. BCK is a component of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. This macromolecular multi-enzyme complex is organized about a 24-meric transacylase (E2b) scaffold, to which a decarboxylase (Elb), a dehydrogenase (E3), the BCK and the BCKD phosphatase are attached through ionic interactions. The P.I.'s laboratory has recently determined the structure of the rat BCK. The BCK structure features a characteristic nucleotide-binding domain and a four-helix bundle domain. These two domains are reminiscent of modules found in protein histidine kinases (PHKs), which are involved in two-component signal transduction systems. In this application, the P.I. proposes: 1) to identify and characterize the domains/regions in BCK, which interact with Elb (the substrate) and E2b (the regulator) components of the BCKD complex; 2) to decipher the functional significance of nucleotide-induced domain communication in BCK; 3) to elucidate the reaction mechanisms for the BCK-catalyzed ATP hydrolysis and phosphotransfer in BCK. The information derived from the proposed studies will provide mechanistic insights into the regulation of alpha-ketoacid dehydrogenase complexes by reversible phosphorylation. This knowledge will have wide implications for understanding conservation in the reaction mechanism for protein kinases involved in signal transduction as well as how this mechanism is perturbed in human diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SUBUNIT STRUCTURE AND FUNCTION IN VACUOLAR H+ATPASE Principal Investigator & Institution: Kane, Patricia M.; Professor; Biochem and Molecular Biology; Upstate Medical University Research Administration Syracuse, Ny 13210 Timing: Fiscal Year 2003; Project Start 01-MAR-1994; Project End 31-MAY-2007 Summary: (provided by applicant): Vacuolar proton-translocating ATPases (V-ATPases) couple hydrolysis of cytosolic ATP to proton transport into organelles of all eukaryotic cells and across the plasma membrane of some cell types. Organelle acidification, the major constitutive function of V-ATPases, is essntial for many physiological processes, but is also linked to a number of disease states. For example, acidification of phagosomes is essential for killing invading bacteria, but many viruses and toxins exploit the acidic environment generated by V-ATPases to facilitate their escape from organelles into the cytoplasm where they become biologically active. Plasma membrane V-ATPases are involved in renal acid secretion and osteoclast bone dissolution; mutations in tissue-specific V-ATPase subunit isoforms necessary for these processes result in genetic diseases characterized by metabolic acidosis and osteoporosis. The long-term goal of the lab is to understand the structure, function, assembly and regulation of V-ATPases by studying the yeast V-ATPase, which has proven to be an excellent model for all eukaryotic V-ATPases. All V-ATPases are composed of two multisubunit domains, a peripheral membrane complex involved in ATP hydrolysis and an integral membrane complex required for proton transport. In this proposal, we focus on the "stalk" subunits that structurally and functionally bridge these two domains. These subunits are responsible for transmission of conformational changes resulting from ATP hydrolysis to the proton pore, and are also key players in regulated disassembly of V-ATPases, an important regulatory mechanism. The aims of this proposal are: 1) to position the stalk subunits in the yeast V-ATPase, by a combination of
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electron microscopy, hydrodynamic studies of subcomplexes, mutagenesis, and crosslinking experiments, 2) to elucidate the roles of the C and H subunits, particularly in the functionally important conformational change accompanying release of the peripheral sector from the membrane sector, 3) to examine protein-protein interactions with two isoforms of the "a" subunit and test their importance in regulated disassembly, and 4) to follow V-ATPase assembly and disassembly in vivo using GFP-tagged VATPase subunits. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THEORY OF SOLUTE AND WATER TRANSPORT ACROSS EPITHELIA Principal Investigator & Institution: Weinstein, Alan M.; Professor of Medicine and Physiology; Physiology and Biophysics; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2003; Project Start 01-AUG-1981; Project End 31-JAN-2006 Summary: A mathematical model of the mammalian distal nephron will be developed, comprised of cellular models of ascending Henle limb, distal tubule, and collecting duct. The model will represent sodium, potassium, and acid/base transport under normal and pathological conditions, and will predict renal excretion from distal delivery. The project begins with models of the three collecting duct segments; it will require development of two distal tubule segments plus an ascending limb, and then concatenation of all segments into a distal nephron. The segmental models will incorporate representations of specific membrane transporters: in distal tubule, the NaCI cotransporter, and in ascending limb, the luminal Na-K-2CI and peritubular K-CI cotransporters. Segment-specific issues, as well as segmental interactions will be considered. For the collecting duct, proposed lesions underlying distal renal tubular acidosis (ATPase failure, base-exit defects, or paracellular leak) will be examined, and clinical tests for identifying these lesions will be simulated. In this, the objective is to examine the rationalization for the clinical taxonomy of distal tubular acidosis. The distal tubule model will be used to examine flow- dependence of potassium secretion, to estimate the component attributable to luminal gradient attenuation. This will be preliminary to quantifying the alkalinizing and potassium-wasting effect of thiazide diuretics, which act on distal tubule. In the ascending limb, an important focus will be identifying the modulated transporters responsible for cellular homeostasis, specifically, mechanisms used to accommodate large reabsorptive fluxes of sodium and ammonium, while preserving cell volume and pH. In ascending limb, the three different transport defects which all present as Bartter's syndrome will be simulated, to understand the potassium depletion alkalosis common to all three. The full distal nephron model will be required to critically examine the proposal that medullary interstitial potassium concentration modulates overall renal potassium and acid excretion: namely, that by blunting ascending limb sodium reabsorption, peritubular potassium sends more sodium to distal tubule and collecting duct where potassium secretion and base reabsorption depend on sodium delivery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TISSUE SPECIFIC NUTRITIONAL ADAPTATIONS IN RENAL FAILURE Principal Investigator & Institution: Price, S Russ.; Associate Professor; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322
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Timing: Fiscal Year 2002; Project Start 01-AUG-1996; Project End 31-MAY-2004 Summary: The essential branched-chain amino acids (BCAA) play critical roles in maintaining normal protein homeostasis and they influence critical intracellular signaling pathways that regulate metabolic functions. In normal individuals, nutritional adaptations to a reduced dietary protein intake (e.g., fasting, a low protein diet prescription) decrease the irreversible degradation of BCAA. Catabolic conditions like chronic renal failure (CRF) or acute diabetes impair these adaptive responses that preserve protein mass, thus contributing to the loss of lean body mass. The goals of Dr. Price and colleagues are to understand the mechanisms that regulate the activity of branched-chain alpha-ketoacid dehydrogenase (BCKAD), the rate-limiting enzyme in BCAA degradation, in the major tissues where BCAA are catabolized, and to determine if there are common signals in different catabolic states that regulate BCKAD activity, and hence, BCAA levels. To address these goals, the investigators will evaluate three hypotheses: 1) Acidification and glucocorticoids influence transcription of BCKAD subunit genes through specific cis-acting response elements. The investigators will identify specific DNA promoter elements in the BCKAD E2 gene that confer responses to acidification and glucocorticoids. 2) Abnormalities in BCAA utilization in rats with CRF result from tissue-specific alterations in BCKAD activity at both genetic and biochemical levels. The investigators will define how CRF influences the activities of BCKAD and BCKAD kinase, a unique kinase that inhibits BCKAD activity, in muscle, liver and kidney in a well-established rat model. They will measure BCKAD activity, BCKAD subunit and kinase proteins and amounts of subunit and kinase mRNAs 3) Insulin modulates BCKAD and/or BCKAD activities in different tissues by a mechanism requiring the critical signaling enzyme phosphatidylinositol 3-kinase. The investigators will determine the biochemical mechanism(s) that increase BCKAD activity in rat muscle, liver and kidney in response to acute diabetes mellitus (i.e., insulin insufficiency) and then examine the signaling mechanisms by which insulin regulates BCKAD and BCKAD kinase in cultured L6 muscle cells. The investigators findings will define cellular mechanisms regulating BCAA degradation in uremia, acute diabetes and other catabolic conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRIAL OF OCTREOTIDE IN HOSPITALIZED PATIENTS Principal Investigator & Institution: Burge, Mark R.; Assistant Professor; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TROPONIN AND HEART FUNCTION IN HEALTH AND DISEASE Principal Investigator & Institution: Metzger, Joseph M.; Professor; Molecular and Integrative Physiology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 08-DEC-1997; Project End 31-AUG-2006 Summary: (provided by applicant): This grant is focused on cardiac troponin I (cTnl), an essential protein of the cardiac sarcomere. Transgenic mouse studies have given conflicting results as to whether Tnl phosphorylation plays any role in the increased rate of myocardial relaxation during adrenergic stimulation. In addition, a major theme of this proposal is that heart function differs markedly between rodents and higher
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mammals due to key differences in contractile isoforms and calcium handling. Consequently, results obtained from transgenic experiments may not necessarily translate to cardiac myocytes that have more "human-like" functional properties. The working hypothesis of this proposal is that cTnl phosphorylation status has an important role in the relaxation rate of canine myocytes that more closely resemble the functional properties of human cardiac muscle. Additionally, the acidosis accrued in myocardial infarction depresses cardiac function in part by altering Tnl function. The working hypothesis is that a charged amino-acid motif in the C-terminus of cTnl defines the critical switch domain responsible for acidic pH-induced alterations in Tnl function in myocytes from both small and large mammals. We have developed and optimized a gene transfer/primary culture system that takes advantage of the broad j species tropism of adenoviral vectors to accomplish rapid and efficient replacement of Tnl in living adult cardiac myocytes isolated from functionally divergent mammals. This technology is unique in the field as it allows rapid genetic engineering of TnI in living cardiac myocytes with "human-like" contractile function. The Specific Aims are: Aim 1. To compare in adult cardiac myocytes from small and large mammals the direct effects of b-adrenergic-mediated Tnl phosphorylation on contractile performance. Aim 2. To compare transgenesis versus gene transfer, focusing on the functional effects of phospho-mimetic Tnls in adult cardiac myocytes. Hypothesis: In comparison to wildtype rodent cardiac myocytes, myocytes expressing a phosphorylation mimetic cTnI (Ser23/24Asp) obtained by transgenesis or gene transfer will exhibit desensitization of calcium-activated isometric tension and enhanced relaxation kinetics. Aim 3. To establish in a range of mammalian myocytes, the molecular basis for Tnl-isoform dependent altered calcium sensitivity of tension under normal and acidic pH conditions. Hypothesis: A highly charged and isoform variable motif in the C-terminus of Tnl defines the acidic pH-mediated decrease in tension in all mammalian species. Collectively, these studies will provide new information about Tnl function in cardiac myocytes from large versus small mammals, and will help identify new potential therapies for enhanced myofilament function in diseased myocardium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: UTILIZING ETHYL NITRATE GAS IN LAPAROSCOPIC SURGERY Principal Investigator & Institution: Reynolds, James D.; Anesthesiology; Duke University Durham, Nc 27710 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: The principal goal of this project is to evaluate the ability of ethyl nitrate to attenuate the reduced tissue perfusion and respiratory acidosis produced during carbon dioxide pneumoperitoneum. The studies will use a novel method of drug delivery: inclusion of ethyl nitrate in the insufflating gas. Laparoseopy has rapidly become the method of choice for surgical intervention to correct abdominal pathologies. However, pneumoperiteneum, the act of insufflating the peritoneal cavity with gas, is not without physiologic consequence: pulmonary function is impaired and organ blood flows altered. In addition, due to its plasma solubility, insufflation with CO2 will increase pCOz and decrease blood pH, actions that can produce respiratory acidosis, tachycardia, and arrhythmia. The overall effects can become profound in the presence of underlying vascular disease, in[ the elderly, if the patient is pregnant, and/or when the duration of surgery is extended. In all situations, tissue ischemia and fetal ischemia (where applicable) can produce significant morbidity. To control this, it is a logical supposition that administration of a vasoactive agent to increase tissue blood flow and gas exchange would be beneficial. For the purposes of this study, we propose to
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introduce a nitric oxide donator (ethyl nitrate; E-NO) into the insufflating gas. As the released nitric oxide can act locally (i.e. within the peritoneum) as well as entering the systemic circulation and, in the case of the gravid patient, the fetal circulation (either by diffusion or maternal-fetal exchange), this would appear to be an ideal methodology to abate the CO2 pnenmoperiteneum-mediated changes in physiologic status. Such abatement is expected to be of long-term benefit to all laparoscopic patients including the parturient and her fetus. To evaluate this novel therapy, we will test two research hypotheses: 1. In the non-gravida, inclusion of E-NO in the insufflating gas attenuates the tissue perfusion changes produced by CO2 pneumoperitoneum; and 2. In the parturient, inclusion of E-NO during maternal pneumoperitoneum stabilizes fetal physiologic status. Studies will utilize adult swine and pregnant sheep. Completion of this investigation will produce clinically-relevant information that will be of significant interest to surgeons With patients in need of laparoscopic surgery and to obstetricians who are presented with parturients in abdominal distress. It is expected that the results of these studies will be used to further develop and refine standards of care for human laparoscopy and will lead to a novel therapy for controlling the blood flow changes produced during pneumoperitoneum. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VASCULAR KATP CHANNEL MODULATION IN HYPERCAPNIC ACIDOSIS Principal Investigator & Institution: Jiang, Chun; Associate Professor; Biology; Georgia State University University Plaza Atlanta, Ga 30303 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): ATP-sensitive K+ channels (KATP) couple the intermediary metabolism to cellular excitability, and play an important role in reactive hyperemia. It is known that hyperemia underlies the cardio-protective effect of ischemic preconditioning and the activity-dependent auto-regulation of cerebral circulation, and involves sensing of O2, CO2 and pH. Our recent studies indicate that KATP channels are indeed activated with high COz / low pH. The regulation of KATP by protons is significant, because a drop in pH levels often accompanies various metabolic stresses and is more frequently seen than sole energy depletion. Such regulation may enable cells to change their membrane excitability in response to a wide variety of physiologic and pathophysiologic conditions. However, previous studies on the pH sensitivity were rather controversial: proton was shown to stimulate cell-endogenous KATP in some studies but inhibit it in others. The inconsistence is further complicated by the indirect effect of ATP, ADP and Mg ++ on channel activity. Thereby, it is unclear how the KATP is modulated during hypercapnia and acidosis, whether these channels are inherently pH-sensitive, and what the molecular mechanisms underlying the modulation are. The cloned KATP channels are ideal for addressing these questions, which allow a fine dissection of the modulatory mechanisms and elaborate manipulations of PCO2 and pH in the expression system. Thereby, we have been studying the pH sensitivity of the cloned KATP over the past 3 years. Our preliminary data have clearly shown that proton is a potent activator of the KATP. TO further these observations, we have proposed studies aimed at 1) elucidating the modulation of KATP by hypercapnia and acidosis, 2) demonstrating the sensing mechanisms in the channel proteins, 3) determining factors and their interactions with protons in regulating the pH sensitivity, and 4) identifying the pH-sensitive KATP isoforms in vascular smooth muscles. This information should have profound impacts not only on cardiovascular physiology but
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also on the design of therapeutical modalities by manipulating the pH-sensing mechanisms to control cellular activity in stroke, epilepsy and coronary heart disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VENTILATOR-INDUCED CONSEQUENCES
LUNG
INJURY:MECHANISMS
&
Principal Investigator & Institution: Sinclair, Scott E.; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-AUG-2002 Summary: Mechanical ventilation is an important tool in the management of respiratory failure. However, the ventilation strategy can initiate or exacerbate lung injury. Several mechanisms have been implicated in ventilator-induced lung injury (VILI), particularly cyclical airway collapse and reopening. Inferential data supports cyclical airway collapse as an important factor in the genesis of VILI, but it has never been definitively documented. Strategies minimizing alveolar over distension and cyclical airway closure decrease mortality in ARDS patients but are confounded by hypercapnic acidosis, itself a potential modulator of lung injury. Establishing the presence of cyclical airway collapse, its abolition with palliative interventions, and correlation with severity and distribution of injury is vital to understanding VILI and developing relevant strategies to prevent it. This proposal will evaluate mechanisms by which mechanical ventilation induces lung injury and initiates inflammation in a rabbit model of VILI caused solely by mechanical forces. I will address the following questions: 1) Is cyclical airway collapse and reopening a stimulus for inflammation? 2) Where in the lung and on which cell types do mechanical forces exert their effects? 3) Can we definitively document cyclical airway closure? 4) If so, can we accurately predict ventilatory conditions that prevent it? 5) Do non- mechanical forces (hypercapnia) play a protective role in VILI? Methods: Spatial inflammation distribution measured with monoclonal antibody ELISA and immunohistochemistry. Spatial injury measured by extravascular albumin accumulation and gravimetrics. Regional V and Q measured with aerosolized and perfused fluorescent microspheres. Global gas exchange measured with the multiple inert gas elimination technique. Ventilation heterogeneity measured with multiple breath nitrogen washout. Aim 1A: Examine how posture change and PEEP effect severity and distribution of injury and inflammation. Aim 1B: Determine the anatomical location and cell type(s) responsible inflammation in VILI. Aim 2A : Measure effects of hypercapnia on lung injury and inflammation during VILI. Aim 2B: Examine how hypercapnia alters hypoxic pulmonary vasoconstriction and reduces VILI. Aim 2C : Examine how hypercapnia effects ventilation heterogeneity and reduces VILI. Aim 3A: Document cyclical airway collapse and reopening via changes in regional ventilation distribution. Aim 3B: Validate a method to estimate appropriate PEEP level to prevent cyclical airway collapse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ZINC NEUROTOXICITY IN TRAUMATIC BRAIN INJURY Principal Investigator & Institution: Prough, Donald S.; Chairman; Anesthesiology; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 15-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): After traumatic brain injury (TBI), systemic hypotension causes secondary ischemic brain injury that markedly worsens mortality and neurologic outcome. We will test the hypothesis that, as a consequence of TBI and
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posttraumatic hemorrhagic hypotension, neurotoxic concentrations of Zn2+ are released from presynaptic glutamatergic vesicles in association with glutamate, enter postsynaptic neurons through receptor-associated calcium channels (especially AMPA/kainite receptors) and voltage-operated calcium channels, and worsen outcome by accumulating in postsynaptic neurons. Specific aim 1: In rats subjected to TBI with our without hypotension, we will test the hypothesis that neuronal Zn2+ accumulation is related to Zn2+ release, which is proportional to the severity of TBI and hypotension and the interval between TBI and hypotension. Methodologies: microdialysis (Zn2+ and glutamate); staining with the Zn2+-specific dye TSQ (intracellular Zn2+ accumulation); vanadium acid fuchsin (VAF) staining (acute cell injury); staining for DNA fragmentation (TUNEL); ribonuclease protection assays (apoptosis); neuronal counts (histopathologic outcome), and beam walking, beam balance and the Morris water maze (neurobehavioral outcome). Specific aim 2: In rats subjected to moderate TBI with or without hypotension, we will address the hypothesis that after TBI, Zn2+ enters neurons through receptor-associated calcium channels and voltage-operated calcium channels (VOCCs) and that entry through (VOCCs) is enhanced by posttraumatic brain tissue acidosis. Interventions: the NMDA receptor antagonist MK-801, the AMPA/kainite receptor antagonist LY300164, the L-type calcium channel antagonist nimodipine, and increases and decreases in extracellular pH. Methodologies: microdialysis, TSQ staining, and VAF staining. Specific aim 3: In rats subjected to moderate TBI and hypotension, we will address the hypothesis that after, TBI and hypotension, modifying extracellular Zn2+ concentrations will modify neurobehavioral and histopathologic injury. We will test this hypothesis by using intracerebroventricular (icv) injection of Zn2+ and by icv injection of the specific Zn2+-binding apoenzyme of carbonic anhydrase. Methodologies: identical to specific aim 1 plus monitoring for signs of neurologic zinc deficiency. 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 “acidosis” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for acidosis in the PubMed Central database: •
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A Comparison of the Effects of Glucose Ingestion and NH4Cl Acidosis on Urinary Calcium and Magnesium Excretion in Man. by Lennon EJ, Piering WF.; 1970 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=322619
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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A Point Mutation of the Na+/H+ Exchanger Gene (NHE1) and Amplification of the Mutated Allele Confer Amiloride Resistance Upon Chronic Acidosis. by Counillon L, Franchi A, Pouyssegur J.; 1993 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46541
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Acute metabolic acidosis enhances circulating parathyroid hormone, which contributes to the renal response against acidosis in the rat. by Bichara M, Mercier O, Borensztein P, Paillard M.; 1990 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296745
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Acute Reversal of Experimental Diabetic Ketoacidosis in the Rat with (+)Decanoylcarnitine. by McGarry JD, Foster DW.; 1973 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302335
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An Experimental Renal Acidification Defect in Patients with Hereditary Fructose Intolerance. I. ITS RESEMBLANCE TO RENAL TUBULAR ACIDOSIS. by Morris RC Jr.; 1968 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=297294
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An Experimental Renal Acidification Defect in Patients with Hereditary Fructose Intolerance. II. ITS DISTINCTION FROM CLASSIC RENAL TUBULAR ACIDOSIS; ITS RESEMBLANCE TO THE RENAL ACIDIFICATION DEFECT ASSOCIATED WITH THE FANCONI SYNDROME OF CHILDREN WITH CYSTINOSIS. by Morris RC Jr.; 1968 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=297322
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An Inherited Defect Affecting the Tricarboxylic Acid Cycle in a Patient with Congenital Lactic Acidosis. by Blass JP, Schulman JD, Young DS, Hom E.; 1972 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292332
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Attainment and Maintenance of Normal Stature with Alkali Therapy in Infants and Children with Classic Renal Tubular Acidosis. by McSherry E, Morris RC Jr.; 1978 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=372562
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Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. by Sly WS, Hewett-Emmett D, Whyte MP, Yu YS, Tashian RE.; 1983 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=393906
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Changes in Bone Sodium and Carbonate in Metabolic Acidosis and Alkalosis in the Dog. by Burnell JM.; 1971 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=291928
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Conventional or physicochemical approach in intensive care unit patients with metabolic acidosis. by Moviat MA, van Haren FM, van der Hoeven JG.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=270679
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Cytoplasmic acidosis as a determinant of flooding intolerance in plants. by Roberts JK, Callis J, Jardetzky O, Walbot V, Freeling M.; 1984 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=391852
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Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. by King MP, Koga Y, Davidson M, Schon EA.; 1992 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=364194
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Deficiency in ubiquinone cytochrome c reductase in a patient with mitochondrial myopathy and lactic acidosis. by Darley-Usmar VM, Kennaway NG, Buist NR, Capaldi RA.; 1983 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=384197
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Delivery dependence of early proximal bicarbonate reabsorption in the rat in respiratory acidosis and alkalosis. by Santella RN, Maddox DA, Gennari FJ.; 1991 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296353
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Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state. by Chiasson JL, Aris-Jilwan N, Belanger R, Bertrand S, Beauregard H, Ekoe JM, Fournier H, Havrankova J.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151994
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Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1. by Blomqvist SR, Vidarsson H, Fitzgerald S, Johansson BR, Ollerstam A, Brown R, Persson AE, Bergstrom G, Enerback S.; 2004 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=419486
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Drug points: Fatal lactic acidosis associated with tenofovir. by Rivas P, Polo J, de Gorgolas M, Fernandez-Guerrero ML.; 2003 Sep 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=200801
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Effect of Acute Hypoxia and Hypercapnic Acidosis on the Development of Acetylstrophanthidin-Induced Arrhythmias. by Williams JF Jr, Boyd DL, Border JF.; 1968 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=297349
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EFFECT OF ACUTE METABOLIC ACIDOSIS AND ALKALOSIS ON ACETATE AND CITRATE METABOLISM IN THE RAT. by Gordon EE.; 1963 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=289262
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Effects of the ionophores monensin and tetronasin on simulated development of ruminal lactic acidosis in vitro. by Newbold CJ, Wallace RJ.; 1988 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=204415
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Endothelin-1/endothelin-B receptor --mediated increases in NHE3 activity in chronic metabolic acidosis. by Laghmani K, Preisig PA, Moe OW, Yanagisawa M, Alpern RJ.; 2001 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=200190
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Enzymatically Inactive Red Cell Carbonic Anhydrase B in a Family with Renal Tubular Acidosis. by Shapira E, Ben-Yoseph Y, Eyal FG, Russell A.; 1974 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=301438
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Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency. by Haller RG, Lewis SF, Estabrook RW, DiMauro S, Servidei S, Foster DW.; 1989 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303965
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Experimental Metabolic Acidosis: The Enzymatic Basis of Ammonia Production by the Dog Kidney. by Pollak VE, Mattenheimer H, DeBruin H, Weinman KJ.; 1965 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292466
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Expression of rat renal Na/H antiporter mRNA levels in response to respiratory and metabolic acidosis. by Krapf R, Pearce D, Lynch C, Xi XP, Reudelhuber TL, Pouyssegur J, Rector FC Jr.; 1991 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296370
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Generation of chemotactic factors by Rhizopus oryzae in the presence and absence of serum: relationship to hyphal damage mediated by human neutrophils and effects of hyperglycemia and ketoacidosis. by Chinn RY, Diamond RD.; 1982 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=347866
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Glucose Utilization and Production by the Dog Kidney In Vivo in Metabolic Acidosis and Alkalosis. by Costello J, Scott JM, Wilson P, Bourke E.; 1973 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302299
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Glutamine Transport in Rat Kidney Mitochondria in Metabolic Acidosis. by Adam W, Simpson DP.; 1974 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=301536
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Hepatic Fructose-1,6-Diphosphatase Deficiency. A CAUSE OF LACTIC ACIDOSIS AND HYPOGLYCEMIA IN INFANCY. by Pagliara AS, Karl IE, Keating JP, Brown BI, Kipnis DM.; 1972 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292368
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Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. by Kubasiak LA, Hernandez OM, Bishopric NH, Webster KA.; 2002 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130544
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Inactive form of erythrocyte carbonic anhydrase B in patients with primary renal tubular acidosis. by Kondo T, Taniguchi N, Taniguchi K, Matsuda I, Murao M.; 1978 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=371806
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Intracellular pH during "chemical hypoxia" in cultured rat hepatocytes. Protection by intracellular acidosis against the onset of cell death. by Gores GJ, Nieminen AL, Wray BE, Herman B, Lemasters JJ.; 1989 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303693
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Lactic Acidosis as a Result of Iron Deficiency. by Finch CA, Gollnick PD, Hlastala MP, Miller LR, Dillmann E, Mackler B.; 1979 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=372098
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Low Temperature-Induced Cytoplasmic Acidosis in Cultured Mung Bean (Vigna radiata [L.] Wilczek) Cells. by Yoshida S.; 1994 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=159273
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Management of acidosis: the role of buffer agents. by Weil MH, Tang W.; 1997; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137219
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Mechanisms of adaptation to chronic respiratory acidosis in the rabbit proximal tubule. by Krapf R.; 1989 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303763
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Metabolic Acidosis Suppresses 25-Hydroxyvitamin D3-1[alpha]-Hydroxylase in the Rat Kidney DISTINCT SITE AND MECHANISM OF ACTION. by Kawashima H, Kraut JA, Kurokawa K.; 1982 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=370235
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Metabolism of Glutamine by the Intact Functioning Kidney of the Dog STUDIES IN METABOLIC ACIDOSIS AND ALKALOSIS. by Pitts RF, Pilkington LA, MacLeod MB, Leal-Pinto E.; 1972 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302161
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Molecular basis of ocular abnormalities associated with proximal renal tubular acidosis. by Usui T, Hara M, Satoh H, Moriyama N, Kagaya H, Amano S, Oshika T, Ishii Y, Ibaraki N, Hara C, Kunimi M, Noiri E, Tsukamoto K, Inatomi J, Kawakami H, Endou H, Igarashi T, Goto A, Fujita T, Araie M, Seki G.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=209339
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Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis. by Karet FE, Gainza FJ, Gyory AZ, Unwin RJ, Wrong O, Tanner MJ, Nayir A, Alpay H, Santos F, Hulton SA, Bakkaloglu A, Ozen S, Cunningham MJ, di Pietro A, Walker WG, Lifton RP.; 1998 May 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27686
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Na+-H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: The role of glucocorticoids. by Kinsella J, Cujdik T, Sacktor B.; 1984 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=344733
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On the Mechanism of Renal Potassium Wasting in Renal Tubular Acidosis Associated with the Fanconi Syndrome (Type 2 RTA). by Sebastian A, McSherry E, Morris RC Jr.; 1971 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=291912
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Pathways of Glutamine and Organic Acid Metabolism in Renal Cortex in Chronic Metabolic Acidosis. by Simpson DP.; 1972 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292353
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Pediatric diabetic ketoacidosis. by Lawrence S, Pacaud D, Dean H, Lawson M, Daneman D.; 2003 Aug 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=180639
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Phosphorus-31 magnetic resonance spectra reveal prolonged intracellular acidosis in the brain following subarachnoid hemorrhage. by Brooke NS, Ouwerkerk R, Adams CB, Radda GK, Ledingham JG, Rajagopalan B.; 1994 Mar 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=43272
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Production, Excretion, and Net Balance of Fixed Acid in Patients with Renal Acidosis. by Goodman AD, Lemann J Jr, Lennon EJ, Relman AS.; 1965 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292514
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Regulatory Mechanisms of Hemoglobin Oxygen Affinity in Acidosis and Alkalosis. by Bellingham AJ, Detter JC, Lenfant C.; 1971 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=291978
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Renal ammoniagenesis in an early stage of metabolic acidosis in man. by Tizianello A, Deferrari G, Garibotto G, Robaudo C, Acquarone N, Ghiggeri GM.; 1982 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=371188
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Renal gluconeogenesis in acidosis, alkalosis, and potassium deficiency: its possible role in regulation of renal ammonia production. by Goodman AD, Fuisz RE, Cahill GF Jr.; 1966 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292735
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Renal Metabolic Response to Acid-Base Changes. II. THE EARLY EFFECTS OF METABOLIC ACIDOSIS ON RENAL METABOLISM IN THE RAT. by Alleyne GA.; 1970 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=322557
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Renal Potassium Wasting in Renal Tubular Acidosis (RTA). ITS OCCURRENCE IN TYPES 1 AND 2 RTA DESPITE SUSTAINED CORRECTION OF SYSTEMIC ACIDOSIS. by Sebastian A, McSherry E, Morris RC Jr.; 1971 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=291975
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Renal Tubular Acidosis in Infants: the Several Kinds, Including BicarbonateWasting, Classic Renal Tubular Acidosis. by McSherry E, Sebastian A, Morris RC Jr.; 1972 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302155
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Role of increased cytosolic free calcium in the pathogenesis of rabbit proximal tubule cell injury and protection by glycine or acidosis. by Weinberg JM, Davis JA, Roeser NF, Venkatachalam MA.; 1991 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296346
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Skeletal Troponin C Reduces Contractile Sensitivity to Acidosis in Cardiac Myocytes from Transgenic Mice. by Metzger JM, Parmacek MS, Barr E, Pasyk K, Lin W, Cochrane KL, Field LJ, Leiden JM.; 1993 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47496
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Studies of the Mechanism by Which Chronic Metabolic Acidosis Augments Urinary Calcium Excretion in Man. by Lemann J Jr, Litzow JR, Lennon EJ.; 1967 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=297133
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Studies on the Pathogenesis of Type I (Distal) Renal Tubular Acidosis as Revealed by the Urinary Pco2 Tensions. by Halperin ML, Goldstein MB, Haig A, Johnson MD, Stinebaugh BJ.; 1974 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=333046
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Succinyl-CoA: 3-Ketoacid CoA-Transferase Deficiency. A CAUSE FOR KETOACIDOSIS IN INFANCY. by Tildon JT, Cornblath M.; 1972 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302154
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The Effect of Steroids and Ammonium Chloride Acidosis on Phosphoenolpyruvate Carboxykinase in Rat Kidney Cortex II. THE KINETICS OF ENZYME INDUCTION. by Longshaw ID, Alleyne GA, Pogson CI.; 1972 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292393
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The Effect of Steroids and Ammonium Chloride Acidosis on Phosphoenolpyruvate Carboxykinase in Rat Kidney Cortex. I. DIFFERENTIATION OF THE INDUCTIVE PROCESSES AND CHARACTERIZATION OF ENZYME ACTIVITIES. by Longshaw ID, Pogson CI.; 1972 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292392
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The Effect of Treatment of Acidosis on Calcium Balance in Patients with Chronic Azotemic Renal Disease. by Litzow JR, Lemann J Jr, Lennon EJ.; 1967 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=297046
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The Effects of Acidosis and Alkalosis on the Metabolism of Glutamine and Glutamate in Renal Cortex Slices. by Kamm DE, Strope GL.; 1972 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292257
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The effects of chronic acid loads in normal man: further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis. by Lemann J Jr, Litzow JR, Lennon EJ.; 1966 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292842
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The Maladaptive Renal Response to Secondary Hypocapnia during Chronic HCl Acidosis in the Dog. by Madias NE, Schwartz WB, Cohen JJ.; 1977 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=372497
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The Mechanism of Acidosis Produced by Hyperosmotic Infusions. by Winters RW, Scaglione PR, Nahas GG, Verosky M.; 1964 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=289542
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Treatment of Lactic Acidosis with Dichloroacetate in Dogs. by Park R, Arieff AI, Leach W, Lazarowitz VC.; 1982 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=370294
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Water, Acidosis, and Experimental Pyelonephritis. by Andriole VT.; 1970 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=322440
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 acidosis, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “acidosis” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for acidosis (hyperlinks lead to article summaries): •
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A 52-year-old acyanotic man with severe hypoxia and profound metabolic acidosis following an industry chemical exposure. Author(s): Zavotsky KE, Mentler P, Gronczewski C, Torres P. Source: Journal of Emergency Nursing: Jen : Official Publication of the Emergency Department Nurses Association. 2004 April; 30(2): 113-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039666
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 case of lactic acidosis caused by stavudine in an AIDS patient. Author(s): Cho BC, Han SH, Choi SH, Choi JY, Chang KH, Song YG, Kim JM. Source: Korean J Intern Med. 2004 March; 19(1): 66-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15053048
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A case of PDH-E1 alpha mosaicism in a male patient with severe metabolic lactic acidosis. Author(s): Seyda A, Chun K, Packman S, Robinson BH. Source: Journal of Inherited Metabolic Disease. 2001 October; 24(5): 551-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11757583
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A cautionary tale: fatal lactic acidosis complicating nucleoside analogue and metformin therapy. Author(s): Worth L, Elliott J, Anderson J, Sasadeusz J, Street A, Lewin S. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 July 15; 37(2): 315-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12856228
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A novel missense mutation in AE1 causing autosomal dominant distal renal tubular acidosis retains normal transport function but is mistargeted in polarized epithelial cells. Author(s): Rungroj N, Devonald MA, Cuthbert AW, Reimann F, Akkarapatumwong V, Yenchitsomanus PT, Bennett WM, Karet FE. Source: The Journal of Biological Chemistry. 2004 April 2; 279(14): 13833-8. Epub 2004 January 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14734552
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A novel mutation in the anion exchanger 1 gene is associated with familial distal renal tubular acidosis and nephrocalcinosis. Author(s): Cheidde L, Vieira TC, Lima PR, Saad ST, Heilberg IP. Source: Pediatrics. 2003 December; 112(6 Pt 1): 1361-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14654610
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Abdominal pain and lactic acidosis with ethylene glycol poisoning. Author(s): Singh M, Murtaza M, D'souza N, Gnanasekaran I. Source: The American Journal of Emergency Medicine. 2001 October; 19(6): 529-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11593483
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Acetazolamide, alternate carbonic anhydrase inhibitors and hypoglycaemic agents: comparing enzymatic with diuresis induced metabolic acidosis following intraocular surgery in diabetes. Author(s): Zaidi FH, Kinnear PE. Source: The British Journal of Ophthalmology. 2004 May; 88(5): 714-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15090429
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Acidosis correction with a new 25 mmol/l bicarbonate/15 mmol/l lactate peritoneal dialysis solution. Author(s): Carrasco AM, Rubio MA, Sanchez Tommero JA, Fernandez Giron F, Gonzalez Rico M, del Peso Gilsanz G, Fernandez Perpen A, Ramon RG, Bueno IF, Tranaeus A, Faict D, Hopwood A. Source: Perit Dial Int. 2001 November-December; 21(6): 546-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11783762
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Acidosis following aortic cross-clamping: is it the acid or carbon dioxide? Author(s): Tobias JD, Johnson JO, Lemoine K, Lawson NW. Source: Journal of Cardiothoracic and Vascular Anesthesia. 2002 February; 16(1): 73-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11854883
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Acidosis-induced apoptosis in human and porcine heart. Author(s): Thatte HS, Rhee JH, Zagarins SE, Treanor PR, Birjiniuk V, Crittenden MD, Khuri SF. Source: The Annals of Thoracic Surgery. 2004 April; 77(4): 1376-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15063270
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Acute correction of metabolic acidosis increases serum procollagen type I carboxyterminal propeptide in patients with chronic renal failure. Author(s): Chu P, Lu KC, Lin YF. Source: J Formos Med Assoc. 2001 November; 100(11): 748-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11802533
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Acute lymphoblastic leukemia presenting with lactic acidosis and renal tubular dysfunction. Author(s): Hayek M, Srinivasan A. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 June; 25(6): 488-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12794529
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Acute metabolic acidosis decreases muscle protein synthesis but not albumin synthesis in humans. Author(s): Kleger GR, Turgay M, Imoberdorf R, McNurlan MA, Garlick PJ, Ballmer PE. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2001 December; 38(6): 1199-207. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11728951
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Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positive women taking antiretroviral medication. Author(s): Sarner L, Fakoya A. Source: Sexually Transmitted Infections. 2002 February; 78(1): 58-9. Erratum In: Sex Transm Infect. 2003 October; 79(5): 429. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11872862
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Acute respiratory and metabolic acidosis induced by excessive muscle contraction during spinal evoked stimulation. Author(s): Tohdoh Y, Sumita S, Kawamata T, Omote K, Kawana S, Namiki A. Source: British Journal of Anaesthesia. 2001 April; 86(4): 589-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11573641
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Albuterol-induced lactic acidosis. Author(s): Liem EB, Mnookin SC, Mahla ME. Source: Anesthesiology. 2003 August; 99(2): 505-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883427
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An 11-month-old girl with arrested psychomotor development and lactic acidosis. Author(s): Mizuguchi M, Itoh M, Ozawa H. Source: Neuropathology : Official Journal of the Japanese Society of Neuropathology. 2004 March; 24(1): 103-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15068179
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Anaesthesia for an adolescent with mitochondrial encephalomyopathy-lactic acidosisstroke-like episodes syndrome. Author(s): Bolton P, Peutrell J, Zuberi S, Robinson P. Source: Paediatric Anaesthesia. 2003 June; 13(5): 453-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791122
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Anion exchanger 1 mutations associated with distal renal tubular acidosis in the Thai population. Author(s): Yenchitsomanus PT, Sawasdee N, Paemanee A, Keskanokwong T, Vasuvattakul S, Bejrachandra S, Kunachiwa W, Fucharoen S, Jittphakdee P, Yindee W, Promwong C. Source: Journal of Human Genetics. 2003; 48(9): 451-6. Epub 2003 August 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12938018
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Band 3 mutations, distal renal tubular acidosis, and Southeast Asian ovalocytosis. Author(s): Wrong O, Bruce LJ, Unwin RJ, Toye AM, Tanner MJ. Source: Kidney International. 2002 July; 62(1): 10-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12081559
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Band 3 mutations, renal tubular acidosis and South-East Asian ovalocytosis in Malaysia and Papua New Guinea: loss of up to 95% band 3 transport in red cells. Author(s): Bruce LJ, Wrong O, Toye AM, Young MT, Ogle G, Ismail Z, Sinha AK, McMaster P, Hwaihwanje I, Nash GB, Hart S, Lavu E, Palmer R, Othman A, Unwin RJ, Tanner MJ. Source: The Biochemical Journal. 2000 August 15; 350 Pt 1: 41-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10926824
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Band 3 Walton, a C-terminal deletion associated with distal renal tubular acidosis, is expressed in the red cell membrane but retained internally in kidney cells. Author(s): Toye AM, Bruce LJ, Unwin RJ, Wrong O, Tanner MJ. Source: Blood. 2002 January 1; 99(1): 342-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11756190
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Base deficit does not predict mortality when secondary to hyperchloremic acidosis. Author(s): Brill SA, Stewart TR, Brundage SI, Schreiber MA. Source: Shock (Augusta, Ga.). 2002 June; 17(6): 459-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12069180
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Base deficit is superior to pH in evaluating clearance of acidosis after traumatic shock. Author(s): Davis JW, Kaups KL, Parks SN. Source: The Journal of Trauma. 1998 January; 44(1): 114-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9464758
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Bench-to-bedside review: severe lactic acidosis in HIV patients treated with nucleoside analogue reverse transcriptase inhibitors. Author(s): Claessens YE, Chiche JD, Mira JP, Cariou A. Source: Critical Care (London, England). 2003 June; 7(3): 226-32. Epub 2003 February 28. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12793872
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Benign methylmalonic acidemia in a sibship with distal renal tubular acidosis. Author(s): Dudley J, Allen J, Tizard J, McGraw M. Source: Pediatric Nephrology (Berlin, Germany). 1998 September; 12(7): 564-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9761355
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Better correction of metabolic acidosis, blood pressure control, and phagocytosis with bicarbonate compared to lactate solution in acute peritoneal dialysis. Author(s): Thongboonkerd V, Lumlertgul D, Supajatura V. Source: Artificial Organs. 2001 February; 25(2): 99-108. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11251475
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Bicarbonate administration is potentially harmful in patients with moderate acidosis. Author(s): Soto R. Source: Anesthesia and Analgesia. 2002 July; 95(1): 256; Author Reply 256. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12088990
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Bicarbonate therapy and intracellular acidosis. Author(s): Goldsmith DJ, Forni LG, Hilton PJ. Source: Clinical Science (London, England : 1979). 1997 December; 93(6): 593-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9497798
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Bicarbonate therapy of metabolic acidosis. Author(s): Kaehny WD, Anderson RJ. Source: Critical Care Medicine. 1994 October; 22(10): 1525-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7924360
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Bicarbonate-based haemofiltration in the management of acute renal failure with lactic acidosis. Author(s): Hilton PJ, Taylor J, Forni LG, Treacher DF. Source: Qjm : Monthly Journal of the Association of Physicians. 1998 April; 91(4): 279-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9666950
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Biochemical and genetic advances in distal renal tubular acidosis. Author(s): Sabatini S, Kurtzman NA. Source: Semin Nephrol. 2001 March; 21(2): 94-106. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11245773
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Blood glucose threshold and the metabolic responses to incremental exercise tests with and without prior lactic acidosis induction. Author(s): Simoes HG, Campbell CS, Kushnick MR, Nakamura A, Katsanos CS, Baldissera V, Moffatt RJ. Source: European Journal of Applied Physiology. 2003 August; 89(6): 603-11. Epub 2003 May 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12759761
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Bone histology and bone mineral density after correction of acidosis in distal renal tubular acidosis. Author(s): Domrongkitchaiporn S, Pongskul C, Sirikulchayanonta V, Stitchantrakul W, Leeprasert V, Ongphiphadhanakul B, Radinahamed P, Rajatanavin R. Source: Kidney International. 2002 December; 62(6): 2160-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12427141
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Bone loss after renal transplantation: role of hyperparathyroidism, acidosis, cyclosporine and systemic disease. Author(s): Heaf J, Tvedegaard E, Kanstrup IL, Fogh-Andersen N. Source: Clinical Transplantation. 2000 October; 14(5): 457-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11048990
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Bone mineral density and histology in distal renal tubular acidosis. Author(s): Domrongkitchaiporn S, Pongsakul C, Stitchantrakul W, Sirikulchayanonta V, Ongphiphadhanakul B, Radinahamed P, Karnsombut P, Kunkitti N, Ruang-raksa C, Rajatanavin R. Source: Kidney International. 2001 March; 59(3): 1086-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11231364
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Breath-hold training of humans reduces oxidative stress and blood acidosis after static and dynamic apnea. Author(s): Joulia F, Steinberg JG, Faucher M, Jamin T, Ulmer C, Kipson N, Jammes Y. Source: Respiratory Physiology & Neurobiology. 2003 August 14; 137(1): 19-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871674
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Broadsheet number 40: the diagnosis of renal tubular acidosis. Author(s): Clague A, Krause H. Source: Pathology. 1997 February; 29(1): 34-40. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9094175
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Butoxyethanol ingestion with prolonged hyperchloremic metabolic acidosis treated with ethanol therapy. Author(s): McKinney PE, Palmer RB, Blackwell W, Benson BE. Source: Journal of Toxicology. Clinical Toxicology. 2000; 38(7): 787-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11192467
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Calcium nephrolithiasis and distal tubular acidosis in type 1 glycogen storage disease. Author(s): Iida S, Matsuoka K, Inoue M, Tomiyasu K, Noda S. Source: International Journal of Urology : Official Journal of the Japanese Urological Association. 2003 January; 10(1): 56-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12534929
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Case report: nucleoside analogue-induced lactic acidosis in the third trimester of pregnancy. Author(s): Mandelbrot L, Kermarrec N, Marcollet A, Lafanechere A, Longuet P, Chosidow D, Saada M. Source: Aids (London, England). 2003 January 24; 17(2): 272-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12545093
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Case study: metformin-associated lactic acidosis: could orlistat be relevant? Author(s): Dawson D, Conlon C. Source: Diabetes Care. 2003 August; 26(8): 2471-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12882884
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Catabolism in uremia: the impact of metabolic acidosis. Author(s): Franch HA, Mitch WE. Source: Journal of the American Society of Nephrology : Jasn. 1998 December; 9(12 Suppl): S78-81. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11443773
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Cerebrovascular response to acute metabolic acidosis in humans. Author(s): van de Ven M, Colier WN, Kersten BT, Oeseburg B, Folgering H. Source: Advances in Experimental Medicine and Biology. 2003; 530: 707-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14562769
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Changes in serum leptin levels in chronic renal failure patients with metabolic acidosis. Author(s): Zheng F, Qiu X, Yin S, Li Y. Source: Journal of Renal Nutrition : the Official Journal of the Council on Renal Nutrition of the National Kidney Foundation. 2001 October; 11(4): 207-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11680001
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Child abuse by intentional iron poisoning presenting as shock and persistent acidosis. Author(s): Black J, Zenel JA. Source: Pediatrics. 2003 January; 111(1): 197-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12509576
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Childhood onset mitochondrial myopathy and lactic acidosis caused by a stop mutation in the mitochondrial cytochrome c oxidase III gene. Author(s): Horvath R, Scharfe C, Hoeltzenbein M, Do BH, Schroder C, Warzok R, Vogelgesang S, Lochmuller H, Muller-Hocker J, Gerbitz KD, Oefner PJ, Jaksch M. Source: Journal of Medical Genetics. 2002 November; 39(11): 812-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12414820
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Citric acid ingestion: a life-threatening cause of metabolic acidosis. Author(s): DeMars CS, Hollister K, Tomassoni A, Himmelfarb J, Halperin ML. Source: Annals of Emergency Medicine. 2001 November; 38(5): 588-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11679874
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Clinical pharmacology physiology conference: metformin and lactic acidosis (LA). Author(s): Alkhalil C, Zavros G, Bailony F, Lowenthal DT. Source: International Urology and Nephrology. 2002; 34(3): 419-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899240
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Clinical predictors of acute respiratory acidosis during exacerbation of asthma and chronic obstructive pulmonary disease. Author(s): Cham GW, Tan WP, Earnest A, Soh CH. Source: European Journal of Emergency Medicine : Official Journal of the European Society for Emergency Medicine. 2002 September; 9(3): 225-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12394618
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Coagulopathy, hypothermia and acidosis in trauma patients: the rationale for damage control surgery. Author(s): De Waele JJ, Vermassen FE. Source: Acta Chir Belg. 2002 October; 102(5): 313-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12471762
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Cochlear implantation in a patient with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome. Author(s): Yasumura S, Aso S, Fujisaka M, Watanabe Y. Source: Acta Oto-Laryngologica. 2003 January; 123(1): 55-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12625574
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Comparison of lactate or BE during out-of-hospital cardiac arrest to determine metabolic acidosis. Author(s): Prause G, Ratzenhofer-Comenda B, Smolle-Juttner F, Heydar-Fadai J, Wildner G, Spernbauer P, Smolle J, Hetz H. Source: Resuscitation. 2001 December; 51(3): 297-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11738782
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Confirmation of the ATP6B1 gene as responsible for distal renal tubular acidosis. Author(s): Ruf R, Rensing C, Topaloglu R, Guay-Woodford L, Klein C, Vollmer M, Otto E, Beekmann F, Haller M, Wiedensohler A, Leumann E, Antignac C, Rizzoni G, Filler G, Brandis M, Weber JL, Hildebrandt F. Source: Pediatric Nephrology (Berlin, Germany). 2003 February; 18(2): 105-9. Epub 2002 December 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12579397
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Continuous pH monitoring using the Paratrend 7 inserted into a peripheral vein in a patient with shock and congenital lactic acidosis. Author(s): Easley RB, Johnson TR, Tobias JD. Source: Clinical Pediatrics. 2002 June; 41(5): 351-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12086201
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Contribution of respiratory acidosis to diaphragmatic fatigue at exercise. Author(s): Jonville S, Delpech N, Denjean A. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 June; 19(6): 1079-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12108860
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Conventional or physicochemical approach in intensive care unit patients with metabolic acidosis. Author(s): Moviat M, van Haren F, van der Hoeven H. Source: Critical Care (London, England). 2003 June; 7(3): R41-5. Epub 2003 May 01. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12793889
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Correction of acidosis by hemodialysis: proposal of a correlation with urea kinetics. Author(s): Leite M Jr, Leal E, Cardoso LR. Source: Blood Purification. 2002; 20(6): 551-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12566671
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Critical hypokalemic renal tubular acidosis due to Sjogren's syndrome: association with the purported immune stimulant echinacea. Author(s): Logan JL, Ahmed J. Source: Clinical Rheumatology. 2003 May; 22(2): 158-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12740687
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Design and use of a peptide nucleic acid for detection of the heteroplasmic lowfrequency mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) mutation in human mitochondrial DNA. Author(s): Hancock DK, Schwarz FP, Song F, Wong LJ, Levin BC. Source: Clinical Chemistry. 2002 December; 48(12): 2155-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12446471
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Detecting life-threatening lactic acidosis related to nucleoside-analog treatment of human immunodeficiency virus-infected patients, and treatment with L-carnitine. Author(s): Claessens YE, Cariou A, Monchi M, Soufir L, Azoulay E, Rouges P, Goldgran-Toledano D, Branche F, Dhainaut JF. Source: Critical Care Medicine. 2003 April; 31(4): 1042-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12682470
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Diagnosing the cause of a hyperosmolar anion-gap metabolic acidosis. Author(s): Markowitz DH. Source: Journal of Intensive Care Medicine. 2003 May-June; 18(3): 160-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14984636
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Dichloroacetate treatment for severe refractory metabolic acidosis during neonatal sepsis. Author(s): Arnon S, Litmanovits I, Regev R, Elpeleg O, Dolfin T. Source: The Pediatric Infectious Disease Journal. 2001 February; 20(2): 218-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11224847
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Dilutional acidosis: an endless story of confusion. Author(s): Doberer D, Funk GC, Schneeweiss B. Source: Critical Care Medicine. 2003 January; 31(1): 337-8; Author Reply 338. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12545056
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Dimercaptosuccinic acid distribution in renal tubular acidosis. Author(s): Green DA, Davies SG. Source: The British Journal of Radiology. 1997 December; 70(840): 1291-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9505851
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Direct activation of cloned K(atp) channels by intracellular acidosis. Author(s): Xu H, Cui N, Yang Z, Wu J, Giwa LR, Abdulkadir L, Sharma P, Jiang C. Source: The Journal of Biological Chemistry. 2001 April 20; 276(16): 12898-902. Epub 2001 January 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11278532
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Direct effect of the correction of acidosis on plasma parathyroid hormone concentrations, calcium and phosphate in hemodialysis patients: a prospective study. Author(s): Movilli E, Zani R, Carli O, Sangalli L, Pola A, Camerini C, Scolari F, Cancarini GC, Maiorca R. Source: Nephron. 2001 March; 87(3): 257-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11287761
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Discordance between cerebral oxygen and glucose metabolism, and hemodynamics in a mitochondrial encephalomyopathy, lactic acidosis, and strokelike episode patient. Author(s): Nariai T, Ohno K, Ohta Y, Hirakawa K, Ishii K, Senda M. Source: Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging. 2001 July; 11(3): 325-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11462305
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Distal renal tubular acidosis associated with hypercalcemia and nephrocalcinosis in an infant. Author(s): Maruyama K, Shinohara M, Hatakeyama S, Onigata K. Source: Pediatric Nephrology (Berlin, Germany). 2002 November; 17(11): 977-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12506914
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Distal renal tubular acidosis with severe bony deformities and multiple fractures. Author(s): Bagga A, Bajpai A, Gulati S, Singh A. Source: Indian Pediatrics. 2001 November; 38(11): 1301-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11721074
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D-lactic acidosis in a diabetic patient with a short bowel. Author(s): Azhar SS, Beach RE. Source: The Journal of the American Board of Family Practice / American Board of Family Practice. 2002 July-August; 15(4): 316-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12150467
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D-lactic acidosis in a patient after subtotal colectomy. Author(s): Kamar M, Raziel A, Susmallian S, Kyzer S, Charuzi I. Source: Isr Med Assoc J. 2003 December; 5(12): 891-2. No Abstract Available. Erratum In: Isr Med Assoc J. 2004 February; 6(2): 123. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14689763
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D-lactic acidosis secondary to short bowel syndrome. Author(s): Zhang DL, Jiang ZW, Jiang J, Cao B, Li JS. Source: Postgraduate Medical Journal. 2003 February; 79(928): 110-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12612331
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D-lactic acidosis. A review of clinical presentation, biochemical features, and pathophysiologic mechanisms. Author(s): Uribarri J, Oh MS, Carroll HJ. Source: Medicine; Analytical Reviews of General Medicine, Neurology, Psychiatry, Dermatology, and Pediatrics. 1998 March; 77(2): 73-82. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9556700
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D-lactic acidosis: pathologic consequence of saprophytism. Author(s): Vella A, Farrugia G. Source: Mayo Clinic Proceedings. 1998 May; 73(5): 451-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9581587
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Dosage of potassium citrate in the correction of urinary abnormalities in pediatric distal renal tubular acidosis patients. Author(s): Domrongkitchaiporn S, Khositseth S, Stitchantrakul W, Tapaneya-olarn W, Radinahamed P. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2002 February; 39(2): 383-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11840381
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Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. Author(s): Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, Hartshorn MA, Tanzi RE, Bush AI. Source: The Journal of Biological Chemistry. 1998 May 22; 273(21): 12817-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9582309
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Drug points: Fatal lactic acidosis associated with tenofovir. Author(s): Rivas P, Polo J, de Gorgolas M, Fernandez-Guerrero ML. Source: Bmj (Clinical Research Ed.). 2003 September 27; 327(7417): 711. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14512477
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Dysfunctional labor and myometrial lactic acidosis. Author(s): Quenby S, Pierce SJ, Brigham S, Wray S. Source: Obstetrics and Gynecology. 2004 April; 103(4): 718-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15051564
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Early postoperative respiratory acidosis after large intravascular volume infusion of lactated ringer's solution during major spine surgery. Author(s): Takil A, Eti Z, Irmak P, Yilmaz Gogus F. Source: Anesthesia and Analgesia. 2002 August; 95(2): 294-8, Table of Contents. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12145036
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Effect of acidosis on bilirubin-induced toxicity to human erythrocytes. Author(s): Brito MA, Brites D. Source: Molecular and Cellular Biochemistry. 2003 May; 247(1-2): 155-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12841643
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Effect of exercise-induced acidosis on aldosterone secretion in men. Author(s): Yamauchi T, Harada T, Kurono M, Matsui N. Source: European Journal of Applied Physiology and Occupational Physiology. 1998 April; 77(5): 409-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9562290
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Effect of induced metabolic acidosis on human skeletal muscle metabolism during exercise. Author(s): Hollidge-Horvat MG, Parolin ML, Wong D, Jones NL, Heigenhauser GJ. Source: The American Journal of Physiology. 1999 October; 277(4 Pt 1): E647-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10516124
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Effect of metabolic acidosis on hyperlipidemia in uremia. Author(s): Mak RH. Source: Pediatric Nephrology (Berlin, Germany). 1999 November; 13(9): 891-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10603143
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Effect of the correction of metabolic acidosis on nutritional status in elderly patients with chronic renal failure. Author(s): Verove C, Maisonneuve N, El Azouzi A, Boldron A, Azar R. Source: Journal of Renal Nutrition : the Official Journal of the Council on Renal Nutrition of the National Kidney Foundation. 2002 October; 12(4): 224-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12382214
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Effects of acidosis on acute phase protein metabolism in liver cells. Author(s): Ulrich C, Kruger B, Kohler H, Riegel W. Source: Mineral and Electrolyte Metabolism. 1999 July-December; 25(4-6): 228-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10681645
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Effects of dobutamine on critical capillary PO(2) and lactic acidosis threshold in patients with cardiovascular disease. Author(s): Koike A, Kobayashi K, Adachi H, Shimizu N, Itoh H, Hiroe M, Wasserman K. Source: Chest. 2001 October; 120(4): 1218-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11591564
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Effects of methamphetamine on trauma patients: a cause of severe metabolic acidosis? Author(s): Burchell SA, Ho HC, Yu M, Margulies DR. Source: Critical Care Medicine. 2000 June; 28(6): 2112-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10890674
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Efficacy of continuous venovenous haemofiltration (CVVH) in the treatment of severe phenformin-induced lactic acidosis. Author(s): Mariano F, Benzi L, Cecchetti P, Rosatello A, Merante D, Goia F, Capra L, Lanza G, Curto V, Cavalli PL. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 1998 April; 13(4): 1012-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9568872
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Emerging role of riboflavin in the treatment of nucleoside analogue-induced type B lactic acidosis. Author(s): Dalton SD, Rahimi AR. Source: Aids Patient Care and Stds. 2001 December; 15(12): 611-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11788075
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Encephalopathy, lactic acidosis, hyperammonaemia and 5-fluorouracil toxicity. Author(s): Valik D. Source: British Journal of Cancer. 1998 May; 77(10): 1710-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9635854
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End-tidal carbon dioxide predicts the presence and severity of acidosis in children with diabetes. Author(s): Fearon DM, Steele DW. Source: Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. 2002 December; 9(12): 1373-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12460840
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Environmental distal renal tubular acidosis in Thailand: an enigma. Author(s): Tosukhowong P, Tungsanga K, Eiam-Ong S, Sitprija V. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 1999 June; 33(6): 1180-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10352213
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Evaluation of failure to thrive: diagnostic yield of testing for renal tubular acidosis. Author(s): Adedoyin O, Gottlieb B, Frank R, Vento S, Vergara M, Gauthier B, Trachtman H. Source: Pediatrics. 2003 December; 112(6 Pt 1): E463. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14654646
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Evaluation of prescribing practices: risk of lactic acidosis with metformin therapy. Author(s): Calabrese AT, Coley KC, DaPos SV, Swanson D, Rao RH. Source: Archives of Internal Medicine. 2002 February 25; 162(4): 434-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11863476
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Evaluation of protein S-100 serum concentrations in healthy newborns and seven newborns with perinatal acidosis. Author(s): Maschmann J, Erb, Heinemann MK, Ziemer G, Speer CP. Source: Acta Paediatrica (Oslo, Norway : 1992). 2000 May; 89(5): 553-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10852191
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Evidence for an independent role of metabolic acidosis on nutritional status in haemodialysis patients. Author(s): Movilli E, Bossini N, Viola BF, Camerini C, Cancarini GC, Feller P, Strada A, Maiorca R. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 1998 March; 13(3): 674-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9550646
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Excessive use of normal saline in managing traumatized patients in shock: a preventable contributor to acidosis. Author(s): Ho AM, Karmakar MK, Contardi LH, Ng SS, Hewson JR. Source: The Journal of Trauma. 2001 July; 51(1): 173-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11468491
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Experimental tissue acidosis leads to increased pain in complex regional pain syndrome (CRPS). Author(s): Birklein F, Weber M, Ernst M, Riedl B, Neundorfer B, Handwerker HO. Source: Pain. 2000 August; 87(2): 227-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10924816
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Factors which influence alterations of phosphates and pH in exercising human skeletal muscle: measurement error, reproducibility, and effects of fasting, carbohydrate loading, and metabolic acidosis. Author(s): Miller RG, Carson PJ, Moussavi RS, Green A, Baker A, Boska MD, Weiner MW. Source: Muscle & Nerve. 1995 January; 18(1): 60-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7799999
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Failure to thrive in children with primary distal type renal tubular acidosis. Author(s): Chang CY, Lin CY. Source: Acta Paediatr Taiwan. 2002 November-December; 43(6): 334-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12632787
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Familial recurrence of atypical symptoms in an extended pedigree with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Author(s): Dougherty FE, Ernst SG, Aprille JR. Source: The Journal of Pediatrics. 1994 November; 125(5 Pt 1): 758-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7965431
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Fatal acidosis in a neonate with Pearson syndrome. Author(s): Gurakan B, Ozbek N, Varan B, Demirhan B. Source: Turk J Pediatr. 1999 July-September; 41(3): 361-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10770098
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Fatal lactic acidosis and acute renal failure after addition of tenofovir to an antiretroviral regimen containing didanosine. Author(s): Murphy MD, O'Hearn M, Chou S. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 April 15; 36(8): 1082-5. Epub 2003 Apr 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12684925
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Fatal lactic acidosis and liver steatosis associated with didanosine and stavudine treatment: a respiratory chain dysfunction? Author(s): Brivet FG, Nion I, Megarbane B, Slama A, Brivet M, Rustin P, Munnich A. Source: Journal of Hepatology. 2000 February; 32(2): 364-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10707883
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Fatal lactic acidosis and mimicking Guillain-Barre syndrome in an adolescent with human immunodeficiency virus infection. Author(s): Rosso R, Di Biagio A, Ferrazin A, Bassetti M, Ciravegna BW, Bassetti D. Source: The Pediatric Infectious Disease Journal. 2003 July; 22(7): 668-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12886900
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Fatal lactic acidosis and pancreatitis associated with ribavirin and didanosine therapy. Author(s): Butt AA. Source: Aids Read. 2003 July; 13(7): 344-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12889452
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Fatal lactic acidosis associated with antiretroviral therapy. Author(s): Sharma RS, Smina M, Manthous CA. Source: Aids Patient Care and Stds. 2002 November; 16(11): 515-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12513899
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Fatal lactic acidosis during antiretroviral therapy. Author(s): Rey C, Prieto S, Medina A, Perez C, Concha A, Menendez S. 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 October; 4(4): 485-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14525648
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Fatal lactic acidosis in a HIV-positive patient treated with interferon and ribavirin for chronic hepatitis C. Author(s): Guyader D, Poinsignon Y, Cano Y, Saout L. Source: Journal of Hepatology. 2002 August; 37(2): 289-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12127440
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Fatal nucleoside-associated lactic acidosis in an obese woman with human immunodeficiency virus type 1 infection on a very low-calorie diet. Author(s): Sipsas NV, Kosmas N, Kontos A, Eftychiadis C, Agapitos E, Kordossis T. Source: Scandinavian Journal of Infectious Diseases. 2003; 35(4): 291-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12839166
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Fetal acidosis, spinal anaesthesia and phenylephrine. Author(s): Carpenter MR, Cooper DW. Source: Anaesthesia. 2001 September; 56(9): 920-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11550692
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Fetal oxygen saturation and fractional extraction at birth and the relationship to measures of acidosis. Author(s): Richardson B, Nodwell A, Webster K, Alshimmiri M, Gagnon R, Natale R. Source: American Journal of Obstetrics and Gynecology. 1998 March; 178(3): 572-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9539528
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Flaccid paresis due to distal renal tubular acidosis preceding systemic lupus erythematosus. Author(s): Cochrane Database Syst Rev. 2003;(2):CD002967 Source: The Netherlands Journal of Medicine. 2002 March; 60(1): 29-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12804446
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Focal hyperperfusion in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Case report. Author(s): Amagasaki K, Shimizu T, Suzuki Y, Kakizawa T. Source: Journal of Neurosurgery. 2001 January; 94(1): 133-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11147883
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Focal segmental glomerulosclerosis, proteinuria and nephrocalcinosis associated with renal tubular acidosis. Author(s): Balogun RA, Adams ND, Palmisano J, Yamase H, Chughtai I, Kaplan AA. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2002 February; 17(2): 308-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11812889
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Free circulating magnesium and renal magnesium handling during acute metabolic acidosis in humans. Author(s): Blumberg D, Bonetti A, Jacomella V, Capillo S, Truttmann AC, Luthy CM, Colombo JP, Bianchetti MG. Source: American Journal of Nephrology. 1998; 18(3): 233-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9627040
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Fulminant neuropathy and lactic acidosis associated with nucleoside analog therapy. Author(s): Verma A, Schein RM, Jayaweera DT, Kett DH. Source: Neurology. 1999 October 12; 53(6): 1365-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10522907
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Functional mitochondrial heterogeneity in heteroplasmic cells carrying the mitochondrial DNA mutation associated with the MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes). Author(s): Bakker A, Barthelemy C, Frachon P, Chateau D, Sternberg D, Mazat JP, Lombes A. Source: Pediatric Research. 2000 August; 48(2): 143-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10926287
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Gas exchange theory and the lactic acidosis (anaerobic) threshold. Author(s): Wasserman K, Beaver WL, Whipp BJ. Source: Circulation. 1990 January; 81(1 Suppl): Ii14-30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2403868
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General aspects of physiology and pathophysiology of metabolic acidosis in the critically ill. Author(s): Van Biesen W, Lameire N. Source: Acta Clin Belg. 2000 May-June; 55(3): 133-40. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10981320
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Genetic analysis of three pedigrees of mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) Author(s): Sato W, Hayasaka K, Komatsu K, Sawaishi Y, Sakemi K, Shoji Y, Takada G. Source: American Journal of Human Genetics. 1992 March; 50(3): 655-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1539604
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Genetic and long-term data on a patient with permanent isolated proximal renal tubular acidosis. Author(s): Shiohara M, Igarashi T, Mori T, Komiyama A. Source: European Journal of Pediatrics. 2000 December; 159(12): 892-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11131345
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Glycosylated hemoglobin A1, acidosis and secondary erythrocytosis in chronic respiratory failure. Author(s): De Marchi S, Cecchin E. Source: Haematologica. 1988 September-October; 73(5): 347-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3143631
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Graft failure of autologous peripheral blood stem cell transplantation due to acute metabolic acidosis associated with total parenteral nutrition in a patient with relapsed breast cancer. Author(s): Sawada M, Tsurumi H, Hara T, Goto H, Yamada T, Oyama M, Moriwaki H. Source: Acta Haematologica. 2000; 102(3): 157-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10692681
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Growth failure in children with renal tubular acidosis. Author(s): Donckerwolcke R, Yang WN, Chan JC. Source: Semin Nephrol. 1989 March; 9(1): 72-4. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2662306
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Growth hormone and insulin-like growth factor in non-uremic acidosis and uremic acidosis. Author(s): Kuemmerle N, Krieg RJ Jr, Latta K, Challa A, Hanna JD, Chan JC. Source: Kidney International. Supplement. 1997 March; 58: S102-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9067956
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Growth hormone corrects acidosis-induced renal nitrogen wasting and renal phosphate depletion and attenuates renal magnesium wasting in humans. Author(s): Mahlbacher K, Sicuro A, Gerber H, Hulter HN, Krapf R. Source: Metabolism: Clinical and Experimental. 1999 June; 48(6): 763-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10381152
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Growth hormone stimulation tests in chronic renal failure with metabolic acidosis. Author(s): Bircan Z, Kervancioglu M, Soran M, Yildirim I. Source: Acta Paediatr Jpn. 1998 February; 40(1): 70-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9583205
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High anion gap metabolic acidosis in suicide: don't forget metformin intoxication-two patients' experiences. Author(s): Chang CT, Chen YC, Fang JT, Huang CC. Source: Renal Failure. 2002 September; 24(5): 671-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12380915
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High prevalence of Southeast Asian ovalocytosis in Malays with distal renal tubular acidosis. Author(s): Yusoff NM, Van Rostenberghe H, Shirakawa T, Nishiyama K, Amin N, Darus Z, Zainal N, Isa N, Nozu H, Matsuo M. Source: Journal of Human Genetics. 2003; 48(12): 650-3. Epub 2003 November 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14618420
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How well does reflectance pulse oximetry reflect intrapartum fetal acidosis? Author(s): Stiller R, von Mering R, Konig V, Huch A, Huch R. Source: American Journal of Obstetrics and Gynecology. 2002 June; 186(6): 1351-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12066121
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Human anion exchanger1 mutations and distal renal tubular acidosis. Author(s): Yenchitsomanus PT. Source: Southeast Asian J Trop Med Public Health. 2003 September; 34(3): 651-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15115146
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Human immunodeficiency virus infection with human granulocytic ehrlichiosis complicated by symptomatic lactic acidosis. Author(s): Springer SA, Altice FL. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 June 15; 36(12): E162-4. Epub 2003 Jun 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12802782
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Hypercalcemia and distal renal tubular acidosis: an association not only in the newborn. Author(s): Pela I, Seracini D, Lavoratti G, Materassi M. Source: Pediatric Nephrology (Berlin, Germany). 2003 August; 18(8): 850. Epub 2003 June 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12820054
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Hypercapnic acidosis activates KATP channels in vascular smooth muscles. Author(s): Wang X, Wu J, Li L, Chen F, Wang R, Jiang C. Source: Circulation Research. 2003 June 13; 92(11): 1225-32. Epub 2003 May 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12738754
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Hyperchloraemic acidosis consistent with ammonium chloride administration. Author(s): Bajpai A, Tikaria A, Kabra SK, Arya LS. Source: Archives of Disease in Childhood. 2004 January; 89(1): 92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709530
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Hyperchloremic acidosis. Author(s): Parekh N. Source: Anesthesia and Analgesia. 2002 December; 95(6): 1821; Author Reply 1821-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12456471
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Hyperchloremic acidosis: the classic example of strong ion acidosis. Author(s): Constable PD. Source: Anesthesia and Analgesia. 2003 April; 96(4): 919-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12651634
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Hyperlactataemia and lactic acidosis during antiretroviral therapy: relevance, reproducibility and possible risk factors. Author(s): Moyle GJ, Datta D, Mandalia S, Morlese J, Asboe D, Gazzard BG. Source: Aids (London, England). 2002 July 5; 16(10): 1341-9. Erratum In: Aids. 2002 August 16; 16(12): 1708. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12131210
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Hyperlactatemia and lactic acidosis: should routine screening be considered? Author(s): Moyle G. Source: Aids Read. 2002 August; 12(8): 344-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12229891
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Hyperleukocytosis presenting as myocardial ischemia, altered sensorium, and metabolic acidosis. Author(s): Jacob S, Jain H, Mathew M, Gay R, Goldberg JB, Dollard DJ. Source: The American Journal of Emergency Medicine. 2004 March; 22(2): 127-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15011235
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Hyperosmolar metabolic acidosis and intravenous Lorazepam. Author(s): Mullins ME, Barnes BJ. Source: The New England Journal of Medicine. 2002 September 12; 347(11): 857-8; Author Reply 857-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12226165
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Hyperoxaluria in patients with primary distal renal tubular acidosis. Author(s): Mehler K, Stapenhorst L, Beck B, Hoppe B. Source: Pediatric Nephrology (Berlin, Germany). 2003 July; 18(7): 722-3. Epub 2003 May 01. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12728365
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Hypoglycaemia and lactic acidosis in a MALT non Hodgkin's lymphoma. Author(s): Di Comite G, Dagna L, Piatti PM, Monti LD, Tantardini F, Praderio L. Source: Leukemia & Lymphoma. 2002 June; 43(6): 1341-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12153006
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Hypopotassemic paralysis: a rare presentation of proximal renal tubular acidosis. Author(s): Deda G, Ekim M, Guven A, Karagol U, Tumer N. Source: Journal of Child Neurology. 2001 October; 16(10): 770-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11669354
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Hypotension, acidosis and vasodilation syndrome after heart transplant: incidence, risk factors, and prognosis. Author(s): Paniagua MJ, Crespo-Leiro MG, Muniz J, Vazquez E, Tabuyo T, CastroOrjales M, Fojon S, Lopez JM, Garrido IP, Juffe A, Castro-Beiras A. Source: Transplantation Proceedings. 2003 August; 35(5): 1957-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12962862
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Hypotension, acidosis, and vasodilatation syndrome post-heart transplant: prognostic variables and outcomes. Author(s): Chemmalakuzhy J, Costanzo MR, Meyer P, Piccione W, Kao W, Winkel E, Saltzberg M, Heroux A, Parrillo J. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 October; 20(10): 1075-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11595562
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Hypothalamic growth hormone deficiency and supplementary GH therapy in two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes. Author(s): Matsuzaki M, Izumi T, Shishikura K, Suzuki H, Hirayama Y. Source: Neuropediatrics. 2002 October; 33(5): 271-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12536371
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Impact of dialysis modality and acidosis on nutritional status. Author(s): Dumler F, Falla P, Butler R, Wagner C, Francisco K. Source: Asaio Journal (American Society for Artificial Internal Organs : 1992). 1999 September-October; 45(5): 413-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10503617
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Impact of peritoneal dialysis modality and acidosis on nutritional status in peritoneal dialysis patients. Author(s): Dumler F, Falla P, Butler R, Wagner C, Francisco K. Source: Adv Perit Dial. 1998; 14: 205-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10649725
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Impaired trafficking of human kidney anion exchanger (kAE1) caused by heterooligomer formation with a truncated mutant associated with distal renal tubular acidosis. Author(s): Quilty JA, Cordat E, Reithmeier RA. Source: The Biochemical Journal. 2002 December 15; 368(Pt 3): 895-903. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12227829
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Impairment of ventilatory response to metabolic acidosis in insulin-dependent diabetic patients with advanced nephropathy. Author(s): Ikegaya N, Yonemura K, Suzuki T, Kato-Ohishi H, Taminato T, Hishida A. Source: Renal Failure. 1999 September; 21(5): 495-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10516994
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Incidence and severity of neovascularization in oxygen- and metabolic acidosisinduced retinopathy depend on rat source. Author(s): Kitzmann A, Leske D, Chen Y, Kendall A, Lanier W, Holmes J. Source: Current Eye Research. 2002 October; 25(4): 215-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12658554
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Incomplete renal tubular acidosis in 'primary' osteoporosis. Author(s): Sanchez A, Libman J. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. 2000; 11(8): 725-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11095178
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Incomplete renal tubular acidosis in 'primary' osteoporosis. Author(s): Weger M, Deutschmann H, Weger W, Kotanko P, Skrabal F. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. 1999; 10(4): 325-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10692983
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Inherited distal renal tubular acidosis. Author(s): Karet FE. Source: Journal of the American Society of Nephrology : Jasn. 2002 August; 13(8): 217884. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12138152
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Inherited renal tubular acidosis. Author(s): Karet FE. Source: Adv Nephrol Necker Hosp. 2000; 30: 147-62. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11068640
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Inherited renal tubular acidosis. Author(s): Shayakul C, Alper SL. Source: Current Opinion in Nephrology and Hypertension. 2000 September; 9(5): 541-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10990375
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Initial severity of metabolic acidosis predicts the development of acute lung injury in severely traumatized patients. Author(s): Eberhard LW, Morabito DJ, Matthay MA, Mackersie RC, Campbell AR, Marks JD, Alonso JA, Pittet JF. Source: Critical Care Medicine. 2000 January; 28(1): 125-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10667511
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Insulin and sodium bicarbonate treatment of diabetic acidosis. Author(s): Monteleone JA. Source: The Journal of Pediatrics. 1974 January; 84(1): 162. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12119950
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Insulin and sodium bicarbonate treatment of diabetic acidosis. Author(s): Holzman IR. Source: The Journal of Pediatrics. 1974 January; 84(1): 162; Author Reply 162. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12119949
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Insulin-mediated changes in PD and glucose uptake after correction of acidosis in humans with CRF. Author(s): Reaich D, Graham KA, Channon SM, Hetherington C, Scrimgeour CM, Wilkinson R, Goodship TH. Source: The American Journal of Physiology. 1995 January; 268(1 Pt 1): E121-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7840169
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Interrelationship between plasma leptin concentration and severity of metabolic acidosis in haemodialysed patients with chronical renal failure. Author(s): Kokot F, Chudek J, Adamczak M, Wiecek A. Source: Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association. 2001; 109(7): 370-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11573148
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Intrapartum computerized fetal heart rate parameters and metabolic acidosis at birth. Author(s): Agrawal SK, Doucette F, Gratton R, Richardson B, Gagnon R. Source: Obstetrics and Gynecology. 2003 October; 102(4): 731-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14551003
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Intravenous pyridoxine-induced metabolic acidosis. Author(s): Lovecchio F, Curry SC, Graeme KA, Wallace KL, Suchard J. Source: Annals of Emergency Medicine. 2001 July; 38(1): 62-4. Erratum In: Ann Emerg Med 2001 September; 38(3): 341. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11423814
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Is amniotic fluid volume status predictive of fetal acidosis at delivery? Author(s): Magann EF, Chauhan SP, Martin JN Jr. Source: The Australian & New Zealand Journal of Obstetrics & Gynaecology. 2003 April; 43(2): 129-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14712968
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Is chloride or dilution of bicarbonate the cause of metabolic acidosis from fluid administration? Author(s): Mathes DD. Source: Anesthesiology. 2001 September; 95(3): 809; Author Reply 810-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11575564
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Is intrapartum vibroacoustic stimulation an effective predictor of fetal acidosis? Author(s): Lin CC, Vassallo B, Mittendorf R. Source: Journal of Perinatal Medicine. 2001; 29(6): 506-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11776681
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Kearns-Sayre syndrome presenting as renal tubular acidosis. Author(s): Eviatar L, Shanske S, Gauthier B, Abrams C, Maytal J, Slavin M, Valderrama E, DiMauro S. Source: Neurology. 1990 November; 40(11): 1761-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2234434
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Ketoacidosis accompanied by epileptic seizures in a patient with diabetes mellitus and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Author(s): Nakamura S, Yoshinari M, Wakisaka M, Kodera H, Doi Y, Yoshizumi H, Asano T, Iwase M, Mihara F, Fujishima M. Source: Diabetes & Metabolism. 2000 November; 26(5): 407-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11119021
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Ketoacidosis and lactic acidosis--frequent causes of death in chronic alcoholics? Author(s): Brinkmann B, Fechner G, Karger B, DuChesne A. Source: International Journal of Legal Medicine. 1998; 111(3): 115-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9587792
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Kussmaul respiration and abdominal pain secondary to metabolic acidosis in AIDS patients with disseminated Mycobacterium avium complex infection receiving clofazimine. Author(s): Soriano V, Moreno V, Alba A, Laguna F, Gonzalez-Lahoz J. Source: Aids (London, England). 1993 June; 7(6): 894-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8363767
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Lactic acidosis after cardiac surgery is associated with polymorphisms in tumor necrosis factor and interleukin 10 genes. Author(s): Ryan T, Balding J, McGovern EM, Hinchion J, Livingstone W, Chughtai Z, Smith OP. Source: The Annals of Thoracic Surgery. 2002 June; 73(6): 1905-9; Discussion 1910-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12078789
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Lactic acidosis and abnormal liver function in advanced HIV disease. Author(s): Shahmanesh M, Cartledge J, Miller R. Source: Sexually Transmitted Infections. 2002 April; 78(2): 139-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12081178
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Lactic acidosis and status asthmaticus: how common in pediatrics? Author(s): Yousef E, McGeady SJ. Source: Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology. 2002 December; 89(6): 585-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12487224
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Lactic acidosis associated with the usual theophylline dose in a patient with asthma. Author(s): Koh YI, Choi IS. Source: Korean J Intern Med. 2002 June; 17(2): 147-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12164093
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Lactic acidosis during nucleoside antiretroviral HIV therapy. Author(s): Khater FJ, Youssef S, Iskandar SB, Myers JW, Moorman JP. Source: Southern Medical Journal. 2004 February; 97(2): 208. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14982278
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Lactic acidosis following convulsions. Author(s): Lipka K, Bulow HH. Source: Acta Anaesthesiologica Scandinavica. 2003 May; 47(5): 616-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12699523
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Lactic acidosis in asthma: report of two cases and review of the literature. Author(s): Prakash S, Mehta S. Source: Can Respir J. 2002 May-June; 9(3): 203-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12068341
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Lactic acidosis in HIV infected patients: a systematic review of published cases. Author(s): Arenas-Pinto A, Grant AD, Edwards S, Weller IV. Source: Sexually Transmitted Infections. 2003 August; 79(4): 340-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12902594
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Lactic Acidosis in Non-Hodgkin's Lymphoma and response to Chemotherapy. Author(s): Osorio S, Bernis C, de La Camara R. Source: Haematologica. 2002 February; 87(2): Elt05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11836182
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Lactic acidosis in the rectal lumen of patients with septic shock measured by luminal equilibrium dialysis. Author(s): Due V, Bonde J, Espersen K, Jensen TH, Perner A. Source: British Journal of Anaesthesia. 2002 December; 89(6): 919-22. Erratum In: Br J Anaesth. 2003 March; 90(3): 424. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453938
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Lactic acidosis related to nucleoside therapy in HIV-infected patients. Author(s): Falco V, Crespo M, Ribera E. Source: Expert Opinion on Pharmacotherapy. 2003 August; 4(8): 1321-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12877640
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Lactic acidosis, potassium, and the heart rate deflection point in professional road cyclists. Author(s): Lucia A, Hoyos J, Santalla A, Perez M, Carvajal A, Chicharro JL. Source: British Journal of Sports Medicine. 2002 April; 36(2): 113-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11916893
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Lactic acidosis. Author(s): De Backer D. Source: Minerva Anestesiol. 2003 April; 69(4): 281-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766720
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Lactic acidosis. Author(s): De Backer D. Source: Intensive Care Medicine. 2003 May; 29(5): 699-702. Epub 2003 April 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12682722
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Lactic acidosis: a metabolic complication of hematologic malignancies: case report and review of the literature. Author(s): Sillos EM, Shenep JL, Burghen GA, Pui CH, Behm FG, Sandlund JT. Source: Cancer. 2001 November 1; 92(9): 2237-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11745277
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Lactic acidosis: an early marker of propofol infusion syndrome? Author(s): Koch M, De Backer D, Vincent JL. Source: Intensive Care Medicine. 2004 March; 30(3): 522. Epub 2003 December 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14685664
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Lactic acidosis: pathophysiology, diagnosis and treatment. Author(s): Koornstra JJ, van de Loosdrecht AA, van Imhoff GW. Source: The Netherlands Journal of Medicine. 2001 December; 59(6): 300-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11744183
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Life threatening hyperkalemia and acidosis secondary to trimethoprimsulfamethoxazole treatment. Author(s): Margassery S, Bastani B. Source: Journal of Nephrology. 2001 September-October; 14(5): 410-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11730276
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Linezolid-induced lactic acidosis. Author(s): Apodaca AA, Rakita RM. Source: The New England Journal of Medicine. 2003 January 2; 348(1): 86-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12510056
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Lipid myopathy associated with renal tubular acidosis and spastic diplegia in two brothers. Author(s): Tung YC, Tsau YK, Chu LW, Young C, Shen YZ. Source: J Formos Med Assoc. 2001 July; 100(7): 484-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11579615
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Management of acidosis during lung-protective ventilation in acute respiratory distress syndrome. Author(s): Kallet RH, Liu K, Tang J. Source: Respir Care Clin N Am. 2003 December; 9(4): 437-56. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14984065
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Metabolic acidosis stimulates intestinal glutamine absorption. Author(s): Epler MJ, Souba WW, Meng Q, Lin C, Karinch AM, Vary TC, Pan M. Source: Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract. 2003 December; 7(8): 1045-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675714
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Metabolic acidosis, core-peripheral temperature difference and blood pressure response to albumin infusion in hypotensive, very premature infants. Author(s): Dimitriou G, Greenough A, Mantagos J, Skinner S. Source: Journal of Perinatal Medicine. 2001; 29(5): 442-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11723846
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Metabolic acidosis, rhabdomyolysis, and cardiovascular collapse after prolonged propofol infusion. Author(s): Cannon ML, Glazier SS, Bauman LA. Source: Journal of Neurosurgery. 2001 December; 95(6): 1053-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11765823
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Metformin and lactic acidosis: cause or coincidence? A review of case reports. Author(s): Stades AM, Heikens JT, Erkelens DW, Holleman F, Hoekstra JB. Source: Journal of Internal Medicine. 2004 February; 255(2): 179-87. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14746555
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Metformin lactic acidosis, acute renal failure and rofecoxib. Author(s): Price G. Source: British Journal of Anaesthesia. 2003 December; 91(6): 909-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14633764
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Metformin-associated lactic acidosis and acute renal failure in a type 2 diabetic patient. Author(s): Chu CK, Chang YT, Lee BJ, Hu SY, Hu WH, Yang DY. Source: J Chin Med Assoc. 2003 August; 66(8): 505-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14604317
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Metformin-induced acidosis due to a warfarin adverse drug event. Author(s): Schier JG, Hoffman RS, Nelson LS. Source: The Annals of Pharmacotherapy. 2003 July-August; 37(7-8): 1145. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12841833
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Metformin-induced encephalopathy without lactic acidosis. Author(s): Vander T, Hallevy H, Ifergane G, Herishanu YO. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2004 February; 21(2): 194-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14984458
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Miller Fisher variant of Guillain-Barre syndrome associated with lactic acidosis and stavudine therapy. Author(s): Shah SS, Rodriguez T, McGowan JP. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 May 15; 36(10): E131-3. Epub 2003 May 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12746793
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Multiple acyl-CoA dehydrogenase deficiency: a rare cause of acidosis with an increased anion gap. Author(s): Grice AS, Peck TE. Source: British Journal of Anaesthesia. 2001 March; 86(3): 437-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11573539
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Neonatal onset propionic acidemia without acidosis: a case report. Author(s): Akman I, Imamoglu S, Demirkol M, Alpay H, Ozek E. Source: Turk J Pediatr. 2002 October-December; 44(4): 339-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12458812
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New insights into the pathogenesis of renal tubular acidosis--from functional to molecular studies. Author(s): Rodriguez-Soriano J. Source: Pediatric Nephrology (Berlin, Germany). 2000 October; 14(12): 1121-36. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11045400
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Nitric oxide production modulates cyclosporin A-induced distal renal tubular acidosis in the rat. Author(s): Tsuruoka S, Schwartz GJ, Wakaumi M, Nishiki K, Yamamoto H, Purkerson JM, Fujimura A. Source: The Journal of Pharmacology and Experimental Therapeutics. 2003 June; 305(3): 840-5. Epub 2003 March 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12626650
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Nonanion gap metabolic acidosis in a newborn. Author(s): Jorquera P, Wu J, Bockenhauer D. Source: Current Opinion in Pediatrics. 1999 April; 11(2): 169-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10202628
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Non-polarized targeting of AE1 causes autosomal dominant distal renal tubular acidosis. Author(s): Devonald MA, Smith AN, Poon JP, Ihrke G, Karet FE. Source: Nature Genetics. 2003 February; 33(2): 125-7. Epub 2003 January 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12539048
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Novel AE1 mutations in recessive distal renal tubular acidosis. Loss-of-function is rescued by glycophorin A. Author(s): Tanphaichitr VS, Sumboonnanonda A, Ideguchi H, Shayakul C, Brugnara C, Takao M, Veerakul G, Alper SL. Source: The Journal of Clinical Investigation. 1998 December 15; 102(12): 2173-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9854053
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Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. Author(s): Stover EH, Borthwick KJ, Bavalia C, Eady N, Fritz DM, Rungroj N, Giersch AB, Morton CC, Axon PR, Akil I, Al-Sabban EA, Baguley DM, Bianca S, Bakkaloglu A, Bircan Z, Chauveau D, Clermont MJ, Guala A, Hulton SA, Kroes H, Li Volti G, Mir S, Mocan H, Nayir A, Ozen S, Rodriguez Soriano J, Sanjad SA, Tasic V, Taylor CM, Topaloglu R, Smith AN, Karet FE. Source: Journal of Medical Genetics. 2002 November; 39(11): 796-803. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12414817
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Novel nonsense mutation in the Na+/HCO3- cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma. Author(s): Igarashi T, Inatomi J, Sekine T, Seki G, Shimadzu M, Tozawa F, Takeshima Y, Takumi T, Takahashi T, Yoshikawa N, Nakamura H, Endou H. Source: Journal of the American Society of Nephrology : Jasn. 2001 April; 12(4): 713-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11274232
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Nuclear DNA origin of mitochondrial complex I deficiency in fatal infantile lactic acidosis evidenced by transnuclear complementation of cultured fibroblasts. Author(s): Procaccio V, Mousson B, Beugnot R, Duborjal H, Feillet F, Putet G, PignotPaintrand I, Lombes A, De Coo R, Smeets H, Lunardi J, Issartel JP. Source: The Journal of Clinical Investigation. 1999 July; 104(1): 83-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10393702
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Nucleoside analogue-induced fatal lactic acidosis in two HIV-infected patients in Singapore. Author(s): Hwang SW, Leo YS. Source: Singapore Med J. 2001 June; 42(6): 247-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11547960
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O2 uptake kinetics above and below the lactic acidosis threshold during sinusoidal exercise. Author(s): Haouzi P, Fukuba Y, Casaburi R, Stringer W, Wasserman K. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 1993 October; 75(4): 168390. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8282620
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Olanzapine-associated severe hyperglycemia, ketonuria, and acidosis: case report and review of literature. Author(s): Seaburg HL, McLendon BM, Doraiswamy PM. Source: Pharmacotherapy. 2001 November; 21(11): 1448-54. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11714220
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On the mechanism of impaired distal acidification in hyperkalemic renal tubular acidosis: evaluation with amiloride and bumetanide. Author(s): Schlueter W, Keilani T, Hizon M, Kaplan B, Batlle DC. Source: Journal of the American Society of Nephrology : Jasn. 1992 October; 3(4): 953-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1450372
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One year period prevalence study of respiratory acidosis in acute exacerbations of COPD: implications for the provision of non-invasive ventilation and oxygen administration. Author(s): Plant PK, Owen JL, Elliott MW. Source: Thorax. 2000 July; 55(7): 550-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10856313
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Optimal correction of acidosis changes progression of dialysis osteodystrophy. Author(s): Lefebvre A, de Vernejoul MC, Gueris J, Goldfarb B, Graulet AM, Morieux C. Source: Kidney International. 1989 December; 36(6): 1112-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2557481
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Osmolar gap metabolic acidosis in a 60-year-old man treated for hypoxemic respiratory failure. Author(s): Arbour R, Esparis B. Source: Chest. 2000 August; 118(2): 545-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10936154
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Osmolar gap with minimal acidosis in combined methanol and methyl ethyl ketone ingestion. Author(s): Price EA, D'Alessandro A, Kearney T, Olson KR, Blanc PD. Source: Journal of Toxicology. Clinical Toxicology. 1994; 32(1): 79-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8308953
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Osteomalacia secondary to renal tubular acidosis in a patient with primary Sjogren's syndrome. Author(s): Monte Neto JT, Sesso R, Kirsztajn GM, Da Silva LC, De Carvalho AB, Pereira AB. Source: Clin Exp Rheumatol. 1991 November-December; 9(6): 625-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1764843
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Osteomalacia secondary to renal tubular acidosis masquerading as primary biliary cirrhosis. Author(s): Davidson BK, Haslock I. Source: Rheumatology (Oxford, England). 2000 December; 39(12): 1428-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11136892
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Osteopetrosis, renal tubular acidosis without urinary concentration abnormality, cerebral calcification and severe mental retardation in three Turkish brothers. Author(s): Ocal G, Berberoglu M, Adiyaman P, Cetinkaya E, Ekim M, Aycan Z, Evliyaoglu O. Source: J Pediatr Endocrinol Metab. 2001 November-December; 14(9): 1671-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11795660
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Pathogenic mechanism, prophylaxis, and therapy of symptomatic acidosis induced by acetazolamide. Author(s): Filippi L, Bagnoli F, Margollicci M, Zammarchi E, Tronchin M, Rubaltelli FF. Source: Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research. 2002 March; 50(2): 125-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11928941
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Persistent non-gastrointestinal metabolic acidosis in pediatric HIV-1 infection. Author(s): Chakraborty R, Uy CS, Oleske JM, Coen PG, McSherry GD. Source: Aids (London, England). 2003 March 28; 17(5): 673-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12646789
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Plasma prolactin concentration increases after hypercapnia acidosis. Author(s): Rojas Vega S, Struder HK, Hollmann W. Source: Hormone and Metabolic Research. Hormon- Und Stoffwechselforschung. Hormones Et Metabolisme. 2003 October; 35(10): 598-601. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14605994
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Polymodal regulation of hTREK1 by pH, arachidonic acid, and hypoxia: physiological impact in acidosis and alkalosis. Author(s): Miller P, Peers C, Kemp PJ. Source: American Journal of Physiology. Cell Physiology. 2004 February; 286(2): C27282. Epub 2003 October 01. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14522822
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Population kinetics, efficacy, and safety of dichloroacetate for lactic acidosis due to severe malaria in children. Author(s): Agbenyega T, Planche T, Bedu-Addo G, Ansong D, Owusu-Ofori A, Bhattaram VA, Nagaraja NV, Shroads AL, Henderson GN, Hutson AD, Derendorf H, Krishna S, Stacpoole PW. Source: Journal of Clinical Pharmacology. 2003 April; 43(4): 386-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12723459
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Pregnancy and delivery complicated by mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Author(s): Kokawa N, Ishii Y, Yamoto M, Nakano R. Source: Obstetrics and Gynecology. 1998 May; 91(5 Pt 2): 865. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9572197
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Pre-HD dilution acidosis, without post-HD contraction alkalosis in uremic patients. Author(s): Agroyannis B, Fourtounas C, Tzanatos H, Kapetanaki A, Dalamangas A, Vlahakos DV. Source: Int J Artif Organs. 2003 February; 26(2): 135-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12653347
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Prognostic significance of distal renal tubular acidosis in posterior urethral valve. Author(s): Sharma RK, Sharma AP, Kapoor R, Gupta A. Source: Pediatric Nephrology (Berlin, Germany). 2001 July; 16(7): 581-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11465808
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Propofol anaesthesia and metabolic acidosis in children. Author(s): Ozlu O, Ozkara HA, Eris S, Ocal T. Source: Paediatric Anaesthesia. 2003 January; 13(1): 53-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12535040
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Protective effects of acidosis. Author(s): Laffey JG. Source: Anaesthesia. 2001 October; 56(10): 1013-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11576122
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Quality control of perfusion: monitoring venous blood oxygen tension to prevent hypoxic acidosis. Author(s): Swan H, Sanchez M, Tyndall M, Koch C. Source: The Journal of Thoracic and Cardiovascular Surgery. 1990 May; 99(5): 868-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2329825
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Quiz of the month. Severe acidosis and an osmolar gap in an alcoholic. Author(s): Norris SH. Source: American Journal of Nephrology. 1989; 9(2): 144, 175-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2741992
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Quiz page. Severe metabolic acidosis, caused by an enteric augmentation of urinary tract and renal impairment. Decompensation was caused by lack of selfcatheterization. Author(s): Jones G, Wheeler D, Davenport A; American Journal of Kidney Diseases. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2004 February; 43(2): Ra42, E1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14750125
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Recovery from pH 6.38: lactic acidosis complicated by hypothermia. Author(s): Ahmad S, Beckett M. Source: Emergency Medicine Journal : Emj. 2002 March; 19(2): 169-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11904273
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Recurrent severe anion gap metabolic acidosis secondary to episodic ethylene glycol intoxication. Author(s): Moossavi S, Wadhwa NK, Nord EP. Source: Clinical Nephrology. 2003 September; 60(3): 205-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14524585
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Re-evaluation of acid-base prediction rules in patients with chronic respiratory acidosis. Author(s): Martinu T, Menzies D, Dial S. Source: Can Respir J. 2003 September; 10(6): 311-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14530822
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Renal excretion of calcium and phosphorus in premature infants with incipient late metabolic acidosis. Author(s): Kalhoff H, Diekmann L, Rudloff S, Manz F. Source: Journal of Pediatric Gastroenterology and Nutrition. 2001 November; 33(5): 5659. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11740230
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Renal manifestations of congenital lactic acidosis. Author(s): Neiberger RE, George JC, Perkins LA, Theriaque DW, Hutson AD, Stacpoole PW. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2002 January; 39(1): 12-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11774096
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Renal tubular acidosis secondary to FK506 in living donor liver transplantation: a case report. Author(s): Ogita K, Takada N, Taguchi T, Suita S, Soejima Y, Suehiro T, Shimada M, Maehara Y. Source: Asian J Surg. 2003 October; 26(4): 218-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14530108
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Renal tubular acidosis, Sjogren syndrome, and bone disease. Author(s): Fulop M, Mackay M. Source: Archives of Internal Medicine. 2004 April 26; 164(8): 905-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15111378
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Renal tubular acidosis: a new look at an old problem. Author(s): Roth KS, Chan JC. Source: Clinical Pediatrics. 2001 October; 40(10): 533-43. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11681819
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Respiratory acidosis sans acidemia. Author(s): Jones NL. Source: Can Respir J. 2003 September; 10(6): 301-3. English, French. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14530819
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Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Author(s): Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Source: Archives of Internal Medicine. 2003 November 24; 163(21): 2594-602. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638559
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Saline-induced hyperchloremic metabolic acidosis. Author(s): Kellum JA. Source: Critical Care Medicine. 2002 January; 30(1): 259-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11902280
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Severe lactic acidosis due to thiamine deficiency in a patient with B-cell leukemia/lymphoma on total parenteral nutrition during high-dose methotrexate therapy. Author(s): Svahn J, Schiaffino MC, Caruso U, Calvillo M, Minniti G, Dufour C. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 December; 25(12): 965-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14663281
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Severe lactic acidosis in association with reverse transcriptase inhibitors with potential response to L-carnitine in a pediatric HIV-positive patient. Author(s): Carter RW, Singh J, Archambault C, Arrieta A. Source: Aids Patient Care and Stds. 2004 March; 18(3): 131-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15104873
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Severe metabolic acidosis and heart failure due to thiamine deficiency. Author(s): Blanc P, Henriette K, Boussuges A. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2002 January; 18(1): 118. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11827785
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Severe metabolic acidosis during haemodialysis: a rare but life threatening complication. Author(s): Fourtounas C, Kopelias I, Dimitriadis G, Paraskevopoulos A, Agroyannis B. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2001 December; 16(12): 2416-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11733636
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Severe nucleoside-associated lactic acidosis in human immunodeficiency virusinfected patients: report of 12 cases and review of the literature. Author(s): Falco V, Rodriguez D, Ribera E, Martinez E, Miro JM, Domingo P, Diazaraque R, Arribas JR, Gonzalez-Garcia JJ, Montero F, Sanchez L, Pahissa A. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 March 15; 34(6): 838-46. Epub 2002 February 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11850865
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Strong ion difference: metabolic acidosis or alkalosis? Author(s): Roncoroni AJ. Source: Respiratory Care. 2002 January; 47(1): 94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11811151
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Subclinical rumen acidosis as a cause of reduced appetite in newly calved dairy cows in Denmark: results of a poll among Danish dairy practitioners. Author(s): Enemark JM, Jorgensen RJ. Source: Vet Q. 2001 November; 23(4): 206-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11765242
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Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with human immunodeficiency virus infection: a report of 12 cases. Author(s): Coghlan ME, Sommadossi JP, Jhala NC, Many WJ, Saag MS, Johnson VA. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 December 1; 33(11): 1914-21. Epub 2001 October 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11692304
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Syndrome of mitochondrial myopathy of the heart and skeletal muscle, congenital cataract and lactic acidosis. Author(s): Liao SL, Huang SF, Lin JL, Lai SH, Chou YH, Kuo CY. Source: Acta Paediatr Taiwan. 2003 November-December; 44(6): 360-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14983659
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The acidosis paradox: asphyxial brain injury without coincident acidemia. Author(s): Hermansen MC. Source: Developmental Medicine and Child Neurology. 2003 May; 45(5): 353-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12729151
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The exercise metaboreflex is maintained in the absence of muscle acidosis: insights from muscle microdialysis in humans with McArdle's disease. Author(s): Vissing J, MacLean DA, Vissing SF, Sander M, Saltin B, Haller RG. Source: The Journal of Physiology. 2001 December 1; 537(Pt 2): 641-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11731594
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The synergistic effects of hypoxia/reoxygenation or tissue acidosis and bacteria on intestinal epithelial cell apoptosis. Author(s): Baylor AE 3rd, Diebel LN, Liberati DM, Dulchavsky SA, Brown WJ, Diglio CA. Source: The Journal of Trauma. 2003 August; 55(2): 241-7; Discussion 247-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12913632
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Thiamine deficiency as a cause of metabolic acidosis. Author(s): Logan G, Goli SA, McGonagle M, Byrd RP Jr, Roy TM. Source: Tenn Med. 2003 December; 96(12): 553-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15077560
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Topical dorzolamide and metabolic acidosis in a neonate. Author(s): Morris S, Geh V, Nischal KK, Sahi S, Ahmed MA. Source: The British Journal of Ophthalmology. 2003 August; 87(8): 1052-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12881361
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Topiramate-induced metabolic acidosis: report of two cases. Author(s): Ko CH, Kong CK. Source: Developmental Medicine and Child Neurology. 2001 October; 43(10): 701-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11665828
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Topiramate-induced renal tubular acidosis. Author(s): Izzedine H, Launay-Vacher V, Deray G. Source: The American Journal of Medicine. 2004 February 15; 116(4): 281-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14969660
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Treating intraoperative hyperchloremic acidosis with sodium bicarbonate or trishydroxymethyl aminomethane: a randomized prospective study. Author(s): Rehm M, Finsterer U. Source: Anesthesia and Analgesia. 2003 April; 96(4): 1201-8, Table of Contents. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12651685
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Treatment of metabolic acidosis. Author(s): Levraut J, Grimaud D. Source: Current Opinion in Critical Care. 2003 August; 9(4): 260-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883279
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Type IV renal tubular acidosis presenting as dyspnea in two older patients taking angiotensin-converting enzyme inhibitors. Author(s): Bomann JS, Peckler BF. Source: Annals of Emergency Medicine. 2002 January; 39(1): 73-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11782734
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Umbilical arteriovenous PO2 and PCO2 differences and neonatal morbidity in term infants with severe acidosis. Author(s): Belai Y, Goodwin TM, Durand M, Greenspoon JS, Paul RH, Walther FJ. Source: American Journal of Obstetrics and Gynecology. 1998 January; 178(1 Pt 1): 13-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9465796
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Underlying defects in distal renal tubular acidosis: new understandings. Author(s): Batlle D, Flores G. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 1996 June; 27(6): 896-915. Review. Erratum In: Am J Kidney Dis 1997 May; 29(5): 815. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8651257
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Unexpected survival from severe metformin-associated lactic acidosis. Author(s): Schure PJ, de Gooijer A, van Zanten AR. Source: The Netherlands Journal of Medicine. 2003 October; 61(10): 331-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14708912
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Unexplained metabolic acidosis in critically ill patients: the role of pyroglutamic acid. Author(s): Mizock BA, Belyaev S, Mecher C. Source: Intensive Care Medicine. 2004 March; 30(3): 502-5. Epub 2003 December 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14685659
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Unique astrocytic inclusion in a 2 month-old baby showing Leigh-like brain lesions with lactic acidosis. Author(s): Yamamoto T, Armstrong D, Shibata N, Kato Y, Kobayashi M. Source: Brain & Development. 2000 June; 22(4): 234-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10838110
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Unraveling the molecular pathogenesis of isolated proximal renal tubular acidosis. Author(s): Igarashi T, Sekine T, Inatomi J, Seki G. Source: Journal of the American Society of Nephrology : Jasn. 2002 August; 13(8): 2171-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12138151
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Urate nephropathy following chronic ileostomy acidosis. Author(s): Randall RE Jr. Source: American Journal of Nephrology. 2002 July-August; 22(4): 372-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12169871
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Uremic acidosis and protein metabolism. Author(s): Mitch WE. Source: Current Opinion in Nephrology and Hypertension. 1995 November; 4(6): 488-92. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8591056
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Urinary net charge in hyperchloremic metabolic acidosis. Author(s): Kumar S, Vaswani M, Srivastava RN, Bagga A. Source: Indian Pediatrics. 1998 January; 35(1): 13-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9707899
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Urolithiasis and distal renal tubular acidosis preceding primary Sjogren's syndrome: a retrospective study 5-53 years after the presentation of urolithiasis. Author(s): Eriksson P, Denneberg T, Enestrom S, Johansson B, Lindstrom F, Skogh T. Source: Journal of Internal Medicine. 1996 June; 239(6): 483-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8656141
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Vaginally born low-risk preterm infants: fetal acidosis and outcome at 6 years of age. Author(s): Holmqvist P, Pleven H, Svenningsen NW. Source: Acta Paediatr Scand. 1988 September; 77(5): 638-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3201969
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Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning. Author(s): Baud FJ, Borron SW, Megarbane B, Trout H, Lapostolle F, Vicaut E, Debray M, Bismuth C. Source: Critical Care Medicine. 2002 September; 30(9): 2044-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12352039
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Ventilatory management casebook. Error in blood gas sampling resulting in a spurious interpretation of compensated metabolic acidosis. Author(s): Goldsmith JP. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 1993 March-April; 13(2): 165-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8515314
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Ventilatory response in metabolic acidosis and cerebral blood volume in humans. Author(s): Van de Ven MJ, Colier WN, van der Sluijs MC, Oeseburg B, Folgering H. Source: Respiration Physiology. 2001 January; 124(2): 105-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11164202
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Vitamin-responsive complex I deficiency in a myopathic patient with increased activity of the terminal respiratory chain and lactic acidosis. Author(s): Bakker HD, Scholte HR, Jeneson JA, Busch HF, Abeling NG, van Gennip AH. Source: Journal of Inherited Metabolic Disease. 1994; 17(2): 196-204. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7967474
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Vitamin-responsive pyruvate dehydrogenase deficiency in a young girl with external ophthalmoplegia, myopathy and lactic acidosis. Author(s): Scholte HR, Busch HF, Luyt-Houwen IE. Source: Journal of Inherited Metabolic Disease. 1992; 15(3): 331-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1405466
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Water intoxication and lactic acidosis caused by excessive intake of commercial sports drink. Author(s): Nozue H, Kamoda T, Matsui A. Source: Acta Paediatrica (Oslo, Norway : 1992). 2001 November; 90(11): 1357-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11808915
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What have isotope studies in humans told us about the nutritional effects of acidosis in dialysis? Author(s): Louden JD, Roberts RG, Goodship TH. Source: Seminars in Dialysis. 2000 July-August; 13(4): 247-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10923353
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What is the clinical relevance of dilutional acidosis? Author(s): Roth JV. Source: Anesthesiology. 2001 September; 95(3): 810-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11575565
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What is the relationship between metabolic acidosis and nutritional status in dialysis patients? Author(s): Goodship TH. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 1998 May; 31(5): 884-6; Discussion 886-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9590204
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What is the underlying defect in patients with isolated, proximal renal tubular acidosis? Author(s): Halperin ML, Kamel KS, Ethier JH, Magner PO. Source: American Journal of Nephrology. 1989; 9(4): 265-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2817016
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Whole blood ionized magnesium in neonatal acidosis and preterm infants: a prospective consecutive study. Author(s): Olofsson K, Matthiesen G, Rudnicki M. Source: Acta Paediatrica (Oslo, Norway : 1992). 2001 December; 90(12): 1398-401. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11853336
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Why does lactic acidosis occur in acute lung injury? Author(s): Effros RM, Lipchik RJ. Source: Chest. 1997 May; 111(5): 1157-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9149562
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Why does renal tubular acidosis cause hypercalciuria? Author(s): Rodriguez-Soriano J. Source: Pediatric Nephrology (Berlin, Germany). 1992 March; 6(2): 144. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1571209
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Wound hypoxia and acidosis limit neutrophil bacterial killing mechanisms. Author(s): Allen DB, Maguire JJ, Mahdavian M, Wicke C, Marcocci L, Scheuenstuhl H, Chang M, Le AX, Hopf HW, Hunt TK. Source: Archives of Surgery (Chicago, Ill. : 1960). 1997 September; 132(9): 991-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9301612
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Zidovudine-associated type B lactic acidosis and hepatic steatosis in an HIV-infected patient. Author(s): Acosta BS, Grimsley EW. Source: Southern Medical Journal. 1999 April; 92(4): 421-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10219365
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CHAPTER 2. NUTRITION AND ACIDOSIS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and acidosis.
Finding Nutrition Studies on Acidosis 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 “acidosis” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
7
Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
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The following is a typical result when searching for recently indexed consumer information on acidosis: •
Lactic acidosis and mitochondrial myopathy in a young woman. Source: Anonymous Nutr-Revolume 1988 April; 46(4): 157-63 0029-6643
The following information is typical of that found when using the “Full IBIDS Database” to search for “acidosis” (or a synonym): •
Absence of metabolic acidosis in toxic methanol ingestion: a case report and review. Author(s): Department of Emergency Medicine, Christiana Care Health Services, Newark, Delaware, USA. Source: Sullivan, M Chen, C L Madden, J F Del-Med-J. 1999 October; 71(10): 421-6 00117781
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Acidosis of pregnant ewes: so-called pregnancy disease of sheep. Source: Dimock, W.W. Healy, D.J. Hull, F.E. Circ-Univ-Ky-Agric-Exp-Stn. Lexington, Ky. : The Station. October 1928. (39) 8 page
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Acidosis plus melphalan induces nitric oxide-mediated tumor regression in an isolated limb perfusion human melanoma xenograft model. Author(s): Department of Surgery, University of Pennsylvania, Philadelphia 19104, USA. Source: Kelley, S T Menon, C Buerk, D G Bauer, T W Fraker, D L Surgery. 2002 August; 132(2): 252-8 0039-6060
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Alcoholic ketoacidosis--a review. Author(s): Emergency Medical Services, Denver General Hospital, CO 80204-4507. Source: Duffens, K Marx, J A J-Emerg-Med. 1987 Sep-October; 5(5): 399-406 0736-4679
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Characterisation of the calcium paradox in the isolated perfused pigeon heart: protection by hypothermia, acidosis and alkalosis. Author(s): Department of Animal and Human Physiology, School of Biology, Faculty of Sciences, University of Athens, Panepistimioupolis, Athens. Source: Gaitanaki, C Anezaki, M Margieti, M M Papazafiri, P Beis, I Cell-PhysiolBiochem. 2002; 12(2-3): 93-100 1015-8987
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Compensatory role of CaMKII on ICa and SR function during acidosis in rat ventricular myocytes. Author(s): School of Biomedical Sciences, University of Leeds, UK. Source: Komukai, K Pascarel, C Orchard, C H Pflugers-Arch. 2001 June; 442(3): 353-61 0031-6768
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Congenital lactic acidosis. Author(s): Department of Pediatrics, School of Medicine, University of Tokushima, Japan. Source: Kuroda, Y Naito, E Takeda, E Yokota, I Miyao, M Enzyme. 1987; 38(1-4): 108-14 0013-9432
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Effect of lactobacillus acidophilus on subacute acidosis and cattle performance. Source: Klopfenstein, T. Huffman, R. Stock, R. MP-Univ-Neb-Linc-Agric-Res-Divolume Lincoln : Agricultural Research Division, Institute of Agriculture & Natural Resources, University of Nebraska, Lincoln, [1986?-. 1995. (62-A) page 37-38.
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Effect of metabolic acidosis on branched-chain amino acids in uremia. Author(s): Department of Pediatrics, Oregon Health Sciences University, Portland 97201-3098, USA.
[email protected] Source: Mak, R H Pediatr-Nephrol. 1999 May; 13(4): 319-22 0931-041X
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Effects of vasodilatation and acidosis on the blood-brain barrier. Author(s): Department of Internal Medicine, Veterans Administration Medical Center, Iowa City, Iowa. Source: Mayhan, W G Faraci, F M Heistad, D D Microvasc-Res. 1988 March; 35(2): 179-92 0026-2862
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Evaluation of sodium bicarbonate or lactated ringer's solution for the treatment of rumen lactic acidosis in steers. Source: Mendes Netto, D. Ortolani, E.L. Veterinaria-Noticias (Brazil). (2000). volume 6(2) page 31-39. bullocks sodium bicarbonate acidosis rumen 0104-3463
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Evidence that acidosis alters the high-affinity dopamine uptake in rat striatal slices and synaptosomes by different mechanisms partially related to oxidative damage. Author(s): Groupe d'Etudes des Mecanismes Cellulaires de l'Ischemie (GEMCI), UPRES EA 1223, Faculte de Medecine et de Pharmacie, 34 Rue du Jardin des Plantes, BP 199, 86005 Poitiers Cedex, France.
[email protected] Source: Barrier, L Barc, S Fauconneau, B Pontcharraud, R Kelani, A Bestel, E Page, G Neurochem-Int. 2003 January; 42(1): 27-34 0197-0186
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Failure of simulated acidosis to influence 25-hydroxyvitamin D3 (25OHD3) metabolism by kidney cell monolayers. Source: Cunningham, J. Griffin, G. Avioli, L.Volume Vitamin D : chemical, biochemical, and clinical update; proceedings of the Sixth Workshop on Vitamin D, Merano, Italy, March 1985 / editors, A.W. Norman. [et al.]. Berlin [West Ger.] : De Gruyter, 1985. page 521-522. ISBN: 3111010815
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Glucose starvation and acidosis: effect on experimental metastatic potential, DNA content and MTX resistance of murine tumour cells. Author(s): Ontario Cancer Institute, University of Toronto, Canada. Source: Schlappack, O K Zimmermann, A Hill, R P Br-J-Cancer. 1991 October; 64(4): 66370 0007-0920
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Hypoxic ventilatory depression in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Author(s): First Department of Medicine, Asahikawa Medical College, Asahikawa, Japan.
[email protected] Source: Osanai, S Takahashi, T Enomoto, H Satoh, N Yahara, O Akiba, Y Fujiuchi, S Nakano, H Ohsaki, Y Kikuchi, K Respirology. 2001 June; 6(2): 163-6 1323-7799
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Improvement of lactic acidosis from intestinal ischemia using dichloroacetate. Source: McCormack, C J Naim, J O Hinshaw, J R Curr-Surg. 1987 Nov-December; 44(6): 472-6 0149-7944
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Metabolic acidosis and nutritional status of patients receiving continuous ambulatory peritoneal dialysis (CAPD) Source: Szeto, C C Lai, K N Int-J-Artif-Organs. 1998 April; 21(4): 192-5 0391-3988
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Metabolic and endocrine effects of metabolic acidosis in humans. Author(s): Medizinische Universitatsklinik Bruderholz, Bruderholz/Basel, Switzerland. Source: Wiederkehr, M Krapf, R Swiss-Med-Wkly. 2001 March 10; 131(9-10): 127-32 1424-7860
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New feed additive and technique to evaluate acidosis in cattle. Source: Britton, R. Stock, R. Sindt, M. Oliveros, B. Parrott, C. MP-Univ-Nebr-Agric-ExpStn. Lincoln, Neb. : The Station. October 1990. (56) page 55-58. 0748-2884
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Oxygen consumption and force development in turtle and trout cardiac muscle during acidosis and high extracellular potassium. Author(s): Department of Zoophysiology, Institute of Biological Sciences, University of Aarhus, Denmark. Source: Kalinin, A Gesser, H J-Comp-Physiol-[B]. 2002 February; 172(2): 145-51 01741578
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Pathology of lethal fetal growth retardation syndrome with aminoaciduria, iron overload, and lactic acidosis (GRACILE). Author(s): Department of Pathology, Hospital for Children and Adolscents, University Central Hospital and University of Helsinki, Finland.
[email protected] Source: Rapola, J Heikkila, P Fellman, V Pediatr-Pathol-Mol-Med. 2002 Mar-April; 21(2): 183-93 1522-7952
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Reduction in spinal cord postischemic lactic acidosis and functional improvement with dichloroacetate. Author(s): Department of Neurosurgery, Baylor College of Medicine, Houston, Texas. Source: Robertson, C S Goodman, J C Grossman, R G Priessman, A J-Neurotrauma. 1990 Spring; 7(1): 1-12 0897-7151
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Regulation of apoA1 gene expression with acidosis: requirement for a transcriptional repressor. Author(s): Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, Missouri 63110, USA. Source: Haas, M J Reinacher, D Li, J P Wong, N C Mooradian, A D J-Mol-Endocrinol. 2001 August; 27(1): 43-57 0952-5041
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Regulation of renal Na-HCO3 cotransporter: VIII. Mechanism Of stimulatory effect of respiratory acidosis. Author(s): Section of Nephrology, University of Illinois at Chicago and West Side VA Medical Center, IL 60612-7315, USA. Source: Ruiz, O S Qiu, Y Y Wang, L J Cardoso, L R Arruda, J A J-Membr-Biol. 1998 April 1; 162(3): 201-8 0022-2631
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Riboflavin treatment of antiretroviral induced lactic acidosis and hepatic steatosis. Author(s): Department of Diagnostic Imaging, Rhode Island Hospital, Providence, Rhode Island, USA. Source: Posteraro, A F 3rd Mauriello, M Winter, S M Conn-Med. 2001 July; 65(7): 387-90 0010-6178
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Role of endothelial nitric oxide and smooth muscle potassium channels in cerebral arteriolar dilation in response to acidosis. Author(s): Department of Neurosurgery, Washington University School of Medicine, St Louis, Mo 63110, USA. Source: Horiuchi, Tetsuyoshi Dietrich, Hans H Hongo, Kazuhiro Goto, Tetsuya Dacey, Ralph G Jr Stroke. 2002 March; 33(3): 844-9 1524-4628
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Severe lactic acidosis and thiamine administration in an HIV-infected patient on HAART. Author(s): Unita Operativa Perativa di Malattie Infettive, Ospedali Riuniti di Bergamo, Italy.
[email protected]
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Source: Arici, C Tebaldi, A Quinzan, G P Maggiolo, F Ripamonti, D Suter, F Int-J-STDAIDS. 2001 June; 12(6): 407-9 0956-4624 •
The effects of extracellular citric acid acidosis on the viability, cellular adhesion capacity and protein synthesis of cultured human gingival fibroblasts. Author(s): School of Dentistry, College of Medicine, National Taiwan University, Taipei. Source: Lan, W C Lan, W H Chan, C P Hsieh, C C Chang, M C Jeng, J H Aust-Dent-J. 1999 June; 44(2): 123-30 0045-0421
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Thiamine-deficient lactic acidosis with brain tumor treatment. Report of three cases. Author(s): Department of Neurosurgery, Neurological Institute, Faculty of Medicine, Kyushu University, Fukuoka, Japan. Source: Kuba, H Inamura, T Ikezaki, K Kawashima, M Fukui, M J-Neurosurg. 1998 December; 89(6): 1025-8 0022-3085
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 acidosis; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
Minerals Sodium Bicarbonate Source: Healthnotes, Inc.; www.healthnotes.com
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CHAPTER 3. ALTERNATIVE MEDICINE AND ACIDOSIS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to acidosis. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to acidosis and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “acidosis” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to acidosis: •
Acidosis-induced modifications of high-affinity choline uptake by synaptosomes: effects of pH readjustment. Author(s): Cancela JM, Beley A. Source: Neurochemical Research. 1995 July; 20(7): 863-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7477680
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Acute respiratory acidosis: large-dose furosemide and cerebrospinal fluid ions. Author(s): Javaheri S, Corbett W, Adams JM, Davis PJ, Gartside PS. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 1994 June; 76(6): 2651-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7928896
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Antiretroviral combination may put pregnant women at risk of fatal lactic acidosis. Author(s): Thompson CA.
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Source: American Journal of Health-System Pharmacy : Ajhp : Official Journal of the American Society of Health-System Pharmacists. 2001 February 15; 58(4): 291. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11225165 •
Beneficial effects of fasting and low carbohydrate diet in D-lactic acidosis associated with short-bowel syndrome. Author(s): Ramakrishnan T, Stokes P. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 1985 May-June; 9(3): 361-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4009922
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Calcium deficient puberty rickets with acidosis responding to large dose of oral calcium. Author(s): Sulochana G, Balakrishnan S. Source: J Indian Med Assoc. 1982 November; 79(9-10): 140-2. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7169542
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Carbon monoxide poisoning treated with hyperbaric oxygen: metabolic acidosis as a predictor of treatment requirements. Author(s): Turner M, Esaw M, Clark RJ. Source: Journal of Accident & Emergency Medicine. 1999 March; 16(2): 96-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10191440
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Chronic metabolic acidosis increases mRNA levels for components of the ubiquitinmediated proteolytic pathway in skeletal muscle of dairy cows. Author(s): Mutsvangwa T, Gilmore J, Squires JE, Lindinger MI, McBride BW. Source: The Journal of Nutrition. 2004 March; 134(3): 558-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14988446
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Comparative study of different insulin regimens in management of diabetic ketoacidosis. Author(s): Soler NG, FitzGerald MG, Wright AD, Malins JM. Source: Lancet. 1975 December 20; 2(7947): 1221-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=53719
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Comparison of lactate or BE during out-of-hospital cardiac arrest to determine metabolic acidosis. Author(s): Prause G, Ratzenhofer-Comenda B, Smolle-Juttner F, Heydar-Fadai J, Wildner G, Spernbauer P, Smolle J, Hetz H. Source: Resuscitation. 2001 December; 51(3): 297-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11738782
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Critical hypokalemic renal tubular acidosis due to Sjogren's syndrome: association with the purported immune stimulant echinacea. Author(s): Logan JL, Ahmed J. Source: Clinical Rheumatology. 2003 May; 22(2): 158-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12740687
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Development of acidosis in human beings during closed-chest and open-chest CPR. Author(s): Henneman PL, Gruber JE, Marx JA. Source: Annals of Emergency Medicine. 1988 July; 17(7): 672-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3132874
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Diabetic ketoacidosis and hypogonadotropic hypogonadism in association with transfusional hemochromatosis in a man with beta-thalassemia major. Author(s): Lu JY, Chang CC, Tsai HC, Lin KS, Tsang YM, Huang KM. Source: J Formos Med Assoc. 2001 July; 100(7): 492-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11579617
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Diabetic ketoacidosis associated with Metabolife: a report of two cases. Author(s): Case CC, Maldonado M. Source: Diabetes, Obesity & Metabolism. 2002 November; 4(6): 402-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12406039
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Diet-induced ketosis does not cause cerebral acidosis. Author(s): Al-Mudallal AS, LaManna JC, Lust WD, Harik SI. Source: Epilepsia. 1996 March; 37(3): 258-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8598184
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Diets enriched with N-3 fatty acids ameliorate lactic acidosis by improving endotoxin-induced tissue hypoperfusion in guinea pigs. Author(s): Pomposelli JJ, Flores EA, Blackburn GL, Zeisel SH, Bistrian BR. Source: Annals of Surgery. 1991 February; 213(2): 166-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1992944
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Dimethyl sulfoxide, but not acidosis-induced metallothionein mRNA expression in neonatal rat primary astrocyte cultures is inhibited by the bioflavonoid, quercetin. Author(s): Conklin DR, Tan KH, Aschner M. Source: Brain Research. 1998 June 1; 794(2): 304-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9622659
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Direct effect of acute metabolic and respiratory acidosis on parathyroid hormone secretion in the dog. Author(s): Lopez I, Aguilera-Tejero E, Felsenfeld AJ, Estepa JC, Rodriguez M.
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Source: Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research. 2002 September; 17(9): 1691-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12211440 •
Dynamics of ionized magnesium and ionized calcium during recovery from diabetic ketoacidosis managed with conventional treatment. Author(s): Escobar O, Lifshitz F, Mimouni F. Source: Magnes Res. 1998 June; 11(2): 111-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9675755
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Effects of bacterial direct-fed microbials and yeast on site and extent of digestion, blood chemistry, and subclinical ruminal acidosis in feedlot cattle. Author(s): Beauchemin KA, Yang WZ, Morgavi DP, Ghorbani GR, Kautz W, Leedle JA. Source: Journal of Animal Science. 2003 June; 81(6): 1628-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12817511
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Failure of dietary-casein-induced acidosis to explain the hypercholesterolemia of casein-fed rabbits. Author(s): Hermus RJ, West CE, van Weerden EJ. Source: The Journal of Nutrition. 1983 March; 113(3): 618-29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6681835
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Inactive form of erythrocyte carbonic anhydrase B in patients with primary renal tubular acidosis. Author(s): Kondo T, Taniguchi N, Taniguchi K, Matsuda I, Murao M. Source: The Journal of Clinical Investigation. 1978 September; 62(3): 610-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=99456
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Increased red cell osmotic fragility and hematocrit after hyperbaric O2 exposure are related to acidosis. Author(s): Braisted JC, Harabin AL. Source: The Journal of Laboratory and Clinical Medicine. 1994 July; 124(1): 105-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8035092
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Intracellular pH and K+ of cardiac and skeletal muscle in acidosis and alkalosis. Author(s): Poole-Wilson PA, Cameron IR. Source: The American Journal of Physiology. 1975 November; 229(5): 1305-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=911
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Intravenous pyridoxine-induced metabolic acidosis. Author(s): Lovecchio F, Curry SC, Graeme KA, Wallace KL, Suchard J.
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Source: Annals of Emergency Medicine. 2001 July; 38(1): 62-4. Erratum In: Ann Emerg Med 2001 September; 38(3): 341. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11423814 •
Is intrapartum vibroacoustic stimulation an effective predictor of fetal acidosis? Author(s): Lin CC, Vassallo B, Mittendorf R. Source: Journal of Perinatal Medicine. 2001; 29(6): 506-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11776681
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Lactic acidosis as a predictor of downtime during cardiopulmonary arrest in dogs. Author(s): Carden DL, Martin GB, Nowak RM, Foreback CC, Tomlanovich MC. Source: The American Journal of Emergency Medicine. 1985 March; 3(2): 120-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3970767
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Lactic acidosis associated with high-dose niacin therapy. Author(s): Earthman TP, Odom L, Mullins CA. Source: Southern Medical Journal. 1991 April; 84(4): 496-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2014436
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Lactic acidosis associated with Hodgkin's disease: response to chemotherapy. Author(s): Nadiminti Y, Wang JC, Chou SY, Pineles E, Tobin MS. Source: The New England Journal of Medicine. 1980 July 3; 303(1): 15-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7374729
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Lactic acidosis caused by thiamine deficiency in a pregnant alcoholic patient. Author(s): Mukunda BN. Source: The American Journal of the Medical Sciences. 1999 April; 317(4): 261-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10210363
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Lactic acidosis during closed-chest CPR in dogs. Author(s): Carden DL, Martin GB, Nowak RM, Foreback CC, Tomlanovich MC. Source: Annals of Emergency Medicine. 1987 December; 16(12): 1317-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3688590
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Lactic Acidosis in Non-Hodgkin's Lymphoma and response to Chemotherapy. Author(s): Osorio S, Bernis C, de La Camara R. Source: Haematologica. 2002 February; 87(2): Elt05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11836182
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Lactic acidosis in theophylline overdose. Author(s): Leventhal LJ, Kochar G, Feldman NH, Podolsky SM, Stanek MS.
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Source: The American Journal of Emergency Medicine. 1989 July; 7(4): 417-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2567599 •
Lactic acidosis with small cell carcinoma. Rapid response to chemotherapy. Author(s): Rice K, Schwartz SH. Source: The American Journal of Medicine. 1985 October; 79(4): 501-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2996348
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Late metabolic acidosis of the premature infant. Author(s): Brackemyre P, Schreiner RL. Source: Journal of the American Dietetic Association. 1978 March; 72(3): 298-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=564920
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Lipoamide dehydrogenase deficiency with primary lactic acidosis: favorable response to treatment with oral lipoic acid. Author(s): Matalon R, Stumpf DA, Michals K, Hart RD, Parks JK, Goodman SI. Source: The Journal of Pediatrics. 1984 January; 104(1): 65-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6418873
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Low-dose insulin in the treatment of diabetic ketoacidosis. Author(s): Alberti KG. Source: Archives of Internal Medicine. 1977 October; 137(10): 1367-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=411433
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Low-dose versus high-dose insulin therapy for diabetic ketoacidosis. Author(s): Pfeifer MA, Samols E, Wolter CF, Winkler CF. Source: Southern Medical Journal. 1979 February; 72(2): 149-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=106476
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Myocardial ischemia and cell acidosis: Modification by alkali and the effects on ventricular function and cation composition. Author(s): Regan TJ, Effros RM, Haider B, Oldewurtel HA, Ettinger PO, Ahmed SS. Source: The American Journal of Cardiology. 1976 March 31; 37(4): 501-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3959
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Oxidative conversion of 6-nitrocatecholamines to nitrosating products: a possible contributory factor in nitric oxide and catecholamine neurotoxicity associated with oxidative stress and acidosis. Author(s): Palumbo A, Napolitano A, Carraturo A, Russo GL, d'Ischia M. Source: Chemical Research in Toxicology. 2001 September; 14(9): 1296-305. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11559046
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Oxidative phosphorylation in isolated canine myocardial mitochondria. Effects of in vitro volume dilution, lactate, phosphate, and calcium addition, and lactic acidosis. Author(s): Mukherjee A, Wong TM, Buja LM, Willerson JT. Source: Adv Myocardiol. 1980; 2: 339-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6252587
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Pathogenesis and treatment of metabolic acidosis in open heart surgery under surface induced deep hypothermia. Author(s): Shida H. Source: Jpn J Surg. 1974 December; 4(4): 198-203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4465470
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Perinatal acidosis and placental transfusion. Author(s): Chou PJ, Ackerman BD. Source: Acta Paediatr Scand. 1973 July; 62(4): 417-21. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4729692
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pH regulation of endogenous acid production in subjects with chronic ketoacidosis. Author(s): Hood VL. Source: The American Journal of Physiology. 1985 August; 249(2 Pt 2): F220-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4025554
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Phenformin-associated lactic acidosis due to imported phenformin. Author(s): Lu HC, Parikh PP, Lorber DL. Source: Diabetes Care. 1996 December; 19(12): 1449-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8941483
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Possible source of adenosine triphosphate released from rat myocytes in response to hypoxia and acidosis. Author(s): Williams CA, Forrester T. Source: Cardiovascular Research. 1983 May; 17(5): 301-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6411342
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Postnatal growth of infants of less than 1.3 kg birth weight: effects of metabolic acidosis, of caloric intake, and of calcium, sodium, and phosphate supplementation. Author(s): Chance GW, Radde IC, Willis DM, Roy RN, Park E, Ackerman I. Source: The Journal of Pediatrics. 1977 November; 91(5): 787-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=909021
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Proceedings: Metabolic acidosis following regional circulatory arrest: treatment by THAM, hyperventilation and hyperbaric oxygen. Author(s): Benichoux R.
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Source: The Journal of Cardiovascular Surgery. 1973 November-December; 14(6): 573-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4764807 •
Protein wasting due to acidosis of prolonged fasting. Author(s): Hannaford MC, Leiter LA, Josse RG, Goldstein MB, Marliss EB, Halperin ML. Source: The American Journal of Physiology. 1982 September; 243(3): E251-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6287864
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Pyruvate dehydrogenase phosphatase deficiency: a cause of congenital chronic lactic acidosis in infancy. Author(s): Robinson BH, Sherwood WG. Source: Pediatric Research. 1975 December; 9(12): 935-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=172850
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Rapid improvement of osteomalacia by treatment in a case with Sjogren's syndrome, rheumatoid arthritis and renal tubular acidosis type 1. Author(s): Okada M, Suzuki K, Hidaka T, Shinohara T, Kataharada K, Matsumoto M, Takada K, Ohsuzu F. Source: Intern Med. 2001 August; 40(8): 829-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11518137
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Renal tubular acidosis, hypokalemic paralysis, rhabdomyolysis, and acute renal failure--a rare presentation of Chinese herbal nephropathy. Author(s): Lee CT, Wu MS, Lu K, Hsu KT. Source: Renal Failure. 1999 March; 21(2): 227-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10088184
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Role of acidosis-induced increases in calcium on PTH secretion in acute metabolic and respiratory acidosis in the dog. Author(s): Lopez I, Aguilera-Tejero E, Estepa JC, Rodriguez M, Felsenfeld AJ. Source: American Journal of Physiology. Endocrinology and Metabolism. 2004 May; 286(5): E780-5. Epub 2004 January 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722029
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Sauna-induced diabetic ketoacidosis. Author(s): Bienvenu B, Timsit J. Source: Diabetes Care. 1999 September; 22(9): 1584. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10480529
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Severe lactic acidosis due to thiamine deficiency in a patient with B-cell leukemia/lymphoma on total parenteral nutrition during high-dose methotrexate therapy. Author(s): Svahn J, Schiaffino MC, Caruso U, Calvillo M, Minniti G, Dufour C.
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Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 December; 25(12): 965-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14663281 •
Severe metabolic acidosis and “muti” (traditional herbal medicine) ingestion in young children. Author(s): Nkrumah FK, Nathoo KJ, Gomo ZA, Pirie DJ. Source: Cent Afr J Med. 1990 January; 36(1): 16-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2397494
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Sheep fed grain prefer foods and solutions that attenuate acidosis. Author(s): Phy TS, Provenza FD. Source: Journal of Animal Science. 1998 April; 76(4): 954-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9581916
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Short communication: Effects of a monensin premix on milk fatty acid content during subacute ruminal acidosis in dairy cows. Author(s): Mutsvangwa T, Kramer JK, Blackadar CB, Duffield TF, Bagg R, Dick P, Vessie G, McBride BW. Source: Journal of Dairy Science. 2003 December; 86(12): 4043-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14740842
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Short-term TPN containing n-3 fatty acids ameliorate lactic acidosis induced by endotoxin in guinea pigs. Author(s): Pomposelli JJ, Flores E, Hirschberg Y, Teo TC, Blackburn GL, Zeisel SH, Bistrian BR. Source: The American Journal of Clinical Nutrition. 1990 September; 52(3): 548-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2118304
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Simultaneous correction of Ca deficiency and acidosis in fasting obese patients as a prevention of bone demineralisation. Author(s): Kocian J, Brodan V. Source: Nutr Metab. 1979; 23(5): 391-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=481830
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Small versus large doses of insulin in diabetic ketoacidosis. Author(s): Kanter Y, Bessman AN. Source: The Western Journal of Medicine. 1975 June; 122(6): 509-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=237370
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Sublimed (inorganic) sulfur ingestion. A cause of life-threatening metabolic acidosis with a high anion gap. Author(s): Schwartz SM, Carroll HM, Scharschmidt LA.
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Source: Archives of Internal Medicine. 1986 July; 146(7): 1437-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3718141 •
The acute reversal of a diet-induced metabolic acidosis does not restore endurance capacity during high-intensity exercise in man. Author(s): Ball D, Greenhaff PL, Maughan RJ. Source: European Journal of Applied Physiology and Occupational Physiology. 1996; 73(1-2): 105-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8861677
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The danger of high dose sodium bicarbonate in biguanide-induced lactic acidosis: the theory, the practice and alternative therapies. Author(s): Ryder RE. Source: Br J Clin Pract. 1987 May; 41(5): 730-7. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2833297
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The influence of bicarbonate supplementation on plasma levels of branched-chain amino acids in haemodialysis patients with metabolic acidosis. Author(s): Kooman JP, Deutz NE, Zijlmans P, van den Wall Bake A, Gerlag PG, van Hooff JP, Leunissen KM. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 1997 November; 12(11): 2397-401. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9394330
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The synergistic effects of hypoxia/reoxygenation or tissue acidosis and bacteria on intestinal epithelial cell apoptosis. Author(s): Baylor AE 3rd, Diebel LN, Liberati DM, Dulchavsky SA, Brown WJ, Diglio CA. Source: The Journal of Trauma. 2003 August; 55(2): 241-7; Discussion 247-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12913632
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Thiamine deficiency as a cause of metabolic acidosis. Author(s): Logan G, Goli SA, McGonagle M, Byrd RP Jr, Roy TM. Source: Tenn Med. 2003 December; 96(12): 553-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15077560
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Topiramate and metabolic acidosis. Author(s): Wilner A, Raymond K, Pollard R. Source: Epilepsia. 1999 June; 40(6): 792-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10368081
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Treatment of diabetic ketoacidosis by direct addition of insulin to intravenous infusion. A comparison of “high dose” and “low dose” techniques. Author(s): Harrower AD. Source: Br J Clin Pract. 1979 March; 33(3): 85-6. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=109109
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Validation of I.V. small-dose insulin infusion therapy in diabetic ketoacidosis of depancreatized dogs. Author(s): Goriya Y, Kawamori R, Shichiri M, Kikuchi M, Yamasaki Y, Shigeta Y, Abe H. Source: Acta Diabetol Lat. 1978 September-December; 15(5-6): 236-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=107695
Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMDHealth: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to acidosis; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
General Overview Diabetes Mellitus Source: Integrative Medicine Communications; www.drkoop.com
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Herbs and Supplements AZT Source: Healthnotes, Inc.; www.healthnotes.com Didanosine Source: Healthnotes, Inc.; www.healthnotes.com Eugenia Clove Alternative names: Cloves; Eugenia sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Garcinia Cambogia Alternative names: Citrin, Gambooge Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Loop Diuretics Source: Integrative Medicine Communications; www.drkoop.com Stavudine Source: Healthnotes, Inc.; www.healthnotes.com
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON ACIDOSIS Overview In this chapter, we will give you a bibliography on recent dissertations relating to acidosis. 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 “acidosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on acidosis, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Acidosis 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 acidosis. 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: •
Ammoniagenesis in the rat kidney during recovery from metabolic acidosis by Parry, David Morris; PhD from Memorial University of Newfoundland (Canada), 1980 http://wwwlib.umi.com/dissertations/fullcit/NK46775
Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. PATENTS ON ACIDOSIS Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “acidosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on acidosis, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Acidosis By performing a patent search focusing on acidosis, 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
8Adapted
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 acidosis: •
Amino acid solutions for treatment of peritoneal dialysis patients Inventor(s): Jones; Michael R. (Hawthorne Woods, IL), Martis; Leo (Long Grove, IL) Assignee(s): Baxter International Inc. (deerfield, Il) Patent Number: 5,670,176 Date filed: April 4, 1995 Abstract: The present invention provides a dialysis solution that contains amino acids for treating and/or preventing malnutrition in a peritoneal dialysis patient. The amino acid composition is optimized to minimize metabolic acidosis while normalizing amino acid plasma profiles. Excerpt(s): The present invention relates generally to peritoneal dialysis and solutions for same. More specifically, the present invention relates to providing nutrition to peritoneal dialysis patients. Dialysis provides a method for supplementing or replacing renal function in certain patients. Principally, hemodialysis and peritoneal dialysis are utilized. Although dialysis provides in many cases life saving therapy, there are health issues that must be addressed in such patients. In hemodialysis, the patient's blood is passed through an artificial kidney dialysis machine. A membrane in the machine acts as an artificial kidney for cleansing the blood. Because it is an extracorporeal treatment that requires special machinery, there are certain inherent disadvantages with hemodialysis. Web site: http://www.delphion.com/details?pn=US05670176__
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Analytically controlled blood perfusion system Inventor(s): Lee; Albert K. (Washington, DC) Assignee(s): The United States of America AS Represented by the Secretary of the (washington, Dc) Patent Number: 4,717,548 Date filed: September 22, 1982 Abstract: A blood gas analyzer system for monitoring real-time blood gas conditions in a patient perfusion circuit during open-heart surgery and other extracorporeal blood flow situations. Sensing electrodes are employed in the blood flow path for sensing pH, pCO.sub.2, pO.sub.2 and temperature, and electrical circuitry is provided for generating and processing the sensed signal and also for computing a signal representing HCO.sub.3.sup.-; also, these signals are monitored in real time. When situations of metabolic acidosis, metabolic alkalosis, respiratory acidosis or respiratory alkalosis occur, the system activates a corresponding alarm and automatically switches into a compensation mode of effect a change in pump speed, which in turn changes the delivery rate of oxygenated blood to the patient. When the blood gas level returns to normal, the pump speed is likewise automatically returned to a normal value. Excerpt(s): This invention relates to blood gas monitoring systems, and more particularly to a system for monitoring blood gases and maintaining oxygen delivery to a patient during open-heart surgery and other extracorporeal blood flow situations.
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Prior art methods of maintaining blood gas levels in extracorporeal circuits have relied on off-line determinations in a blood sample, namely, obtaining blood samples and reading out blood gas data, on a discontinuous and interrupted (periodic) basis. Thus, the determination of blood gas is made indirectly, and requires the use of a blood withdrawal apparatus, which employs very complicated and delicate electromechanical devices, subject to frequent breakdown and presenting electrical hazards. Also, the determinations frequently take a relatively long period of time, for example, from 10 to 15 minutes. From the results of the tests, the operator can initiate a change in the oxygenated blood pumping rate to compensate for conditions of metabolic acidosis, metabolic alkalosis, respiratory acidosis or respiratory alkalosis. In addition to the above drawbacks, all testing must be performed manually and sometimes requires the use of graphical or slide-rule aids. The records of blood gas data, pumping rates, and time data must be accurately maintained by the operator. Because of the abovedescribed disadvantages, there is a definite need for apparatus which can perform continuous real-time monitoring and recording of such important blood parameters as pO.sub.2, pCO.sub.2, pH, temperature, and HCO.sub.3.sup.-, and for automatically performing required corrections, such as changing oxygenated blood pumping rates, and the like, to compensate for undesired deviations of the monitored conditions, as well as for providing alarms for indicating the abnormal conditions. In particular, there is a need for apparatus providing the continuous monitoring of pH and HCO.sub.3.sup.- for metabolic acidosis, metabolic alkalosis, respiratory acidosis, or respiratory alkalosis, and, if abnormal situations arise, activation of alarms indicating the particular metabolic or respiratory conditions and for automatically restoring the conditions to normal levels preset by the operator. Web site: http://www.delphion.com/details?pn=US04717548__ •
Certain inositol-nicotinate ester derivatives and polyionic complexes therefore useful for treating diabetes meuitus, hyperlipidemia and lactic acidosis Inventor(s): Bodor; Nicholas S. (Gainesville, FL), Stacpoole; Peter W. (Gainesville, FL) Assignee(s): University of Florida (gainesville, Fl) Patent Number: 4,801,597 Date filed: June 11, 1985 Abstract: The present invention relates to pharmaceutical compositions and methods for the treatment of metabolic disorders and to certain inositol-nicotinate dichloroacetate derivatives as the active ingredients therein. Excerpt(s): The invention described herein is related to that disclosed in U.S. application Ser. No. 584,994 filed Mar. 1, 1984, now U.S. Pat. No. 4,558,050 issued Dec. 10, 1985. The pharmacologic and therapeutic properties of salts of dichloroacetic acid (DCA) have been extensively studied over the last several years. Researchers have found that DCA stimulates glucose uptake and utilization by peripheral tissues [Stacpoole et al, Metabolism, 19:71 (1970); McAllister et al, Biochem. J. 134:1067 (1973); Diamond et al, Diabetes 31:326 (1982)] and inhibits hepatic glucose production [Stacpoole, Metabolism 26:107 (1977); Demangre et al, Biochem. J. 172:91 (1978); Diamond et al, Metabolism 30:880 (1981)]. It has also been found to decrease blood glucose levels in patients with diabetes mellitus [Stacpoole et al, N. Eng. J. Med. 298:526 (1978)]. DCA also stimulates lactate oxidation in animal tissues and significantly decreases lactic acid levels and overall morbidity in patients with lactic acidosis [Stacpoole et al, N. Engl. J. Med. 309:390 (1983); Blackshear et al, Diabetes Care 5:391 (1982)]. In addition, DCA reduces
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circulating triglyceride and cholesterol concentrations in obese [Felts et al, Diabetes, 25 (suppl.):363 (1976)] and diabetic [Hayet et al, Metabolism 29:120 (1980); Riles et al, Diabetes 28:852 (1979)] animals. DCA also markedly decreases blood cholesterol levels in patients with various forms of hyperlipidemia [Stacpoole et al, N. Eng. J. Med., 298:526 (1978); Moore et al, Atherosclerosis 33:285 (1979)]. The efficacy of DCA for the treatment of metabolic disorders, however, is compromised by the fact that DCA is toxic to lower animals and humans, particularly upon chronic administration. It has been reported that a human patient who received DCA for about four months developed a mild polyneuropathy that resolved when treatment stopped [Moore et al, ibid.] Chronic administration of DCA to lower animals in doses exceeding those used clinically also induces a reversible peripheral neuropathy, changes in testicular morphology and lenticular opacities [Stacpoole, N. Eng. J. Med. 300:372 (1979)]. Web site: http://www.delphion.com/details?pn=US04801597__ •
Composition and method for treating mammalian acidosis Inventor(s): Filley; Giles F. (Denver, CO), Kindig; Neal B. (Boulder, CO) Assignee(s): Webb-waring Lung Institute (denver, Co) Patent Number: 4,548,817 Date filed: January 20, 1984 Abstract: This invention relates to an improved parenteral composition for the treatment of acidosis in mammals which comprises a mixture of sodium carbonate and sodium bicarbonate with a pharmaceutically acceptable diluent. The invention also encompasses the method of treating the acidotic condition which comprises the parenteral administration of the composition described above. Excerpt(s): where the hydrogen ion concentration is lowered and the pH of the patient elevates to the desired level upon exhalation. It is essential, however, for the carbon dioxide to be removed for the equilibrium to shift to the right and correct the acidic condition. In more recent times, specifically, the last thirty years or so, traditional sodium bicarbonate solutions are being administered in a manner that has proven to have dangerous and sometimes even fatal consequences. The reasons for this are numerous, complex and, all too often, not well understood. The main problem is the widespread use of concentrated sodium bicarbonate under emergency conditions when ventilation, circulation or both are impaired as in patients in cardiopulmonary arrest. These solutions are being injected in such patients more rapidly and in much higher total dosage than ever before. This is because it is frequently forgotten that without adequate ventilation a significant rise of blood pH does not result from NaHCO.sub.3 injections. Thus, the patient may be reinjected repeatedly in a futile attempt to bring the pH to near normal (7.4). Sometime later, when ventilation is restored, blood pH rises to alkalotic levels, 7.5 or higher, showing that the patient was overdosed, perhaps fatally, since reversing severe alkalosis is extremely difficult to achieve. The conditions under which such emergency treatment is given to the patient explain, at least in part, why this occurs. To begin with, a physician trained in emergency procedures is often not present. All too often, the emergency is being attended to in the ambulance on the way to the hospital by relatively unskilled personnel. Even with physicians present, too few of them realize the high CO.sub.2 tension in the traditional solutions and their danger, especially to a non-breathing or poorly ventilated patient. In those instances where the personnel are trained and instructed to only administer these massive doses of bicarbonate to a patient who is breathing or being breathed, the logistics of the
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emergency can still sometimes result in an overdosed patient simply because the person responsible for giving the injection gets his or her job done before others get an airway established, the lungs ventilated, and the circulation restored. Web site: http://www.delphion.com/details?pn=US04548817__ •
Composition containing ascorbic acid Inventor(s): Ichihara; Junji (Takatsuki, JP), Itakura; Yasushi (Nara, JP), Noguchi; Hiroshi (Kawanishi, JP), Taiji; Mutsuo (Takatsuki, JP), Yamaga; Hiroshi (Suita, JP) Assignee(s): Sumitomo Pharmaceuticals Co., Ltd. (osaka, Jp) Patent Number: 6,399,658 Date filed: June 9, 1999 Abstract: L-ascorbic acid, L-ascorbic acid derivatives and salts thereof can reduce lactic acid levels in blood, and are useful for treating lactic acidosis and the like caused by administration of amoxapine, theophylline, metformin, phenformin, buformin, nalidixic acid, hopantenic acid, azidothymidine, dideoxycytidine, high caloric transfusion, propylene glycol, ethylene glycol, xylitol, lactose, sorbitol or the like. Excerpt(s): The present invention relates to a composition containing L-ascorbic acid, an L-ascorbic acid derivative or a salt thereof as an active ingredient. The composition of the present invention has the effect of reducing lactic acid levels in blood, and is useful, for example, for reducing side effect caused by a drug which has lactic acidosis as a side effect. Lactic acidosis is a state in which the lactic acid level in blood is 45 mg/dL or more, and pH of arterial blood is 7.25 or less. As to clinical symptoms, though lactic acidosis usually does not result in any symptoms in the early stage, later there appear, for example, low blood pressure, unconsciousness, nausea, vomiting, stomach ache, diarrhea, muscular ache, the state of hyperventilation and circulatory disorder etc. These symptoms often occur especially severely in elderly persons and patients with cardiac or renal disease etc. Certain kind of drugs and medical supplements are known to cause lactic acid levels to increase in blood as a side effect and to induce lactic acidosis. After lactic acidosis occurs, usage of the drugs and the medical supplements may be restricted, because of the possibility that they might worsen renal failure etc. Web site: http://www.delphion.com/details?pn=US06399658__
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Composition for treatment of acidosis in ruminants and method Inventor(s): Rohwer; Gary L. (Sharp Ln., Parma, ID 83660) Assignee(s): None Reported Patent Number: 4,784,851 Date filed: March 17, 1987 Abstract: A paste-consistency composition consisting essentially by weight of from about 40% to about 60% of a source of alkalinity selected from the group consisting of non-toxic carbonates, bicarbonates and sesquicarbonates, from about 15% to about 40% fatty vehicle and from about 5% to about 40% thickener is applied to the tongue of a ruminant for treatment of acidosis.
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Excerpt(s): This invention relates to the treatment of ruminants for acidosis. The term "ruminant" is used herein in a broad sense as including animals that chew the cud and have a plurality of stomach chambers including a first chamber referred to as a rumen. Ruminants include, for example, cattle (both beef and milk cattle, e.g. bulls, steers and cows), sheep, buffalo, goats, camels, reindeer, water buffalo, elk, deer and giraffes. As used herein, the term "acidosis" means an excess of lactic acid in the rumen and the harmful results that are caused by this. Acidosis in ruminants is normally caused by a feed overload. This occurs, for example, because of a feed error (e.g. too much grain because of accidentally feeding a finish ration instead of a normal ration) or because of a feed breakdown (e.g. because the weather or other cause prevents the animals from eating) followed by overeating. When the feed overload occurs, the bacteria in the rumen have not had a chance to adapt to the temporary situation and produce an excess of lactic acid. The harmful results that occur include the death of rumen bacteria and passage of lactic acid through the rumen wall into the bloodstream to lower the systemic pH. The death of rumen bacteria results in interference with the animal's digestion. The lowering of systemic pH can inhibit nervous system function and muscle response and can result in death. Web site: http://www.delphion.com/details?pn=US04784851__ •
Compounds and method for protection of cells and tissues from irreversible injury due to lactic acidosis Inventor(s): Nakada; Tsutomu (San Francisco, CA) Assignee(s): Regents of the University of California (oakland, Ca) Patent Number: 5,312,839 Date filed: March 5, 1991 Abstract: Compounds and a method useful for protection of tissue cells in a mammalian body from irreversible damages due to lactic acidosis caused by oxygen deficiency. The protection is achieved by administering a compound having a cell membrane permeability and/or ability to cross the blood brain barrier and being able to provide a buffering action to prevent an increase in a hydrogen ion concentration over the physiologically acceptable levels. Excerpt(s): The present invention relates to compounds and to a method for protection of cells and tissues from irreversible injury due to lactic acidosis. More specifically, this invention relates to compounds permeable through the cell membrane and possessing a buffering action against an increase in hydrogen ion concentration and also to a method for protection of tissues and cells in mammals, including humans, from the irreversible damages due to lactic acidosis caused by the accumulation of lactic acid in the cells under the condition of oxygen deficiency such as anoxia, hypoxia or ischemia. Recent findings show that in addition to maintenance of ATP above critical cellular levels, preservation of a normal pH in the presence of excess protons is of fundamental importance to cell survival. Cells, particularly cells of the central nervous system, also called neuronal cells, neurons, or cerebral cells, are heavily dependent on glucose as an energy source. When neuronal cells are placed under the condition of oxygen deficiency such as anoxia, hypoxia or ischemia, the normal oxidative metabolism is inhibited and substituted with anaerobic glycolysis. The glycolytic pathway for production of glucose in the absence of oxygen is not only uneconomical but it also produces lactic acid. As the result of anaerobic glycolysis, lactic acid is accumulated in neuronal or other cells resulting in lactic acidosis. If the lactic acidosis is permitted to develop and persist for
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certain time in cells, those cells are irreversibly injured and damaged. This is known as the "Lactate Hypothesis" described for example in Neurology, 33: 229 (1983); Stroke, 11: 355 (1980); J. Neurochem., 52: 154 (1989). Web site: http://www.delphion.com/details?pn=US05312839__ •
Control of lactic acidosis in ruminants Inventor(s): Barreto; Albert (Milltown, NJ), Muir; Larry A. (Flemington, NJ) Assignee(s): Merck & Co., Inc. (rahway, Nj) Patent Number: 4,061,732 Date filed: November 8, 1976 Abstract: The nutritional disease, lactic acidosis, is successfully prevented by orally administering to the animal an effective amount of a sulfur-containing peptide antibiotic. In particular thiopeptin and thiostrepton are particularly effective sulfurcontaining peptide antibiotics useful against lactic acidosis. Excerpt(s): Lactic acidosis has long been recognized as a nutritional disease that often occurs in ruminants following an extra large intake of readily fermentable carbohydrate. Traditionally, lactic acidosis occurred when cattle accidently gained access to the farmer's grain fields or grain supply. Today with the advent of high concentrate rations for cattle, lactic acidosis occurs frequently in high producing dairy cows that are placed on high concentrate diets too quickly following initiation of lactation; in feedlot cattle that are rushed too quickly onto high concentrate rations and more subtly in feedlot cattle that are adapted to high concentrate consumption but experience changes in ration or feeding pattern. In particular, lactic acidosis is a serious problem in cattle during the first few weeks in the feedlot because of the stress due to starvation from shipping and conversion from a roughage to a concentrate diet. Cattle normally consume 10-12 meals per day which allows rumen microbes to thrive. When no feed is ingested for a prolonged period, such as when cattle are shipped to the feedlot, most protozoa and many types of rumen bacteria perish. The lactate producer Streptococcus bovis, however, survives starvation better than most rumen microbes so that starvation increases the relative number of Streptococcus bovis. Most bacteria in the rumen are gram negative and are involved in the conversion of dietary carbohydrates to volatile fatty acids. Streptococcus bovis on the other hand is a gram positive rumen microorganism that converts readily fermentable carbohydrates to DL-lactic acid. Normally Streptococcus bovis does not play a predominant role in rumen fermentation and lactic acid is a minor product of rumen fermentation, however, when ruminants not adapted to high starch ration consume large quantities of readily fermentable carbohydrate Streptococcus bovis multiplies rapidly often outgrowing all other rumen microorganisms, and produces great quantities of DL-lactic acid. The lactic acid lowers rumen fluid pH which prevents normal fermentation by inhibiting other rumen microorganisms and eventually enables lactobacillus, another lactic acid producer, to establish itself in the rumen. The large quantities of DL-lactic acid produced in the rumen are absorbed. L-lactic acid is metabolized by the animal but D-lactic acid accumulates in the blood causing a depletion of the alkali reserve and a shift in blood pH which can cause death. Lactic acidosis is a major problem in feedlot cattle. Lactic acidosis causes a significant loss in animal production even when the animal survives because of conditions associated directly or indirectly with the disease. These conditions include anorexia, rumen disfunction, diarrhea, weight loss, founder and rumenitis. Rumenitis, an ulceration of the ruminal wall, allows rumen microorganisms especially
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Spherophorus necrophorus to gain access to the portal circulatory system. These microbes are removed by the liver where they cause liver abscesses which reduce weight gain and feed efficiency. In addition, the abscessed livers are condemned at slaughter resulting in further economic losses. Thus lactic acidosis reduces animal productivity not only through death losses but also through reduced performance caused by poor animal health. The only known method of preventing lactic acidosis is to slowly adapt cattle to a high energy ration. The time required to adapt cattle is not well defined, however, most cattle feeders allow at least 3 to 4 weeks. During this time most feeders gradually switch from a ration having a concentrate to roughage ratio of 1:3 to a ration having a ratio of 3:1 or higher. One of the problems with this approach is that the low energy rations used initially do not produce sufficient energy for restoration of animal health and disease resistance following the stress of shipping to the feedlot. In addition, slow adaptation does not allow for rapid adjustment to fattening (high energy) rations which cost the cattle feeder time and money. None of the antibiotics presently available for use in ruminants control lactic acidosis. Web site: http://www.delphion.com/details?pn=US04061732__ •
Digital magnetic resonance shock-monitoring method Inventor(s): Green; Ronald P. (2779 Wilson St., Carlsbad, CA 92008), Howell; Jerome C. (7706 Scrapeshin Trail, Chattanooga, TN 37421) Assignee(s): None Reported Patent Number: 5,375,597 Date filed: October 13, 1993 Abstract: A method for monitoring the pH of a patient includes the step of providing a magnetic resonance system having a magnet with a bore configured to receive a portion of a finger of a patient without receiving a substantially larger portion of the body of the patient. The method proceeds by inserting the finger of the patient into the bore of the magnet and monitoring the pH level of capillary bed tissue in the finger with the magnetic resonance system. Preferably, the system is configured to monitor the spectrum of phosphorus-31 metabolites in the finger and produce information in the form of a normalized phosphorous integral ratio indicative of the spectral area in order to alert an operator of the occurrence of a condition in which the normalized phosphorous integral ratio is greater than one in the setting of decreasing pH, as indicative of capillary bed tissue shock--lactic acidosis. In line with the above, a digital magnetic resonance system includes a superconducting magnet for producing a magnetic field for magnetic resonance monitoring purposes, and a control system operatively coupled to the magnet for cooperating with the magnet in order to produce and display magnetic resonance information related to the portion of the body of a patient. The magnetic has a bore for receiving a portion of the body of a patient, and the bore has a size sufficient to receive a portion of a linger of a patient without receiving a substantially larger portion of the body of the patient. Preferably, the magnet is sufficiently small to enable use in a conventional hospital operating room. Excerpt(s): This invention relates generally to diagnostic medicine, and more particularly to a digital magnetic resonance (MR) method and system for patient monitoring and diagnosis. Recall that some magnetic resonance procedures (MRPs) place the patient directly into the bore of a very large superconducting magnet for diagnosis. The magnetic field within the bore produces an equilibrium condition amongst nuclei in the patient's body that brief pulses of radio frequency (RF) energy
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upset. The nuclei respond to the pulses by changing spin energy states and thereby producing weak RF signals at distinct resonant frequencies that computerized equipment detects and processes for the information conveyed. Such MRPs proceed noninvasively and without harmful radiation effects, and patients appreciate the absence of needles, contrast agents, and radioisotopes. For many such reasons, MRPs, including magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS), continue to grow as valuable clinical and research tools. Details of existing technology appear abundantly in the literature. For further background material and examples, see the articles and references in the publication by Michael Brant-Zawadzki and David Norman entitled Magnetic Resonance Imaging of the Central Nervous System (published in 1987 by Raven Press Books, Library of Congress No. RC361.5.M34). Web site: http://www.delphion.com/details?pn=US05375597__ •
Efficient feeding frequency Inventor(s): Hodge; Dean E. (St. Louis, MO), Jackson, Jr.; Ted C. (Lubbock, TX), Williams; Danny L. (Manchester, MO) Assignee(s): Purina Mills, Inc. (st. Louis, Mo) Patent Number: 5,169,656 Date filed: August 5, 1991 Abstract: Ruminant animals, as herbivores, survive and produce while feeding chiefly on grass or other roughage consisting of large amounts of cellulose. Ruminants which have been consuming primarily diets high in cellulose must gradually be adjusted to high grain rations. When the attempt is made to adapt and feed ruminants diets containing no roughage, metabolic problems surface. The increase in lactic acid and accompanying fall in rumen.sub.p H resulting from roughage or cellulose withdrawal leads not only to the destruction of cellulolytic bacteria which digest cellulose), but to the destruction of lactate utilizing organisms, resulting in acidosis and its attendant adverse effects, which results in less than optimal cattle performance. Herein roughage can be eliminated allowing ruminants to consume an all grain, properly balanced due without these adverse reactions. A roughage free diet for ruminants is provided which alters the eating behavior of cattle. The die incorporates ingredients which modify feed consumption patterns of cattle consuming a roughage free diet. Excerpt(s): This invention relates to feed composition for ruminants, and particularly to roughage-free diets for such animals. Ruminant animals are classified as herbivores, meaning they can survive and produce while feeding chiefly on grass or other roughage feed ingredients consisting of large amounts of cellulose. Beef cattle are classified as ruminants. Those maintained for reproductive purposes normally live on ingested forage consisting of large amounts of cellulose and are supplemented with additional protein, energy, minerals and vitamins when nutrients in forages do not meet nutritional needs of the reproducing animals. However, the offspring from these cattle which are being produced for slaughter will normally be placed in a confined feeding facility (feedlot) at 7-15 months of age, and fed growing diets consisting of 30-60% roughage and/or finishing diets consisting of only 5-15% roughage, the roughage will normally be in the form of hay, silage, fodder, corn cobs, cottonseed hulls, etc. The remainder of the diet will consist of a high energy grain source such as corn, grain sorghum, barley, wheat, etc., and properly balanced for protein, minerals and vitamins. Including 5-15% roughage in the diet of finishing cattle tends to lessen the variation in
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feed intake, to reduce the amount of feed cattle will normally consume at each feeding, and to increase the number of feedings each day compared to cattle receiving feed containing no roughage. In addition, roughage in high grain diets stimulates the flow of saliva, which helps buffer the acids produced during fermentation, intake and reduces the concentration of energy in the diet. When attempts are made to feed ruminants diets containing no roughage, animal performance is reduced and metabolic problems normally occur. Feed intake of cattle receiving roughage diets becomes very erratic, and the amount of buffering capability through salivation is reduced which leads to rumen malfunction problems. Normally cattle will tend to consume more of the no roughage diet at each feeding and reduce the number of feedings each day. This erratic intake of all grain (no roughage) diets, even though properly balanced for protein and minerals, will result in starch overload. When this occurs, conditions in the rumen favor the proliferation of gram-positive microbes whose end product of fermentation is L- and Dlactic acid. The rumen pH can fall to 4.0, destroying the protozoa, cellulolytic digesting organisms and lactate-utilizing organisms. Other potential problems which can result are bloat, founder, abscessed liver, kidney lesions, rumen parakaratosis, abomasal ulcers and death. Web site: http://www.delphion.com/details?pn=US05169656__ •
Fetal monitoring during labor Inventor(s): Kirk; Derrick L. (Nottingham, GB2), Murray; Henry (Giltbrook, GB2) Assignee(s): National Research Development Corporation (london, Gb2) Patent Number: 4,951,680 Date filed: September 27, 1988 Abstract: Apparatus for monitoring fetal health during labor detects the occurrence of a fetal ECG in digital signals derived from electrodes on a fetus using a matched filter routine to detect a QRS complex. The peaks of successive R waves are then found and used to determine fetal heart rate. After time coherent filtering of digital samples representing the fetal ECG the P-R interval and the elevation of the S-T interval are found and a correlation coefficient between the fetal heart rate and the P-R interval is derived. The elevation and the coefficient are displayed. If the correlation coefficient becomes positive for about half an hour and a significant fall in the elevation of the S-T interval also occurs it is an indication of acidosis of the fetus. Excerpt(s): The present invention relates to monitoring fetal health during labor. According to a first aspect of the present invention there is provided a method of monitoring fetal health during laboor comprising the steps of repeatedly deriving a signal representative of the P-R interval of the fetal heart, repeatedly deriving a signal representative of the period of the fetal heart, and repeatedly deriving a signal representative of the relationship between the directions of change, firstly, of the P-R interval and, secondly, the fetal heart rate or the repetition period of the operation of the fetal heart to provide an indication of fetal health. According to a second aspect of the invention there is provided apparatus for monitoring fetal health during labor comprising means for repeatedly deriving a signal representative of the P-R interval of the fetal heart, for repeatedly deriving a signal representative of the period of the fetal heart, and for providing an indication of the relationship between directions of change, firstly, of the P-R interval and, secondly, the fetal heart rate or the repetition period of the operation of the fetal heart to provide an indication of fetal health.
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Web site: http://www.delphion.com/details?pn=US04951680__ •
Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors Inventor(s): Hulin; Bernard (Essex, CT), Parker; Janice C. (Ledyard, CT) Assignee(s): Pfizer Inc. (new York, Ny) Patent Number: 6,710,040 Date filed: June 3, 2003 Abstract: The invention relates to new therapeutically active and selective inhibitors of the enzyme dipeptidyl peptidase-IV, pharmaceutical compositions comprising the compounds and the use of such compounds for treating diseases that are associated with proteins that are subject to processing by DPP-IV, such as Type 2 diabetes mellitus, hyperglycemia, impaired glucose tolerance, metabolic syndrome (Syndrome X or insulin resistance syndrome), glucosuria, metabolic acidosis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, Type 1 diabetes, obesity, conditions exacerbated by obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, acute coronary syndrome, infertility due to polycystic ovary syndrome, short bowel syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy, eating disorders, chronic pain, alcohol addiction, diseases associated with intestinal motility, ulcers, irritable bowel syndrome, inflammatory bowel syndrome and to prevent disease progression in Type 2 diabetes. The invention also relates to a method of identifying an insulin secretagogue agent for diabetes. Excerpt(s): The present invention relates to new therapeutically active and selective inhibitors of the enzyme dipeptidyl peptidase-IV (hereinafter "DPP-IV"), pharmaceutical compositions comprising the compounds and the use of such compounds for treating diseases that are associated with proteins that are subject to processing by DPP-IV, such as Type 2 diabetes, metabolic syndrome (Syndrome X or insulin resistance syndrome), hyperglycemia, impaired glucose tolerance, glucosuria, metabolic acidosis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, Type 1 diabetes, obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, acute coronary syndrome, infertility due to polycystic ovary syndrome, short bowel syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy, eating disorders, chronic pain, alcohol addiction, diseases associated with intestinal motility, ulcers, irritable bowel syndrome, inflammatory bowel syndrome and to prevent disease progression in Type 2 diabetes. The invention also relates to a method of identifying an insulin secretagogue agent for diabetes. Dipeptidyl peptidase-IV (EC 3.4.14.5) is a serine protease that preferentially hydrolyzes an N-terminal dipeptide from proteins having proline or alanine in the 2 position. The physiological role(s) of DPP-IV have not been fully elucidated, but it is believed to be involved in diabetes, glucose tolerance, obesity, appetite regulation, lipidemia, osteoporosis, neuropeptide metabolism and T-cell activation. Administration of DPP-IV inhibitors in vivo prevents N-terminal degradation of GLP-1 and GIP, resulting in higher circulating concentrations of these peptides, increased insulin secretion and improved glucose tolerance. On the basis of these observations, DPP-IV inhibitors are regarded as agents for the treatment of Type 2 diabetes, a disease in which glucose tolerance is impaired. In addition, treatment with DPP-IV inhibitors prevents degradation of Neuropeptide Y (NPY), a peptide associated with a variety of central
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nervous system disorders, and Peptide YY which has been linked to gastrointestinal conditions such as ulcers, irritable bowel disease and inflammatory bowel disease. Web site: http://www.delphion.com/details?pn=US06710040__ •
Identification, functional expression and chromosal localization of a sustained human proton-gated cation channel Inventor(s): Bassilana; Frederic (Nice, FR), DeWeille; Jan R. (Valbonne, FR), Lazdunski; Michel (Nice, FR), Rainer; Waldmann (Les Adrets de l'Ester, FR) Assignee(s): Centre National DE LA Recherche (fr) Patent Number: 6,287,859 Date filed: July 23, 1999 Abstract: Non inactivating or slowly inactivating proton-gated cation channels are thought to play an important role in the perception of pain that accompanies tissue acidosis. We have identified a novel human proton-gated cation channel subunit that has biphasic desensitisation kinetics with both a rapidly inactivating Na.sup.+ -selective and a sustained component. The protein shares 84% sequence identity with the protongated cation channel rASIC3 (rDRASIC) from rat sensory neurones. The biphasic desensitisation kinetics and the sequence homology suggest that this novel clone (hASIC3) is the human orthologue of rASIC3 (rDRASIC). While rASIC3 (rDRASIC) requires very acidic pH (
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Injection of fructose-1,6-diphosphate (FDP) prior to coronary artery bypass grafting surgery Inventor(s): Fox; Anthony W. (Rancho LaCosta, CA), Marangos; Paul J. (La Costa, CA), Riedel; Bernhard (Harefield, GB), Royston; David (Harefield, GB) Assignee(s): Cypros Pharmaceutical Corp. (carlsbad, Ca) Patent Number: 6,076,528 Date filed: April 15, 1998 Abstract: Fructose-1,6-diphosphate (FDP) is used to treat patients who are undergoing coronary artery bypass grafting (CABG) surgery. Before cardiopulmonary bypass begins, a liquid that contains FDP is intravenously infused in the patient, preferably for about 10 to 30 minutes, to allow the FDP to enter the heart and lung tissue while the heart is still beating. FDP can also be added to cardioplegia solution; in addition, FDP can be injected after bypass is terminated, but if post-bypass injection is used, steps should be taken to avoid excess lactic acid accumulation, which appears to increase the risk of atrial fibrillation. To prevent or control lactic acidosis, a buffering or alkalizing agent, such as sodium bicarbonate, or an agent which reduces lactic acid formation, such as dichloroacetate, can be used. In double-blinded trials, this use of FDP substantially reduced heart damage and improved overall outcomes, as shown by lower levels of creatine kinase in blood, improvements in pumping performance, reduced requirements for vasodilator and inotropic drugs, and shorter stays in intensive care units. Certain dosages also reduced the likelihood of atrial fibrillation; however, FDP at high dosages increased the likelihood of A-fib. FDP also helped reduce pulmonary vascular resistance (PVR); this is an important finding, since pulmonary hypertension following cardiopulmonary bypass is a very difficult and often intractable problem, and is a contributing factor in nearly all deaths following CPB surgery. Excerpt(s): This invention relates to a method of using a drug to treat patients who undergo a surgical operation called "coronary artery bypass grafting" (abbreviated herein as CABG). In this type of surgery, segments of coronary arteries are replaced after they have become clogged or blocked (occluded) by cholesterol or fat deposits, to an extent where they cannot be adequately reopened by less invasive techniques such as balloon angioplasty. When replacement or bypass of the artery segments becomes necessary, the chest is opened and the clogged segments of the arteries are bypassed, using blood vessel segments harvested from elsewhere in the patient's body, usually from a saphenous veins in the patient's legs and/or a mammary vein in the patient's chest. Since the original coronary artery segments are usually left in place (empty, and not carrying blood) on the surface of the heart, this procedure is often referred to as an artery bypass, rather than an artery replacement. As used herein, terms such as "artery bypass" and "artery replacement" refer solely to coronary arteries, and are used interchangeably, regardless of whether a native artery segment is left in place or removed from the heart. Web site: http://www.delphion.com/details?pn=US06076528__
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Mechanism mediating ruminal stasis in ruminal lactic acidosis Inventor(s): Crichlow; Eugene C. (25 Moxon Crescent, Saskatoon, Saskatchewan, CA) Assignee(s): None Reported Patent Number: 5,196,432 Date filed: February 14, 1990 Abstract: Ruminal lactic acidosis develops in ruminant animals following the ingestion of large amounts of unaccustomed feeds that are rich in readily fermentable carbohydrates. Characteristics symptoms of this disease include systemic acidosis, ruminal acidosis, forestomach stasis or forestomach hypomotility, inappetence, depression and hemoconcentration. Alpha-2 adrenoceptor antagonists have been found to be capable of re-establishing forestomach motility that has been lost or severely diminished in ruminants suffering from ruminal lactic acidosis. These antagonist compounds have also been found to be effective in the treatment of ruminants experiencing ruminal lactic acidosis. Excerpt(s): This invention relates to the treatment of ruminal lactic acidosis in ruminant animals. Specifically, this invention relates to the use of alpha-2 adrenoceptor antagonists in the treatment of ruminant animals suffering from ruminal lactic acidosis. One embodiment of this invention is directed towards the restoration by alpha-2 adrenoceptor antagonists of forestomach contractions in ruminants with ruminal stasis (forestomach atony) or forestomach hypomotility caused by ruminal lactic acidosis. Another embodiment of this invention is directed towards the overall use of alpha-2 adrenoceptor antagonists in the treatment of ruminant animals suffering from ruminal lactic acidosis. Ruminal lactic acidosis (also referred to as grain overload, rumen overload, carbohydrate engorgement, feedlot founder or D-lactic acidosis) develops in ruminant animals following the ingestion of large amounts of unaccustomed feeds that are rich in readily fermentable carbohydrates. This disease occurs most commonly in ruminant livestock, for example, sheep, feedlot cattle and dairy cows, that are maintained on high energy rations. Characteristic symptoms of this disease include systemic acidosis, (decreased blood pH), ruminal acidosis, (decreased pH of rumen contents), ruminal stasis or forestomach hypomotility, inappetence, depression, and hemoconcentration. These symptoms, reportedly, result from the accumulation of toxic levels of non-metabolized D-lactic acid that are produced by abnormal fermentation in the forestomach. At present, the recommended treatments for this disease involve ruminal lavage and/or rumenotomy and intravenous infusions of bicarbonate to correct the systemic acidosis. Web site: http://www.delphion.com/details?pn=US05196432__
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Medical container with electrolyte solution stored therein Inventor(s): Isono; Keinosuke (Kawaguchi, JP), Motobayashi; Hiroshi (Tokyo, JP), Shichi; Hiroyuki (Tokyo, JP) Assignee(s): Material Engineering Technology Laboratory, Incorporated (tokyo, Jp) Patent Number: 5,871,477 Date filed: November 27, 1996 Abstract: A medical container with an electrolyte solution stored therein is disclosed. It is formed of a resinmade container main body, a base solution compartment, at least one
Patents 149
isolated compartment or connected compartment, and an openable portion. The base solution compartment is arranged in the container main body and is filled with the electrolyte solution in a state steamsterilized together with the container main body. The isolated compartment or connected compartment is arranged in the container main body, is isolated from the base solution compartment by an isolation wall interposed therebetween, and is filled with a bicarbonate. The openable portion permits aseptic communication between the base solution compartment and the isolated compartment or connected compartment by an operation from an outside of the container main body at the time of use. The openable portion is formed at at least a part of the isolation wall. This medical container makes it possible to store an electrolyte solution, dialysate or the like at a pH value close to that of the body fluid without inducing kidney problems, diarrhea, vomiting or the like due to acidosis or the like upon use. Excerpt(s): This invention relates to a medical container with an electrolyte stored therein, and more specifically to a medical container which stores therein a body fluid replenisher to be administered through a peripheral vein or a central vein, such as an infusion solution, a dialysate for a circulatory system, such as an artificial kidney dialysate, or an electrolyte solution as a preserving solution for an organ or the like. Despite the inclusion of bicarbonate ions (HCO.sub.3.sup.-) at a certain specific concentration in the blood or tissue cells of the human body, either absolutely or practically no bicarbonate salt, carbonate salt or the like (hereinafter simply referred to as "bicarbonate" for the sake of brevity) is contained in an infusion solution for use in the treatment or the like of the human body, a dialysate or an organ (tissue) preserving solution, although certain particular electrolytes are contained therein. For example, the concentration of bicarbonate ions in the plasma of the human body is generally around 24 mEq/l or so. When directly administering a bicarbonate into the body by infusion or when indirectly administering it by a blood dialysis or peritoneal dialysis, it is desired to add the bicarbonate in an amount such that the concentration of bicarbonate ions in the solution conforms with that of bicarbonate ions in the plasma. It is however to be noted that an infusion solution or the like is filled in a plastic-made medical container and is supplied to a hospital generally in a state completely sterilized by autoclave sterilization or the like. Bicarbonate ions are therefore caused to decompose substantially into carbon dioxide gas upon autoclave sterilization if a bicarbonate is added beforehand in the electrolyte in the container. Further, a bicarbonate, when filled as a diluted solution in a conventional plastic-made medical container, decomposes into carbon dioxide gas and is hence lost, even when the medical container is not subjected to autoclave sterilization. Web site: http://www.delphion.com/details?pn=US05871477__ •
Method for treating hypoxia-associated ocular complications Inventor(s): Huth; Stanley W. (Newport Beach, CA) Assignee(s): Allergan, Inc. (irvine, Ca) Patent Number: 5,389,383 Date filed: June 18, 1993 Abstract: A method of preventing or treating hypoxia-associated ocular complications in a host in need of such prevention or treatment which comprises administering to the eye of the host a prophylactically or therapeutically effective amount of at least two agents selected from the group consisting of a heme oxygenase inducer, a membranepermeable anti-acidosis buffer, and an osmoprotectant, as well as an aqueous ophthalmic composition useful therefor.
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Excerpt(s): This invention generally relates to a method for the treatment of eye disorders. More specifically, it relates to a method and composition for preventing or treating hypoxia-associated ocular complications which employs at least two agents selected from the group consisting of a heme oxygenase inducer, a membranepermeable anti-acidosis buffer, and an osmoprotectant agent. The majority of people wearing non-gas permeable hard (PMMA; polymethylmethacrylate) lenses, and a significant percentage of soft contact lens wearers experience mild to moderate corneal edema during lens wear. In "extended wear" lens users, the incidence and severity of corneal edema is greater, particularly during sleep. Other corneal complications resulting from the extended lens wear are corneal inflammation, ulcerative keratitis, infection, neovascularization, epithelial microcysts and endothelial polymegathism. Contact lens wear causes corneal epithelial hypoxia, which results in stimulation of anaerobic glycolysis and increased production and accumulation of osmotically active lactate in the stroma. The lactate diffuses to the stroma, where it creates an osmotic imbalance leading to increased corneal hydration (swelling). The lens wear also produces an increase in CO.sub.2 tension brought on by limited CO.sub.2 lens transmissibility. This increase in CO.sub.2 at the tear-film/lens interface, combined with accumulation of stromal lactate, contributes to a reduction in corneal pH (corneal acidosis). When the eye lids are closed, the CO.sub.2 tension will increase further and the epithelial oxygen availability is reduced. These effects lead to a sustained decrease in epithelial pH while a lens is being worn and the acidification will be at its greatest when the eyes are closed. This acidification could easily lead to many corneal changes, which are responsible in part for the above-indicated corneal complications. Web site: http://www.delphion.com/details?pn=US05389383__ •
Method of maintaining ruminants on high energy low fiber diet Inventor(s): Croom, Jr.; Warren J. (Cary, NC), Hagler, Jr.; Winston M. (Raleigh, NC) Assignee(s): North Carolina State University (raleigh, Nc) Patent Number: 4,857,534 Date filed: January 12, 1987 Abstract: This invention relates to the use of parasympathomimetic compounds, their precursors, salts and metabolites, to alter the digestive process in livestock so as to increase the efficiency of food utilization while simultaneously reducing the risk of certain disorders frequently associated with high energy diets. Specifically, the invention comprises administration to ruminants and other livestock of low level dosages of a parasympathomimetic compound to increase salivation during feeding and rumination, thereby increasing rumen digesta turnover rates and efficiency of food utilization while reducing the risk of certain digestive tract disorders such as acidosis and displaced abomasum. Excerpt(s): Rapid production systems currently employed with respect to cattle, sheep and other domestic ruminants typically entail intensive use of relatively expensive high energy feedstuffs to maximize growth rates. Examples include any feedstuffs having a high starch content or a high percentage of total digestive nutrients (TDN). Usually, these feedstuffs contain relatively large quantities of grain or other finely ground energy and protein sources. Although these feedstuffs are almost always high in potential energy content, they differ substantially in fiber content from the grasses, roughage and other forages which it is generally believed ruminants evolved to consume. As a result, stresses are created in the digestive tracts of ruminants which are maintained on
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relatively high energy, low fiber diets. The nature and collective age of the microbial population which exists in the rumen in a symbiotic relationship with the animal can be detrimentally altered, leading to increased production of volatile fatty acids and a subsequent increase in systemic acid load. In severe cases, these stresses can lead to acute digestive dysfunctions, such as acidosis, displaced abomasum and other pathological conditions. However, even in mild, subclinical cases, these stresses decrease the efficiencies with which ruminants digest and utilize high energy feedstuffs. Ultimately, inefficiencies are created in the overall production system, and they are compounded by both the expense of underutilized, high energy or high protein feedstuffs and the cost where veterinary or other corrective treatment is required. Web site: http://www.delphion.com/details?pn=US04857534__ •
Method of preventing development of severe metabolic derangement in inborn errors of metabolism Inventor(s): Kang; Chunghee Kimberly (16 Forest Gate Cir., Oak Brook, IL 60523), Kang; David S. (16 Forest Gate Cir., Oak Brook, IL 60523) Assignee(s): None Reported Patent Number: 6,503,530 Date filed: November 1, 2001 Excerpt(s): The present invention provides a method of avoiding rapid development of extreme hyperammonemia and metabolic acidosis in undiagnosed metabolically abnormal infants having an inherited metabolic disorder. Inborn errors of metabolism occur when there is a block in a pathway in a metabolic sequence. The block results in a rapid accumulation of normal intermediary products in abnormally large amounts and also of products of usually little used metabolic pathways. This biochemical abnormality is when characterized by hyperammonemia and/or ketoacidosis in neonatal-onset metabolic disorder. Restricting the intake of the essential substance from which the toxic metabolite is derived can treat the accumulated toxic effects of these intermediary metabolites. This minimizes the accumulation of intermediates that damage organs, particularly the nervous system, and affects the extent of mental retardation. Conventional management of infants diagnosed with certain inborn errors of amino acid or nitrogen metabolism requires the restriction of the specific amino acid(s) to the minimum amount required for normal growth and development. The amount of the restricted amino acid provided by the diet must be sufficient to meet the metabolic requirements dependent on it, but it must not permit an excess accumulation in the body fluids of the amino acid or its derivatives, or of nitrogen. Web site: http://www.delphion.com/details?pn=US06503530__
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Method of reducing elevated blood sugar in humans Inventor(s): Huang; Laura C. (3512 Marlboro Ct., Charlottesville, VA 22901), Kennington; Alison (5390 Cherokee Ave., Alexandria, VA 22312), Larner; Joseph (1432 Grove Rd., Charlottesville, VA 22901) Assignee(s): None Reported Patent Number: 5,428,066 Date filed: September 12, 1994
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Abstract: A method of treating a cluster of diseases associated with elevated blood sugar levels comprising the administration of a dietary supplement of chiro-inositol. Chiroinositol is an essential element for the synthesis of an insulin-directed mediator apparently responsible for the activation of pyruvate dehydrogenase-phosphatase. Disease conditions commonly associated with insulin-resistance, such as hypertension, lactic acidosis, obesity, coronary artery disease, and the like, are treated by administration of sufficient chiro-inositol to meet normal metabolic levels. Excerpt(s): This invention pertains to the administration of chiro-inositol for the treatment of a variety of disease conditions associated with a failure of pyruvate dehydrogenase-mediated metabolic pathways, or disease conditions otherwise linked to a failure of metabolic activation of PDH pathways, glycogen synthase pathways or other blood sugar maintenance pathways including glucose 6-phosphatase and mechanisms of insulin resistance in mammals. Specifically, chiro-inositol dietary supplements are provided for the biosynthesis of a chiro-inositol containing insulin mediator capable of stimulating PDH and glycogen synthase and inhibiting glucose 6-phosphatase and thus overcoming insulin resistance, lowering blood sugar and lowering elevated lactic acid. In parent application Ser. No. 320,482, filed Mar. 8, 1989, the inventors reported the identification of a high correlation between insulin-resistant diabetic disease states and an absence from the urine of D-chiro-inositol. This correlation led to the observation that insulin resistance may be due to an individual's inability to synthesize chiro-inositol, leading to an inability to form a specific insulin mediator, apparently responsible for the activation of the pyruvate dehydrogenase complex, and in particular, pyruvate dehydrogenase phosphatase, or PDH-P. The mediator also activates glycogen synthase (GS) by activating in particular glycogen synthase phosphatase or GS-P. It also may inhibit glucose 6-phosphatase. Thus, the administration of D-chiro-inositol, as a dietary supplement, is demonstrated and claimed in that parent application as an effective treatment for insulin-resistant diabetics and lowering blood sugar. Other copending applications are directed to the mediator itself, as well as a method of screening individuals for diabetic conditions, involving assaying body fluids, including urine and serum, for the presence of chiro-inositol. It has been widely reported that insulin resistance, which is characterized by the manifestation of non-insulin-dependent diabetes mellitus (NIDDM) is frequently associated with hypertension, coronary artery disease (arteriosclerosis) lactic acidosis and obesity, as well as related disease states. These disease states are associated with a cluster of risk factors, including hyperinsulinemia, high plasma triglyceride concentration, low HDL cholesterol concentration, and other risk factors traditionally associated with coronary artery disease (CAD). Although a variety of possible genetic and treatment methodologies have been proposed, the fundamental connection between these disease states, and a method of treating that fundamental problem remains elusive. Web site: http://www.delphion.com/details?pn=US05428066__ •
Method of reducing pulmonary hypertension and atrial fibrillation after surgery using cardiopulmonary bypass Inventor(s): Fox; Anthony W. (Rancho LaCosta, CA), Marangos; Paul J. (La Costa, CA), Riedel; Bernhard (Harefield, GB), Royston; David (Harefield, GB) Assignee(s): Cypros Pharmaceutical Corp. (carlsbad, Ca) Patent Number: 6,011,017 Date filed: April 15, 1998
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Abstract: A method is disclosed for using fructose-1,6-diphosphate (FDP) to reduce and prevent two very serious problems caused by surgery that requires cardiopulmonary bypass. Before bypass begins, a liquid that contains FDP is intravenously injected into the patient, preferably over a period such as about 10 to 30 minutes, to allow the FDP to permeate in significant quantity into the heart and lungs while the heart is still beating. FDP can be added to the cardioplegia solution that is pumped through the heart to stop the heartbeat, and/or during bypass. This treatment was found to reduce two very important and serious problems that have unavoidably plagued CPB surgery in the past, which are: (1) elevated levels of pulmonary vascular resistance (PVR), which includes pulmonary hypertension; and (2) high occurrence rates for atrial fibrillation. Prior to this discovery, there has never been any satisfactory treatment which could reduce the severity and occurrence rates for these two major problems. FDP also can be co-administered in this manner, along with (1) a buffering or alkalizing agent that counteracts acidosis, such as sodium bicarbonate or THAM, and/or (2) a drug that reduces the formation of lactic acid, such as dichloroacetate. Excerpt(s): This invention relates to a method of using a drug to reduce and prevent two very serious problems that often arise as a result of surgery involving cardiopulmonary bypass. (7) surgery to correct a congenital heart disease, which is done most commonly in children. It should be noted that children who suffer from congenital heart disease that is sufficiently severe to require CPB surgery also tend to suffer from high rates of pulmonary hypertension. All of these types of surgery are described in various wellknown medical texts, such as Gibbon's Surgery of the Chest (Sabiston and Spencer, eds., Saunders Publ., Philadelphia, Pa.) and in various medical journals that are devoted to the subject of cardiac and/or thoracic surgery. Web site: http://www.delphion.com/details?pn=US06011017__ •
Methods for treating renal failure Inventor(s): Hsu; Chen Hsing (3720 Tremont Dt., Ann Harbor, MI 48105) Assignee(s): None Reported Patent Number: 5,753,706 Date filed: February 3, 1997 Abstract: Methods of controlling phosphate metabolism and metabolic acidosis in patients suffering from renal failure and associated hyperphosphatemia or patients predisposed to development of a hyperphosphatemic condition are provided. The method in accordance with this invention comprises administering to a patient a ferriccontaining compound selected from the group consisting of ferric citrate, ferric acetate, and combinations thereof. Therapeutic benefit can be realized in accordance with such method by administering the compound orally to a patient to contact and bind with ingested phosphate in the patient's digestive tract, and thereby prevent its intestinal absorption. Excerpt(s): The present invention relates generally to the control of phosphate retention and particularly, to methods for treating patients suffering from renal failure and associated hyperphosphatemia. Phosphate is primarily excreted through the kidney. Phosphate retention therefore inevitably occurs in renal failure. Phosphate restriction plays an important role in slowing down deterioration of renal function as well as soft tissue calcification in renal failure. A high intake of dietary phosphorus in experimental renal failure worsens renal function (Haut, L. L., Kidney Int 17:722-731 (1980); Karlinsky,
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D. et al., Kidney Int 17:293-302 (1980)) and a low phosphate intake arrests progression of chronic renal failure. Lumlertgul, D. et al., Kidney Int 29:658-666 (1986). Recent studies have demonstrated that phosphate restriction either increases plasma calcitriol (the most potent vitamin D metabolite) and suppresses secondary hyperparathyroidism (Portale, A. A. et al., J. Clin. Invest 73:1580-1589 (1989); Kilav, R. et al., J Clin. Invest 96:327-333 (1995); Lopez, H. et al., Am. J Physiol 259:F432-437 (1990)), or directly inhibits parathyroid cell proliferation. Naveh-Many, T. et al., Am. Soc. Nephrol 6:968 (1995). Taken together, maintaining a normal plasma concentration and tissue content of phosphate is an important means to prevent secondary hyperparathyroidism, renal osteodystrophy and soft tissue calcification in renal failure. Dietary restriction of phosphate is difficult to achieve and thrice weekly dialysis alone can not remove daily absorbed phosphate. Therefore, phosphate binding agents have generally been employed to control phosphate metabolism in renal failure. For the last 30 years nephrologist have been using aluminum carbonate or aluminum hydroxide as phosphate binding agents. Concerns about aluminum toxicity in renal failure have prompted increased use of calcium carbonate and calcium acetate and a cessation in the use of aluminum compounds. However, calcium carbonate or other calcium preparations are not only inadequate to remove all the ingested dietary phosphate, but also provide too much calcium to end stage renal disease (ESRD) patients. Web site: http://www.delphion.com/details?pn=US05753706__ •
Protein mineral dietary module Inventor(s): Klish; William J. (Rochester, NY), Nichols, Jr.; Buford L. (Houston, TX), Potts; Vivian E. (Houston, TX) Assignee(s): Baylor College of Medicine (houston, Tx) Patent Number: 4,419,369 Date filed: September 1, 1982 Abstract: Disclosed is an improved dietary protein mineral module composed of a high quality protein, such as calcium-sodium caseinate, and electrolytes (minerals) combined in a fixed ratio so that when the protein concentration in water is 2.2 g/100 cc (a normal concentration) the normal mineral requirements are met and in which the dietary acid content (chloride) is reduced to a maximum of 2.0% dry weight and there is increased phosphorus content (a minimum of 1.0% up to 4.0% dry weight). The improved module has been quite successful in treating specific problems in infants who have not responded well to any of the existing commercial formulas. These include: acquired monosaccharide intolerance or intractable diarrhea of infancy; weaning from total parental nutrition; alteration of the renal solute load in infants with renal or congenital heart disease; and prevention of acidosis in infants thereby resulting in better growth. Excerpt(s): As pointed out in our publication entitled "Modular Formula: An Approach to Management of Infants with Specific or Complex Food Intolerances" published in Volume 88, No. 6 at pp. 948-952 of the Journal of Pediatrics, June, 1976, the basic modular components of an infant formula are protein, fat, carbohydrate, minerals, vitamins, and water. With existing proprietary infant formulas, the physician can not limit changes to one of the components when a new formula is desired but is obliged to change several of them. As an understanding of chronic diarrheal disease increases, it is becoming obvious that infants can develop complex intestinal intolerances. Carbohydrate malabsorption can be present simply as an intolerance to lactose or as an intolerance to all carbohydrates including glucose. A fermentative diarrhea results if the
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ingested sugar is not altered to correspond to the ability of the intenstine to absorb it. Chronic diarrhea may lead to a depletion of the bile acid pool (personal observation), causing maldigestion of long-chain fats. Specific protein hypersensitivity may go undetected because of the overlap of symptoms associated with other nutrient intolerances. This publication discloses and sets forth a report of our early work in providing a modular formula (original module) comprised of protein in the form of calcium sodium caseinate and electrolytes which was usually used in a concentration of 3 gm of core mix per 100 ml of water which provides 2.2 gm of protein and essentially the same minerals found in most commercial formulas. As pointed out in this publication, the physician may add fat of any nature and in any quantity that he considers desirable with final concentrations ranging between 3.5 and 4.5 gm/100 ml, and the type and amount of carbohydrate to be added are determined by the gastrointestinal tolerance of the individual patient, with final concentrations ranging between 5 and 7 gm/100 ml. We have found, however, that substantially improved results are obtained by significantly altering and improving the original modular or core formula disclosed in the above publication. This includes decreasing the dietary acid content, that is, chloride to a maximum of 2.0% dry weight, and providing a better and more effective array of minerals by providing a minimum of 1.0% dry weight phosphorus (improved module). Web site: http://www.delphion.com/details?pn=US04419369__ •
Ruminal bacterium for preventing acute lactic acidosis Inventor(s): Greening; Richard C. (Richland, MI), Leedle; Jane A. Z. (Manhattan, KS), Smolenski; Walter J. (Richland, MI) Assignee(s): The Upjohn Company (kalamazoo, Mi) Patent Number: 5,380,525 Date filed: August 28, 1992 Abstract: This invention relates to a bacterial culture, NRRL B-18624, method for facilitating adaptation of ruminants from roughage or normal pasture diet to a higher energy diet, and a composition therefor comprising the bacterial culture. Excerpt(s): This invention relates to novel microorganisms. More particularly, it relates to a lactic acid consuming ruminal bacterium which can prevent acute lactic acidosis. particularly in cattle abruptly switched from forage to concentrate (high grain) diets. Intensive beef production involves feeding energy dense, high concentrate diets to cattle. These concentrate diets contain a high percentage of corn, wheat, milo or other starchy components. When starter cattle are switched from forage to concentrate diets, acute indigestion can result, Elam, C. J., J. Anim. Sci., 43, pp. 898-901 (1976); Huber, T. L., J. Anim. Sci., 43, pp. 902-909 (1976); Uhart, B. A. and F. D. Carroll, J. Anim. Sci., 26, pp. 1195-1198 (1967). This indigestion is due to the rapid and extensive fermentation of the starch grain by the rumen microbial community which results in production of large amounts of organic acids, including lactic acid. The production of organic acids can be so great that the balances between ruminal acid production and utilization and ruminal buffering capacity are disrupted. This condition is termed acidosis. Acute acidosis is characterized by a rapid drop in pH and a sharp increase in the level of lactic acid in the rumen and in the blood, Elam, C. J., (supra); Slyter, L. L., J. Anim. Sci., 43, pp. 910-929 (1976); Uhart, B. A. and F. D. Carroll, (supra). If sufficiently severe, the over-production of lactic acid and other acids can contribute to a decrease in ruminal pH such that the normal microbial flora are upset. Often the result is that only a few bacterial species,
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which are tolerant of the acidic conditions, survive, Krogh, N., Acta Vet. Scand 2, pp. 102-119 (1961); Mackie, R. I. and F. M. C. Gilchrist, Appl. Environ. Microbiol., 38, pp. 422-430 (1979); Mann, S. O., J. Appl. Bacteriol., 33, pp. 403-409 (1970). To control the problem of acute lactic acidosis, several researchers have investigated adding viable lactate consuming bacteria or rumen bacteria from animals adapted to high grain diets, to the rumens of cattle that were abruptly changed from low to high concentrate diets, Allison, M. J., et al., J. Anim. Sci., 23, pp. 1164-1171 (1964); Chandler, P. T., et al., J. Dairy Sci., 38, pp. 1660-1665 (1975); Cook, M. K., et al., Am. J. Vet. Res., 38, pp. 1015-1017 (1977); Huber, T. L., Am. J. Vet. Res., 35, pp. 639-641 (1974). They predicted that the added bacteria would consume the higher levels of lactate produced, maintaining the balance between production and consumption and thereby lessening or eliminating the problem of acidosis. Allison et al. and Huber, supra, found that if the rumen of a roughage fed animal was inoculated with rumen fluid from a high concentrate adapted animal the problem of acute acidosis was alleviated when the abrupt shift of ration was made. U.S. Pat. No. 4,138,498, refers to feeding rumen bacterial cultures from an animal adapted to a concentrate diet to a roughage adapted animal then fed a concentrate diet, and claims a reduction or elimination of the symptoms of lactic acidosis. Increases in weight gains and feed conversions also were alleged in cattle receiving these cultures as compared to control cattle. U.S. Pat No. 3,857,791, refers to rumen inoculation with "adapted rumen microorganisms," or a mixture of Megasphaera elsdenii and Selenomonas ruminantium to reduce or eliminate the symptoms of lactic acidosis during the adaptation of ruminants to high grain rations. Additionally, it has been reported that milk production was increased by the intraruminal inoculation of certain live adapted rumen microorganisms to dairy cows, Chandler et al., supra; U.S. Pat. No. 3,956,482. Web site: http://www.delphion.com/details?pn=US05380525__ •
Ruminant feed additive Inventor(s): Das; Naba K. (Ellicott City, MD) Assignee(s): W. R. Grace & Co. (new York, Ny) Patent Number: 4,138,498 Date filed: December 7, 1976 Abstract: Disclosed herein is an improved feed additive for administration to ruminants to prevent or minimize lactic acidosis when the ruminant is switched from a diet of roughage to starch (high energy). The additive comprises a bacterial culture of Megasphaera elsdenii admixed with an ingestible animal feed additive. The additive utilizes the unexpected ability of M. elsdenii to ferment lactic acid in preference to simple sugars, thereby minimizing accumulation of lactic acid. The preferred embodiment is the combination of M. elsdenii with substances (including bacterial cultures) producing ruminal propionic acid, thereby providing a high propionic level while avoiding lactic acid accumulation. Excerpt(s): Changing the diet of a ruminant abruptly from hay or other nutrients consumed on pasture to the high energy feed or feed concentrate given when the animals are brought from pasture into feed lots, often leads to acute indigestion which results in varying degrees of prolonged inappetence and sometimes death. Among the reactions that a ruminant can be expected to exhibit upon ingestion of excessive amounts of grain in the feed lot are a rapid accumulation of lactic acid in the rumen, a fall in ruminal pH, an abrupt rise of lactate circulation in the peripheral blood, and a
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decrease in blood volume and pH along with hemoconcentration. Excessive grain or glucose ingestion can have fatal results in ruminants causing a fall in the pH in the rumen to between 4 and 5 in a few hours, destruction of protozoa, cellulolytic bacteria and lactate utilizing organisms, and a relatively large increase of Gram-positive organisms particularly "Streptococcus bovis", a lactic acid producer. A low pH in the rumen produces stasis of that organ which persists for hours even after the pH is restored to a normal level. Most of these adverse reactions can be attributed, at least in part, to abnormally large amounts of lactic acid in the rumen. A ruminant exhibiting some or all of the above symptoms is said to be suffering from "lactic acidosis". Recently, several treatments for lactic acidosis have been proposed. British Pat. No. 1,251,483 describes a newly discovered organism reportedly having the ability to ferment lactic acid. It is suggested that the organism be administered to ruminants to avoid or alleviate the symptoms of lactic acidosis. U.S. Pat. No. 3,857,971 is based on the discovery that rumen bacteria must be completely conditioned to a high energy ration before being administered to the ruminant. Therefore, samples of rumen microflora and microfauna are cultured in vitro on a high energy starch (as opposed to roughage) ration before administration. Another publication of interest is Huber et al (Am. J. Vet. Res., Vol. 37, No. 5, pages 611-613) describing analysis of rumen fluid during adaptation of cattle to a high energy ration. The object of the study was to discover bacteria having the ability to utilize lactic acid and therefore proliferate during the adaptation process. Lactic acid utilizing bacteria found to be present include Megasphaera elsdenii, Peptococcus asaccharolyticus and Selenomonas ruminantium. M. elsdenii appeared to flourish during the initial stages of adaptation but the population declined significantly in the adjusted rumen fluid. Both P. asaccharolyticus and S. ruminantium exhibited higher counts in cultures obtained from the adjusted rumen fluid. Web site: http://www.delphion.com/details?pn=US04138498__ •
Synthetic buffer composition for clinical use Inventor(s): Swan; Henry (Lakewood, CO) Assignee(s): Henry Swan II Trust (lakewood, Co) Patent Number: 5,256,660 Date filed: March 17, 1992 Abstract: Methods of administering aqueous synthetic buffer compositions of an Nsubstituted aminosulfonic acid and a sodium salt of a different substituted aminosulfonic acid suitable to treat oligemic, respiratory and metabolic acidosis are disclosed. Methods of administering aqueous synthetic buffer compositions of a different N-substituted aminosulfonic acid, a sodium salt of an N-substituted aminosulfonic acid and tris(hydroxymethyl)aminomethane which may be similarly employed are also disclosed. Excerpt(s): This invention relates to synthetic buffer compositions, methods of making same and methods of using same. More specifically, this invention relates to synthetic buffer compositions finding particular but not exclusive utility in the treatment of disturbed metabolism in vertebrates. Even more specifically, this invention relates to aqueous buffering solutions finding particular but not exclusive utility in the treatment of disturbed metabolism in humans associated with disease, trauma or manipulative procedures. Stabilization and preservation of hydrogen ion concentration in both intracellular and extra-cellular body fluids is critical to the health of vertebrates. Considerable attention and scientific study have been devoted to this crucial aspect of
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maintaining internal homeostasis in humans. 3) the PHO.sub.3 /PO.sub.4 phosphate buffer system. Of these three chemical systems, the phosphate buffer system is the least effective, primarily because of the phosphate buffer system's inefficiency as a buffer above pH 7.2, and also because excessive phosphate causes undesirable side effects. For these reasons and others, phosphate buffers have had very limited clinical utility. Web site: http://www.delphion.com/details?pn=US05256660__ •
Therapeutic compositions and methods of use Inventor(s): Brown; Raymond K. (140 W. 69 St., #105A, New York, NY 10023) Assignee(s): None Reported Patent Number: 6,066,670 Date filed: December 8, 1995 Abstract: According to the present invention, there is provided an admixture of sorbic acid, malic acid, fumaric acid, crotonic acid, and optionally aconitic acid. Further contemplated by the present invention are methods for treating various pathological conditions such as viral infections, acidosis, tumors, and bacterial and fungal infections by administering various therapeutically effective amounts of an admixture described above. Excerpt(s): The invention relates to admixture compositions of short chain organic fatty acids which have biological effects. For example, they are useful in the treatment of numerous pathologies that affect mammals. The invention also relates to methods of treatment of such pathologies, wherein appropriate therapeutically effective amounts of the compositions are administered. A wide variety of carboxylic acid containing compositions are biologically active, and several short chain organic acids which are naturally occurring acids have previously been implicated in the treatment of various pathological conditions. For example, Nordman, U.S. Pat. No. 3,291,689, discloses the treatment of hepatic ammonia intoxication with a mixture of L-arginine and malic acid. U.S. Pat. No. 3,718,664 discloses the use of thioctic acid derivatives in the treatment of acidosis. Sloan, U.S. Pat. No. 4,381,307, discloses soft tertiary amine ester derivatives that have biological effects, while U.S. Pat. No. 4,760,078 discloses a 1,2, dithiol-3-thione derivative that has an immunomodulating effect. Web site: http://www.delphion.com/details?pn=US06066670__
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Therapeutically useful mineral composition Inventor(s): Hara; Tadataka (4-31-15 Hamadayama, Suginami-ku, Tokyo 168, JP) Assignee(s): None Reported Patent Number: 5,035,888 Date filed: November 6, 1989 Abstract: The mineral composition is useful for treatment of blood acidosis, peritoneal ascites and anemia. It is a combination of particulate wood ash and calcium carbonate. Excerpt(s): The invention is related to a pharmaceutical mineral composition which is useful for therapeutic treatment of electrolyte imbalance of biological fluids. More specifically, the composition is a mixture of wood ash particles containing mineral
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compounds in combination with calcium carbonate. Mammals, in particular humans, have body compositions which are of approximately fifty to seventy weight percent aqueous media. The aqueous fluids are distributed intra and extracellularly and enable liquid transfer of nutrients, enzymes, hormones, waste products and the like. The extracellular fluids include blood, lymph fluid, gastric juice, urine, bile, perspiration, etc. which all contain inorganic electrolyte salts. Intracellular fluids also contain electrolyte salts but the kinds and proportions differ from those of the extracellular fluids owing to the semipermeability of tissue membranes and cellular function. The inorganic ions present in such electrolyte fluids play an integral part in the proper function of physiological processes. For example, sodium and potassium are necessary for nerve and cellular function. Iron and manganese are necessary for oxidative metabolism and calcium is utilized in bone. In general, inorganic ions usually are present in most physiological processes. Web site: http://www.delphion.com/details?pn=US05035888__ •
Treatment of lactic acidosis in ruminants Inventor(s): Harrison; Ian T. (Palo Alto, CA), Kluge; Arthur F. (Los Altos, CA) Assignee(s): Syntex (usa) Inc. (palo Alto, Ca) Patent Number: 4,174,399 Date filed: July 10, 1978 Abstract: 6-(N-vinylureido)penicillanic acids and salts thereof; and processes for preparing such compounds are disclosed. The compounds are useful as inhibitors of lactic acidosis in ruminants. Excerpt(s): This invention relates to penicillin-type compounds having lactic acidosisinhibitory effects in ruminants and to intermediates and processes for preparing such compounds. In particular, this invention relates to 6-(N'-vinylureido)penicillanic acids and salts thereof; to derivatives and salts thereof; to intermediates for and methods of preparing such compounds. The invention also relates to pharmaceutical compositions containing such compounds and methods for inhibiting lactic acidosis in ruminants. It is common practice in preparing range-fed cattle and other ruminants for market to hold them in "feed-lots" for certain periods of time where feed is restricted to "high energy" (carbohydrate) foods that promote rapid weight gain and develop other desirable characteristics in such animals. Consumption of large amounts of high energy feed stuffs required to promote these effects often results in acute indigestion in the ruminants. This disorder is attributable to a series of biochemical and microbiological events that are triggered by an initial rapid accumulation of lactic acid in the rumen. Symptoms of such lactic acidosis initially appear as decreased feed consumption and rate of weight gain (the "off-feed" syndrome) and may ultimately result in death. A considerable volume of information is available concerning the microbiological processes in the rumen that are associated with high energy, feed-caused acute indigestion. Ruminants not accustomed to these high energy diets have fewer numbers of amylolytic, volatile fatty acid (VFA)-producing rumen bacteria than animals that have already adapted to such diet. However, one saccharolytic, amylolytic, lactate-producing rumen organism, Streptococcus bovus, is present in approximately equal numbers in both high energy-fed and the range-fed animals. Since the total bacterial numbers are lower in range-fed animals, S. bovus is one of the predominant species under this latter feeding regimen. It is recognized that the potential growth rate of S. bovus is much more rapid than other rumen bacteria. An abundance of carbohydrate in the rumen of
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unadapted animals can therefore lead to an almost explosive growth of S. bovus with an accompanying increase in lactic acid production and consequent precipitous drop in pH within the rumen. The normal, major species of rumen microorganisms survive poorly, if at all, at this lowered pH. VFA production is therefore inhibited. Further, S. bovus fails to grow at the acidity that it ultimately produces. Consequently, lacto bacilli predominate and, if sufficient carbohydrate is available, lactic acid production continues with visible symptoms of lactic acidosis becoming extant. As an attempt to diminish the occurance of lactic acidosis, it has been the practice to increase the energy (carbohydrate) intake of feed-lot cattle gradually in order for the rumen microbial population to become adapted to the change in diet. This adaptation typically is ten days or longer in duration. Consequently, rapid initial weight gains for these ruminants are intentionally sacrificed so as to avoid occurrences of lactic acidosis. In addition, since animals are fed in large groups, sub-clinical occurrences of lactic acidosis still occur throughout the feeding period. It is therefore desirable to permit an alternative, less time-consuming method than the typical adaptation period for preventing accumulation of lactic acid in the rumen following engorgement of high-energy feed stuffs. It has now been discovered that the administration of certain penicillanic acids and salts thereof to unadapted, (restricted energy-fed) ruminants on high energy diets prevents the incidence of lactic acidosis in these animals. Web site: http://www.delphion.com/details?pn=US04174399__ •
Treatment of ruminants Inventor(s): Huber; Thomas L. (Watkinsville, GA) Assignee(s): Research Corporation (new York, Ny) Patent Number: 4,112,069 Date filed: September 4, 1975 Abstract: In a feedlot operation wherein ruminant animals, such as cattle or sheep, are fed ad libitum a high-energy ration or feed, lactic acidosis is greatly reduced or eliminated and weight gain and feed conversion are increased by administering to the animal the microorganism Peptococcus asaccharolyticus upon introduction of the animal to the feedlot. The microorganism is conveniently administered to the animal, either by direct injection or introduction into the rumen via a needle or stomach tube or in admixture with the feed or ration. The microorganism is also useful in the treatment of cattle (calves) and sheep ill with lactic acidosis. Excerpt(s): This invention relates to the fattening of ruminant animals, such as in a feedlot, wherein the ruminant animal is permitted access ad libitum to a high-energy ration or feed. One embodiment of this invention is directed to the treatment of ruminant animals before or upon introduction of the animal to a feedlot for fattening. Another embodiment of this invention is directed to the treatment of ruminant animals, such as cattle or sheep, ill with lactic acidosis. Web site: http://www.delphion.com/details?pn=US04112069__
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Use of fructose-1,6-diphosphate for treating myocardial infarction Inventor(s): Markov; Angel K. (353 Northside Cir., Jackson, MS 39206) Assignee(s): None Reported Patent Number: 4,546,095 Date filed: September 3, 1982 Abstract: The invention relates to the treatment of heart disorders. Disruption of heart action or occulision of heart artery results in oxygen deprivation and aerobic metabolism ceases. Unless effective treatment is administered acidosis renders anaerobic metabolism inactive and irreversible tissue damage occurs.Fructose-1,6diphosphate is used as a therapeutic agent for treating mammalian subjects experiencing myocardial infection in order to prevent ischemic tissue from irreversible tissue damage. Excerpt(s): The present invention relates to the methods of treatment of patients with heart disorders and more particularly to the method of using Fructose-1,6-Diphospate in treatment of the above mentioned diseases, and also as a protective agent against unforeseen catastrophic hypotension or hypoxia during operative procedures, and as a preservative agent for transplantation organs. In medicine and physiology it is wellknown that a continuous supply of energy is necessary for the function and maintenance of a living state by cells. The degree of intracellular energy is measured by the ratio of high energy phosphate compounds to those of less energy potential (i.e., adenosine triphosphate to adenosine diphosphate and adenosine monophosphate). The biochemical pathways which produce high energy phosphate compounds have been well established in the scientific literature as a chain of reactions that result in the breakdown of the major substrates, glucose or other sugars to pyruvic and lactic acid and is a process of carbohydrate metabolism. Although one stage of glycolysis requires oxidation by dehydrogenation, this may be accomplished without oxygen, so the process as a whole may be anaerobic. The pyruvic acid formed by glycolysis is then oxidized to carbon dioxide and water. This oxidation is the source of most of the utilizable energy (ATP) derived from carbohydrate metabolism. Glycolysis also yields some energy in the form of ATP which can be utilized for muscle contraction and other functions. This is particularly important during sudden strenuous exercise, when energy must be made available in excess of that which can be provided by oxidation processes. This reaction is reversible. Glyceraldehyde-3-P and dihydroxyacetone-P are freely interconvertible through the action of triose-P-isomerase. Web site: http://www.delphion.com/details?pn=US04546095__
Patent Applications on Acidosis As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to acidosis:
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This has been a common practice outside the United States prior to December 2000.
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Adhesion prevention and an endoscopic insufflation system therefor Inventor(s): Koninckx, Robert; (Leuven, BE) Correspondence: Banner & Witcoff; 1001 G Street N W; Suite 1100; Washington; DC; 20001; US Patent Application Number: 20020183687 Date filed: June 14, 2002 Abstract: A method of treating or preventing adhesion formation following a surgical procedure comprising administering to a patient in need thereof at least one medicament selected from the group consisting of potassium channels; modulators of macrophage activation and leucocyte attraction through cytokines, or their inhibitors, antibodies or inhibitors blocking the effect of VEGF expression; prostaglandin E1; allopurinol; calcium channel blockers; free radical scavengers; lipid peroxysomes; pregnatrienes; calcium antagonists; hypoxia; acidosis; MP; dopamine; and ATPMgCl.sub.2. Excerpt(s): The present invention relates to adhesion prevention in general and to compounds, an endoscopic insufflation system and to a method for preventing adhesion formation in particular. Adhesion formation is a major problem following surgical procedures and is a frequent cause of postoperative pain and of infertility. Adhesions are the major cause of intestinal obstruction and it is estimated that following an intraabdominal procedure, adhesions occur in some 50 to 80 percent of patients. The mechanism of adhesion formation can be summarized as follows: a trauma of the peritoneal lining is rapidly followed by an inflammatory reaction; exudation of plasma, and deposition of a fibrin matrix. Subsequently the lesion is healed by the degradation of the fibrin deposition, and by proliferation of the mesenchy-mal lining of the peritoneum. If the repair process is not completed within a few days, fibroblast proliferation starts which ultimately will end in collagen deposition and adhesion formation. Key players in this process are in particular fibrin and fibrinolysis, macrophages and their secretion products such as growth hormones and cytokines, and obviously the epithelial repair process. From this repair process it results that.adhesion formation is largely independent from the extent of the trauma. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Agent for improving acidosis Inventor(s): Odaka, Hiroyuki; (Kobe-shi, JP), Suzuki, Masami; (Osaka, JP) Correspondence: Takeda Pharmaceuticals North America, Inc; Intellectual Property Department; 475 Half Day Road; Suite 500; Lincolnshire; IL; 60069; US Patent Application Number: 20040106649 Date filed: November 20, 2003 Abstract: An agent for improving ketosis which comprises an insulin sensitizer, which has an excellent action and low toxicity. Excerpt(s): The present invention relates to an agent for improving (ameliorating or treating) ketosis which comprises an insulin sensitizer (insulin resistance-improving agent). Also, the present invention relates to an agent for improving (ameliorating or treating) acidosis which comprises an insulin sensitizer. Further, the present invention relates to an agent for preventing or treating hyperosmolar nonketonic coma, infectious
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disease, diabetic osteoporosis, diabetic gangrene, xerostomia, lowered sense of hearing, angina pectoris, cerebrovascular disease or peripheral circulatory disturbance, which comprises an insulin sensitizer. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Biochemically balanced peritoneal dialysis solutions Inventor(s): Henderson, Lee W.; (Lake Forest, IL), Martis, Leo; (Long Grove, IL) Correspondence: Charles R. Mattenson, ESQ.; Renal Division; Baxter International INC.; One Baxter Parkway; Deerfield; IL; 60015-4633; US Patent Application Number: 20020037329 Date filed: September 17, 2001 Abstract: A peritoneal dialysis solution that is biochemically balanced to correct metabolic acidosis associated with chronic renal failure in a more physiological manner. The peritoneal dialysis solution has a physiological pH, e.g., pH of 7.0 to 7.4, and contains bicarbonate at a concentration that is found in blood involved in Additionally, the solution contains carbon dioxide at a partial pressure that is similar to partial pressure of carbon dioxide found in the blood capillaries. The peritoneal dialysis solution also contains a weak acid with a pKa of less than 5.0. Excerpt(s): The present invention relates generally to peritoneal dialysis. More specifically, the present invention relates to peritoneal dialysis solutions. It is known to use dialysis to support a patient whose renal function has decreased to the point where the kidneys no longer sufficiently function. Two principal dialysis methods are utilized: hemodialysis; and peritoneal dialysis. In hemodialysis, the patient's blood is passed through an artificial kidney dialysis machine. A membrane in the machine acts as an artificial kidney for cleansing the blood. Because it is an extracorporeal treatment that requires special machinery, there are certain inherent disadvantages with hemodialysis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Calcium glutarate supplement and phosphorus binder Inventor(s): Alexandrides, George; (San Antonio, TX), Walsdorf, Neill B. SR.; (San Antonio, TX) Correspondence: Thomas D. Paul; Fulbright & Jaworski, L.L.P.; 1301 Mckinney, Suite 5100; Houston; TX; 77010-3095; US Patent Application Number: 20030077331 Date filed: July 31, 2001 Abstract: Methods of controlling calcium intake and phosphate metabolism and metabolic acidosis in patients suffering from renal failure and associated hyperphosphatemia or patients predisposed to development of a hyperphosphatemic condition are provided. The method in accordance with this invention comprises administering to a patient a calcium glutarate compound. Therapeutic benefit can be realized in accordance with such method by administering the compound orally to a patient to increase available calcium and contact and bind with ingested phosphate in the patient's digestive tract, and thereby prevent its intestinal absorption.
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Excerpt(s): The present invention relates generally to calcium supplementation and controlling phosphate retention and particularly, to methods for treating patients on dialysis and suffering from renal failure and associated hyperphosphatemia. Phosphorus is the sixth most abundant element in the human body. It is critical for bone mineralization, cellular structure, genetic coding, and energy metabolism. Many organic and inorganic forms exist. Approximately 1,000 g of phosphorus is present in an adult, of which 80-90% is in bone. An additional 10-14% is intracellular and the remaining 1%, is extracellular. The phosphorus in plasma is 12-17% protein bound. Free serum compounds represent much less than 1% of the total body phosphorus content. This fraction also varies with shifts between the intracellular and extracellular compartments. Thus, serum phosphorus levels may not accurately reflect the total body phosphorus content. Levels are expressed in terms of serum phosphorus mass (mg/dL). One mg/dL of phosphorus is equal to 0.32 mmol of phosphate. The normal adult range is 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol/L). Levels are 50% higher in infants and 30% higher in children due to growth hormone effects. Hyperphosphatemia is an abnormally elevated serum phosphate level. Normal serum phosphate levels are in the range of 2.5 to 4.5 mg/dl. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Combinations comprising dipeptidylpeptidase-iv inhibitor Inventor(s): Balkan, Bork; (Madison, CT), Holmes, David Grenville; (Binningen, CH), Hughes, Thomas Edward; (Somerville, NJ), Villhauer, Edwin Bernard; (Morristown, NJ) Correspondence: Thomas Hoxie; Novartis, Patent And Trademark Department; One Health Plaza 430/2; East Hanover; NJ; 07936-1080; US Patent Application Number: 20030139434 Date filed: October 10, 2002 Abstract: The invention relates to a combination which comprises a DPP-IV inhibitor and at least one further antidiabetic compound, preferably selected from the group consisting of insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G6Pase), inhibitors of fructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers,.alpha.-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and.alpha.sub.2-adrenergic antagonists, for simultaneous, separate or sequential use in the prevention, delay of progression or treatment of conditions mediated by dipeptidylpeptidase-IV (DPP-IV), in particular diabetes, more especially type 2 diabetes mellitus, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis; and the use of such combination for the cosmetic treatment of a mammal in order to effect a cosmetically beneficial loss of body weight. Excerpt(s): The invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, which comprises a dipeptidylpeptidase-IV (DPP-IV) inhibitor and at least one further antidiabetic compound, preferably selected from the group consisting of insulin signalling pathway modulators, like inhibitors of
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protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6phosphatase (G6Pase), inhibitors of fructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers,.alpha.-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and a.sub.2-adrenergic antagonists, for simultaneous, separate or sequential use, especially in the prevention, delay of progression or treatment of conditions mediated by dipeptidylpeptidase-IV (DPP-IV), in particular diabetes, more particular type 2 diabetes mellitus, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis; the use of such combination for the preparation of a pharmaceutical preparation for the prevention, delay of progression or treatment of such conditions; the use of such combination for the cosmetic treatment of a mammal in order to effect a cosmetically beneficial loss of body weight; a method of prevention, delay of progression or treatment of conditions mediated by DPP-IV; a method of improving the bodily appearance of a warm-blooded animal. DPP-IV is responsible for inactivating GLP-1. More particularly, DPP-IV generates a GLP-1 receptor antagonist and thereby shortens the physiological response to GLP-1. GLP-1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal. Non-insulin dependent diabetes mellitus (type 2 diabetes mellitus) is characterized by both increased peripheral insulin resistance and abnormal insulin secretion. At least three abnormalities of insulin secretion are recognized: in the first phase, insulin secretion is lost and in the second phase insulin is both delayed and inadequate in the face of elevated circulating glucose levels. Several metabolic, hormonal, and pharmacological entities are known to stimulate insulin secretion including glucose, amino-acids and gastrointestinal peptides. The Diabetes Control and Complications Trial (DCCT) has established that lowering of blood glucose is associated with decreases in the onset and progression of diabetic microvascular complications (Diabetes Control and Complications Trial Research Group; N. Engl. J. Med. 1993, 329, 977-986). IGT is an impairment of glucose homeostasis closely related to type 2 diabetes mellitus. Both conditions convey a great risk of macrovascular disease. Therefore, one therapeutic focus is on optimizing and potentially normalizing glycemic control in subjects with type 2 diabetes mellitus, conditions of impaired fasting plasma glucose, or IGT. Presently available agents need to be improved in order to better meet this therapeutic challenge. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Imaging and targeting tumors using sickle cells Inventor(s): Brown, Stephen Lawrence; (Ontario, CA), Kim, Jae Ho; (West Bloomfield, MI), Swerdlow, Paul S.; (Farmington Hills, MI) Correspondence: Kenneth I Kohn; Kohn & Associates; Suite 410; 30500 Northwestern Highway; Farmington Hills; MI; 48334; US Patent Application Number: 20040057940 Date filed: July 1, 2003 Abstract: According to the present invention, there is provided a delivery vehicle including sickle red blood cells carrying a moiety. The moiety can be any type of
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diagnostic or therapeutic agent. The present invention further provides for a method of diagnosing systemic hypoxia, acidosis, or hypertonicity by administering sickle red blood cells to a patient and detecting the location of the sickle red blood cells. Additionally, the present invention provides for a method of therapeutic treatment of systemic hypoxia, acidosis, or hypertonicity by administering sickle red blood cells to a patient. Further, the present invention provides for a delivery vehicle that specifically localizes or concentrates at systemic hypoxia, acidosis, or hypertonicity areas. The delivery vehicle is used in diagnosing and therapeutically treating these areas of hypoxia, acidosis, or hypertonicity also. The present invention further provides for a method of making the delivery vehicle described herein. Excerpt(s): This invention generally relates to the field of delivery vehicles for use in diagnostic and therapeutic applications, and specifically towards diagnostic and therapeutic applications involving hypoxic areas of a patient. Hypoxic tissue areas are defined as areas having low oxygen content. Generally, the hypoxic tissue area is a result of numerous factors including, but not limited to, a reduction of the oxygencarrying capacity of blood as a result of a decrease in the total hemoglobin or an alteration of the hemoglobin constituents, decreased blood flow, and any abnormal cellular growth. As a result of the decreased oxygen content, the hypoxic areas are further characterized as having increased tonicity, and a low pH due to acid build-up resulting from anaerobic glycolosis. Hypoxic areas occur anywhere in the body of a patient, but are particularly found in areas associated with injuries occurring as a result of a stroke, decreased blood flow, reperfusion injury, decreased vascular development, and tumors. With regard to tumors, experiments have provided direct and indirect evidence of hypoxic areas occurring in tumors therein. For example, tests involving glass polarographic electrodes confirm the presence of hypoxia in tumors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods for treating metabolic diseases using malonyl-coa decarboxylase inhibitors Inventor(s): Arrhenius, Thomas; (Del Mar, CA), Brown, Steve Joel; (San Diego, CA), Cheng, Jie Fei; (Carlsbad, CA), Harmon, Charles Stanford; (San Diego, CA), Nishimoto, Masahiro; (Shizuoka, JP), Serafimov, Rossy; (Metz, FR), Tith, Sovouthy; (San Diego, CA), Wallace, David Mark; (San Diego, CA), Wilson, Mark E.; (Lakeside, CA) Correspondence: Daniel W Collins; Chugai Pharma Usa; 6275 Nancy Ridge Drive; San Diego; CA; 92121; US Patent Application Number: 20040082564 Date filed: August 19, 2003 Abstract: The present invention relates to methods of treatment of certain metabolic diseases, and to the use of compounds and their prodrugs, and/or pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds useful in treating such diseases. In particular, the invention relates to the use of compounds and compositions for treatment of cardiovascular diseases, diabetes, cancers, acidosis, and obesity through the inhibition of malonyl-CoA decarboxylase (MCD). These compounds have the following formulae: (I) and (II) Wherein Y, C, R.sub.1, R.sub.2, R.sub.6, and R.sub.7 are defined herein. 1 Excerpt(s): This application claims the benefit of provisional application serial No. 60/270,034 filed on Feb. 20, 2001. The entire disclosure is incorporated herein by reference. The present invention relates to methods of treatment of certain metabolic
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diseases and the use of compounds and their prodrugs, and/or pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds useful in treating such diseases. In particular, the invention relates to the use of compounds and compositions for the prophylaxis, management or treatment of cardiovascular diseases, diabetes, cancers, and obesity through the inhibition of malonyl-coenzyme A decarboxylase (malonyl CoA decarboxylase, MCD). Malonyl-CoA is an important metabolic intermediary produced by the enzyme Acetyl CoA Carboxylase (ACC) in the body. In the liver, adipocytes, and other tissues, malonyl-CoA is a substrate for fatty acid synthase (FAS). ACC and malonyl-CoA are found in skeletal muscle and cardiac muscle tissue, where fatty acid synthase levels are low. The enzyme malonyl-CoA decarboxylase (MCD, EC 4.1.1.9) catalyzes the conversion of malonyl-CoA to acetyl-CoA and thereby regulates malonyl-CoA levels. MCD activity has been described in a wide array of organisms, including prokaryotes, birds, and mammals. It has been purified from the bacteria Rhizobium trifolii (An et al., J. Biochem. Mol. Biol. 32:414-418(1999)), the uropygial glands of waterfowl (Buckner, et al., Arch. Biochem. Biophys 177:539(1976); Kim and Kolattukudy Arch. Biochem. Biophys 190:585(1978)), rat liver mitochondria (Kim and Kolattukudy, Arch. Biochem. Biophys. 190:234(1978)), rat mammary glands (Kim and Kolattukudy, Biochim. Biophys, Acta 531:187(1978)), rat pancreatic.beta.-cell (Voilley et al., Biochem. J. 340:213 (1999)) and goose (Anser anser) (Jang et al., J. Biol. Chem. 264:3500 (1989)). Identification of patients with MCD deficiency lead to the cloning of a human gene homologous to goose and rat MCD genes (Gao et al., J. Lipid. Res. 40:178 (1999); Sacksteder et al., J. Biol. Chem. 274:24461 (1999); FitzPatrick et al., Am. J. Hum. Genet 65:318 (1999)). A single human MCD mRNA is observed by Northern Blot analysis. The highest mRNA expression levels are found in muscle and heart tissues, followed by liver, kidney and pancreas, with detectable amounts in all other tissues examined. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods of administering a synthetic plasma like solution, and systems and kits for use in practicing the same Inventor(s): Sternberg, Hal; (Berkeley, CA) Correspondence: Bret E. Field; Bozicevic, Field And Francis Llp; Suite 200; 200 Middlefield Road; Menlo Park; CA; 94025; US Patent Application Number: 20010048951 Date filed: April 13, 2001 Abstract: Improved methods of administering a synthetic plasma-like solution to a subject, as well as systems and kits for practicing the same, are provided by the subject invention. In the subject methods, the CO.sub.2 level of the subject, particularly the CO.sub.2 level of at least one of the blood and brain of the subject, is reduced prior to administration of the synthetic plasma-like solution. The subject methods find use in a variety of applications where synthetic plasma-like solutions are employed, including the treatment of hypovolemia, hyphemia, and surgical procedures in which at least a portion of a subject's blood is replaced with a synthetic plasma-like solution and provide for a number of improvements, including a reduced risk of acidosis/acidemia and complications associated therewith. Excerpt(s): Pursuant to 35 U.S.C.sctn. 119 (e), this application claims priority to the filing date of the U.S. Provisional Patent Application Ser. No. 60/197,307 filed Apr. 14, 2000; the disclosure of which are herein incorporated by reference. The technical field of this
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invention is plasma substitute solutions. Plasma substitute solutions, or synthetic plasma-like solutions, find use in a variety of different applications in the medical, biomedical research and related fields. For example, physiologically acceptable solutions find use as plasma substitutes in surgical applications that require the replacement of significant amounts of blood plasma volume. Such applications include treatments for blood lost during surgery or trauma, or when a tissue, organ, group of organs or an entire subject needs to be maintained at a hypothermic or frozen state. Such applications also include applications in which a patient s blood is flowed through an external device, such as a cardiopulmonary bypass machine, where the extra circulatory volume space resulting from attachment of the patient s circulatory system to the device must be filled with a compatible blood substitute, i.e. blood volume expander. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Propionibacterium P-63 for use in direct fed microbials for animal feeds Inventor(s): Hibberd, Charles A.; (Scottsbluff, NE), Owens, Fred N.; (West Des Moines, IA), Parrott, Terry D.; (Waukesha, WI), Rehberger, Thomas; (Milwaukee, WI) Correspondence: Fellers Snider Blankenship; Bailey & Tippens; The Kennedy Building; 321 South Boston Suite 800; Tulsa; OK; 74103-3318; US Patent Application Number: 20030007953 Date filed: August 1, 2002 Abstract: A ruminant direct fed microbial composition of matter comprising an acidosis inhibiting effective amount of Propionibacterium P-63 is provided. Also disclosed is a process for reducing acidosis in ruminants or scours in swine by administration of the bacterium to the ruminant or swine. The microbial composition may be administered by itself, or combined with animal feed and/or lactic acid producing cultures. Excerpt(s): The present invention relates generally to a process for improving the utilization of feedstuffs by ruminants, especially during the transition from a roughage diet to a feedlot diet, and more particularly to a process for administering to a ruminant a feed additive composition which includes Propionibacteria jensenii strain P-63, preferably in combination with a lactic acid producing bacteria for improving the production from, and feed conversion efficiency of, a high grain or concentrate feedlot diet. The composition also may be used to reduce scours in swine. Acute indigestion resulting from the transition from a predominantly roughage diet to a feedlot diet could be fatal to ruminants. The purpose of a feedlot operation is to fatten a ruminant, such as beef cattle, for sale or slaughter. The most common and efficient method of fattening ruminants is to feed them a high grain or high energy concentrate diet. However, this abrupt conversion from a roughage or pasture diet of plant food, mainly cellulose, to a feedlot diet predominantly composed of grains and starches can cause decreased production to feedlot cattle and even death from acidosis. Similar diet transitions can result in a decrease in milk production for dairy cows as well as death. As discussed in Diseases of Feedlot Cattle, Second Edition, Lea & Febiger, p 292-293 (1971), acute indigestion in cattle is caused by sudden consumption of large amounts of grain, green corn, green apples or other easily fermentable feeds. During a roughage diet, cellulosic bacteria predominates in ruminal microflora. Volatile fatty acids are usually formed in the following proportions: acetic, 67%; propionic, 19%; and butyric, 14%. These acids constitute an important nutrient from cellulose digestion. However, during the fattening process at the feedlot, cattle are placed on a high grain diet. On a high grain diet, the ruminal microflora ferment the new feed and produce 100 or more milli-moles per liter
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of lactic acid resulting in the rumen becoming immobilized. A large portion of the lactic acid accumulated may be the D(-) isomer which is an unavailable energy source for the ruminant and thus builds up in the rumen. Absorption of the acid into the blood lowers the blood pH and diminishes the content of bicarbonate and glucose bringing about acidosis. Compensation for the acidic condition occurs by excretion of carbonic acid through rapid respiration and by excretion of hydrogen ions through urine. Affected cattle may survive through compensation, however, severe acidosis is fatal. Additionally, the increase in acidity of the rumen damages the mucosa which may result in necrosis of the epithelium which enables bacteria such as Spherophorus necrophorus to enter the veins and be conveyed to the liver where liver abscesses may form in surviving animals. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Substituted amino ketone compounds Inventor(s): Demuth, Hans-Ulrich; (Halle/Saale, DE), Heiser, Ulrich; (Halle/Saale, DE), Hoffmann, Torsten; (Halle/Saale, DE), Niestroj, Andre; (Halle/Saale, DE) Correspondence: Brown Rudnick Berlack Israels Llp; 18th Floor, Box IP; One Financial Center; Boston; MA; 02111; US Patent Application Number: 20030125304 Date filed: November 4, 2002 Abstract: The present invention relates to compounds of the general formula IB--(CH-R.sup.1).sub.n--C(.dbd.X.sup.2)--D (I)and pharmaceutically acceptable salts thereof including stereoisomers, to the use of the compounds for the treatment of impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy and of sequelae caused by diabetes mellitus in mammals. Excerpt(s): The present invention relates to substituted amino ketone compounds and salts thereof, hereinafter referred to as amino ketones, and to the use of the compounds for the preparation of a medicament for the in vivo inhibition of DP IV and/or DP IVlike enzymes. The invention relates especially to the use of the compounds for the preparation of a medicament for the treatment of impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy and of sequelae caused by diabetes mellitus in mammals, for the treatment of metabolism-related hypertension and of cardiovascular sequelae caused by hypertension in mammals, for the prophylaxis or treatment of skin diseases and diseases of the mucosae, autoimmune diseases and inflammatory conditions, and for the treatment of psychosomatic, neuropsychiatric and depressive illnesses, such as anxiety, depression, sleep disorders, chronic fatigue, schizophrenia, epilepsy, nutritional disorders, spasm and chronic pain. Dipeptidyl peptidase IV (DP IV) is a post-proline (to a lesser extent post-alanine, post-serine or post-glycine) cleaving serine protease found in various tissues of the body including kidney, liver, and intestine, where it removes dipeptides from the N-terminus of biologically active peptides with a high specificity when proline or alanine form the residues that are adjacent to the N-terminal amino acid in their sequence. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Synthesis of 3,3,4,4-tetrafluoropyrrolidine and novel dipeptidyl peptidase-IV inhibitor compounds Inventor(s): Hulin, Bernard; (Essex, CT) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20040002609 Date filed: June 3, 2003 Abstract: The present invention relates to a method of making novel dipeptidyl peptidase-IV ("DPP-IV`) inhibitor compounds useful for treating, inter alia, diseases that are associated with proteins that are subject to processing by DPP-IV, such as Type 2 diabetes mellitus, metabolic syndrome (Syndrome X or insulin resistance syndrome), hyperglycemia, impaired glucose tolerance, glucosuria, metabolic acidosis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, Type 1 diabetes, obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, acute coronary syndrome, infertility due to polycystic ovary syndrome, short bowel syndrome and to prevent disease progression in Type 2 diabetes. The invention also relates to a method of making 3,3,4,4-tetrafluoropyrrolidine, a starting material utilized in the afore-mentioned method for preparing DPP-IV compounds. Excerpt(s): This application is filed claiming priority from co-pending U.S. Provisional Application No. 60/386,112, filed Jun. 4, 2002. The present invention relates to a method of making novel dipeptidyl peptidase-IV ("DPP-IV`) inhibitor compounds and a method of making 3,3,4,4-tetrafluoropyrrolidine, a starting material utilized in the aforementioned method for preparing DPP-IV compounds. Dipeptidyl peptidase-IV (EC 3.4.14.5) is a serine protease that preferentially hydrolyzes an N-terminal dipeptide from proteins having proline or alanine in the 2 position. The physiological role(s) of DPP-IV have not been fully elucidated, it is believed to be involved in diabetes, glucose tolerance, obesity, appetite regulation, lipidemia, osteoporosis, neuropeptide metabolism and T-cell activation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Systems and methods of pH tissue monitoring Inventor(s): Khuri, Shukri F.; (Westwood, MA), Treanor, Patrick; (Dedham, MA) Correspondence: Thomas O. Hoover, ESQ.; Bowditch & Dewey, Llp; 161 Worcester Road; P.O. Box 9320; Framingham; MA; 01701-9320; US Patent Application Number: 20030040665 Date filed: May 2, 2002 Abstract: The invention relates to the use of pH measurements of tissue as a system for controlling diagnostic and/or surgical procedures. The invention also relates to an apparatus used to perform tissue pH measurements. Real time tissue pH measurements can be used as a method to determine ischemic segments of the tissue and provide the user with courses of conduct during and after a surgical procedure. When ischemia is found to be present in a tissue, a user can effect an optimal delivery of preservation fluids to the site of interest and/or effect a change in the conduct of the procedure to raise the pH of the site. A preferred embodiment includes a method of detecting
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acidosis in tissue comprising the steps of contacting the tissue of a patient with a first pH electrode disposed in an anterior wall of the left ventricle, and further contacting the tissue of the patient with a second pH electrode disposed in a posterior wall of the left ventricle. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 09/580,809 filed on May 26, 2000 which is a continuation-in-part of U.S. application Ser. No. 09/339,081 filed on Jun. 23, 1999 which claims priority to U.S. Provisional Application No. 60/136,502 filed May 28, 1999, the entire teachings of the above applications being incorporated herein by reference. It is well known in the art to determine the pH in body fluids by using an electrode cell assembly and immersing the measuring electrode into a sample of the bodily fluid. The pH is known to be the symbol for the negative logarithm of the H.sup.+ ion concentration. The pH value of the blood indicates the level of acidity of the blood. High blood acidity, which is reflected by a low pH indicates, in that the organs of the body are not being provided with enough oxygen, which can ultimately prove harmful. It is also known in the art to measure tissue pH in myocardial tissue. Measurement of pH in myocardial tissue has been used to determine the presence of myocardial ischemia, as indicated by tissue acidosis which is reflected by a decrease in pH. During cardiac surgery, the aorta is cross clamped and the myocardium is deprived of its blood and nutrient supply, creating the potential for damage to the heart from ischemia. Ischemia can be diagnosed by monitoring the pH of the myocardium which falls significantly and becomes acidotic during ischemia. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Treatment of rumen acidosis with alpha-amylase inhibitors Inventor(s): Banks, Bernard Joseph; (County of Kent, GB), Haxell, Mark Andrew; (County of Kent, GB), Lunn, Graham; (County of Kent, GB), Pacey, Michael Stephen; (County of Kent, GB), Roberts, Lee Richard; (County of Kent, GB) Correspondence: Pfizer Inc; 150 East 42nd Street; 5th Floor - Stop 49; New York; NY; 10017-5612; US Patent Application Number: 20030060424 Date filed: January 29, 2002 Abstract: The invention described herein relates to: the use of an effective inhibitor of a bacterial.alpha.-amylase and/or.alpha.-glucosidase in the manufacture of a composition for the treatment of acidosis; a method of treatment of rumen acidosis which comprises administration of an effective amount of an effective inhibitor of a bacterial.alpha.amylase and/or.alpha.-glucosidase to a ruminant; a formulation suitable for the treatment of acidosis in an animal which comprises an effective inhibitor of a bacterial.alpha.-amylase and/or.alpha.-glucosidase in admixture with a suitable excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical/veterinary/f- arming practice; screening methods useful in the identification of a suitable inhibitor of a bacterial.alpha.-amylase and/or.alpha.glucosidase for the treatment of acidosis in a ruminant; a process for improving ruminant milk quality and/or quantity which comprises treatment of a ruminant with an effective amount of an inhibitor of bacterial.alpha.-amylase and/or.alpha.glucosidase; a compound of the formula I: 1or veterinarily acceptable salt, solvate (including hydrate) or prodrug thereof; and processes to make an effective inhibitor of a bacterial.alpha.-amylase and/or.alpha.-glucosidase useful for the treatment of acidosis in a ruminant.
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Excerpt(s): The invention described herein relates to the treatment of rumen acidosis, especially chronic acidosis in ruminants, and related conditions. Rumen acidosis is a well-documented metabolic disease of ruminants caused by over-consumption of readily fermentable carbohydrates, and problems associated with the condition have been known for many years: see Nordlund et al. 1995, Nagaraja et al. 1998, Owens et al. 1998 and Dirksen 1969. Acidosis can be divided into two forms: acute and chronic. We define acute acidosis as a rumen pH between pH 4.0 and 5.0 with elevated ruminal lactate, and chronic acidosis as a rumen pH between 5.0 and 5.5 with normal levels of lactate of up to 5 mM. The literature also refers to subacute acidosis, which has rumen pH values below 5.0 but in some cases is associated with high lactate levels and in others is not. We categorise the former case as mild acute acidosis, and the latter as chronic acidosis. The main cause of acidosis is the consumption of a diet with a high content of readily fermentable carbohydrate and/or which is low in roughage. Chronic acidosis can occur when animals eat large quantities of readily fermentable diets and may occur at any stage in production, or indeed throughout the time that they are on the high concentrate diets. Acute acidosis can occur when a large increase in the amount of concentrate in the diet takes place, for example after calving or on transfer to the feedlot. However it can also occur following a disruption in normal feed intake patterns such as accidental presentation of excess feed or a fasting period followed by overeating. Reduced rumen pH can also be caused by a decrease in the proportion of crude fibre in the diet. The aetiology of acidosis is therefore based on the absolute intake of excessive quantities of carbohydrate and/or an unfavourable proportion of basic foodstuffs in the ration. The type of grain (high moisture corn is more acidosis-inducing than dry-rolled corn or sorghum) and the type of processing (steam flaked grain is particularly digestible) along with type and amount of roughage is important. Grains such as barley, wheat and high-moisture corn that have fast rates of ruminal starch digestion generally cause the most problems. For example barley, wheat flour, oats and steam flaked corn all have ruminal starch availability greater than 85%. Guidelines for diets for dairy cattle producing more than 35-40 kg of milk suggest neutral detergent fibre of 25-30% of the diet, with 75% of that from forage, non-structural carbohydrate levels of 35-40% and starch of 30-40% (Nocek 1997). 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 acidosis, 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 “acidosis” (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 acidosis. You can also use this procedure to view pending patent applications concerning acidosis. 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 ACIDOSIS Overview This chapter provides bibliographic book references relating to acidosis. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on acidosis 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 “acidosis” (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 acidosis: •
101 Medication Tips for People with Diabetes Source: Alexandria, VA: American Diabetes Association. 1999. 122 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $14.95 plus shipping and handling. ISBN: 1580400329. Order number 483301. Summary: This book answers 101 of the most commonly asked questions about diabetes and medications to help readers become active members of their health care team, maximize their diabetes management, and stay well. Questions in chapter one provide general information on medications used to treat diabetes. Chapter two focuses on how to get the most out of oral medications. The third chapter deals with common side effects of oral medications, including gastrointestinal and liver problems, weight gain, lactic acidosis, and hypoglycemia. Questions in chapter four provide general
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information on the use of insulin in type 2 diabetes. This is followed by a chapter that explains how to get the most out of insulin therapy. Chapter six identifies the common side effects of insulin, including weight gain. Questions in the next chapter deal with the meditations used to treat complications, including nonprescription analgesics, tricyclic antidepressants, capsaicin cream, angiotensin converting enzyme inhibitors, laxatives, and calcium channel blockers. This is followed by chapters that answer questions about the effect of medications on diabetes; the use of nonprescription medications such as aspirin, cold and allergy medications, herbal supplements, weight loss products, and vitamin and mineral supplements; and common drug interactions that occur with diabetes medications. The final chapter answers miscellaneous questions. The book also includes a glossary and an index. •
Renal Failure: Blackwell's Basics of Medicine Source: Oxford, England: Blackwell Science Ltd. 1995. 295 p. Contact: Available from Blackwell Science, Inc. 238 Main Street, Cambridge, MA 02142. (800) 215-1000 or (617) 876-7000. Fax (617) 492-5263. PRICE: $24.95. ISBN: 0865424306. Summary: This book for health professionals on renal failure is from a series that examines relevant topics in medicine using concepts that pertain to the basic sciences. In this series, readers learn to interpret clinical data based on pathophysiological concepts. Four sections in this book cover the following issues: essentials, pathophysiology, clinical picture, and management of renal failure. Each section offers questions, with answers of one or two paragraphs on relevant topics. The 555 questions are numbered for ease of access through the subject index. Specific topics covered include: the anatomy of the kidneys, the kidney function tests used for diagnosis and monitoring, electrolyte function, urine concentration and dilution, oral water load, the roles of aldosterone, the role of the kidney in acid base balance, potassium, dietary therapy, chronic renal failure, polyuria, water and salt homeostasis, metabolic acidosis, renal tubular acidosis, hyperkalemia, acute tubular necrosis, uremia, renal impairment associated with diabetes mellitus, etiology of renal failure, hepatorenal syndrome, obstructive uropathy, anemia and erythropoietin, osteodystrophy, dialysis, prognosis, cost factors, and kidney transplantation.
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Pathogenetic and Therapeutic Aspects of Chronic Renal Failure Source: New York, NY: Marcel Dekker, Inc. 1997. 242 p. Contact: Available from Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016. (212) 696-9000. Fax (212) 685-4540. PRICE: $115.00. ISBN: 0824798945. Summary: This book is based on an international workshop, Chronic Renal Failure: Pathogenetic and Therapeutic Aspects, held in Berlin in May 1996. The first part of the book deals with arterial hypertension, hyperlipidemia, and metabolic acidosis as factors that accelerate the progression of chronic renal failure (CRF) and with the effect of dietary protein restriction as a measure to slow the advance of renal insufficiency. The second part addresses the etiology and pathophysiology of myocardial hypertrophy in general, and especially in uremia, and the influence of the dialysis regimen on the development of myocardial hypertrophy. The final section discusses the correction of renal anemia via treatment with recombinant human erythropoietin (rhEPO), with special emphasis on its effects on cardiac function and hypertrophy and on the function of parts of the endocrine system. Also included are an analysis of the use of rhEPO in renal transplant patients and an overview of the problems of iron supplementation in
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rhEPO treatment. The 17 chapters, each written by experts in the field, include reference lists; a subject index concludes the book. •
Acid-Base, Fluids, and Electrolytes Made Ridiculously Simple Source: Miami, FL: Medmaster, Inc. 1997. 160 p. Contact: Available from Medmaster, Inc. P.O. Box 640028, Miami, FL 33164. (954) 9628414. Fax (954) 962-4508. E-mail:
[email protected]. Website: www.medmaster.net. PRICE: $17.95 plus shipping and handling. ISBN: 0940780313. Summary: This book on acid base, fluids, and electrolytes is from a series of publications that select material that is most clinically relevant to the medical student and other health professionals. The text then offers a clear conceptual understanding of the subject as a whole, along with those clinically relevant facts that are important to learn (leaving out those facts that can be looked up in a reference text). The book is designed for medical students, interns and residents, nurses, nephrologists, primary care physicians, surgeons, and other clinicians responsible for intravenous fluid therapy. Ten chapters cover the basics, intravenous (IV) solutions and IV orders, hyponatremia (low blood levels of sodium), hypernatremia, hypokalemia (low blood levels of potassium), hyperkalemia, metabolic acidosis, metabolic alkalosis, and mixed acid base disorders. Each chapter concludes with questions and clinical situations for readers to use to review the specific material presented in that chapter. A final chapter offers seven case examples for readers to summarize and combine the concepts presented. Extensive figures and tables also summarize the material in each chapter. The book concludes with a subject index.
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Clinical Nephrology Source: River Edge, NJ: World Scientific Publishing Co., Inc. 1998. 340 p. Contact: Available from World Scientific Publishing Co., Inc. 1060 Main Street, River Edge, NJ 07661. (800) 227-7562 or (201) 487-9655. Fax (888) 977-2665 or (201) 487-9656. Email:
[email protected]. Website: www.wspc.com. PRICE: $15.00 plus shipping and handling. ISBN: 9810234848. Summary: This book provides a broad review of kidney diseases, with regard to symptoms, diagnosis, and treatment; the book is designed to help medical students prepare for their examinations and also to be useful to practicing physicians who need an overview of kidney disease. Twenty-seven chapters are included: the structure and function of the kidneys; symptoms and signs in renal (kidney) medicine; renal investigations (diagnostic tests); glomerulonephritis (inflammation of the kidney glomeruli, bundles of filtering units called nephrons); the nephrotic syndrome (a condition with symptoms of fluid accumulation, protein in the urine, and susceptibility to infections); the pathogenesis (development) and treatment of IgA nephritis (kidney inflammation due to a specific immune system disorder); lupus nephritis (kidney inflammation due to lupus erythematosus, a systemic inflammatory disorder); urinary tract infection; sex and the kidney; hypertension (high blood pressure) and the kidney; diuretics (drugs used to promote the formation of urine); kidney stones (calculi, nephrolithiasis); diabetes mellitus and the kidney; fluid and electrolytes; acid base balance; clinical problems in fluids, electrolytes, and acid base balance; renal tubular acidosis; renal tubular disorders; systemic disease and the kidney; pregnancy and the kidney; cancer and the kidney; inherited kidney diseases; drugs and the kidney; acute renal failure (ARF); chronic renal failure (CRF); dialysis; and renal transplantation. Each
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chapter includes illustrations, tables, answers to common questions, and a list of references for additional study; a subject index concludes the book. •
Churchill's Pocketbook of Diabetes Source: New York, NY: Harcourt Health Sciences. 2000. 316 p. Contact: Available from Harcourt Health Sciences. Foots Cray High Street, Sidcup, Kent DA14 5HP, United Kingdom. 020 8308 5700. Fax 020 8308 5702. E-mail:
[email protected]. PRICE: $24.95 plus shipping and handling. ISBN: 0443061181. Summary: This book serves as a resource for health care workers who are not diabetes specialists but who are in regular contact with people who have diabetes. The book offers guidance on the daily management of these patients. The book begins with a chapter on the key biochemical defects of diabetes and recent changes in classification. Chapter two focuses on the diagnosis and initial management of diabetes. Topics include the clinical presentation of diabetes, the diagnostic criteria for diabetes, the history and physical examination, the influence of comorbidity, the psychological impact of diabetes, the aims of treatment, the relationship between glycemic control and complications, the assessment of glycemic control, the principles of education in diabetes, and the organization and economics of diabetes care. The next chapter discusses the management of diabetes, focusing on nutrition therapy, smoking cessation or reduction, physical exercise, oral antidiabetic agent therapy, insulin therapy, and pancreatic and islet cell transplantation. The focus of the fourth chapter is on the acute metabolic complications of diabetes, including hypoglycemia, diabetic ketoacidosis, diabetic hyperosmolar nonketotic syndrome, and lactic acidosis. The fifth chapter describes the complications of diabetes, including ocular, kidney, nerve, foot, macrovascular, cutaneous, musculoskeletal, and connective tissue problems; hypertension; diabetic dyslipidemia; and infection. The final chapter addresses special topics, including diabetes in children, adolescents, the elderly, and pregnant women; intercurrent illness; surgery and other invasive procedures; and social and legal aspects. The book also presents evidence based boxes providing the rationale underlying treatment decisions. 19 figures. 16 plates. Numerous tables. 74 references.
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Uncomplicated Guide to Diabetes Complications Source: Alexandria, VA: American Diabetes Association. 1998. 256 p. Contact: Available from American Diabetes Association, Inc. Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $18.95 plus shipping and handling. ISBN: 0945448872. Order number 481401. Summary: This book uses a question and answer format to provide information on the symptoms, prevention, treatment, and self-care of diabetes complications. The information presented in the book is intended to help people who have diabetes cope with the uncertainty and fear of developing complications. Chapters cover all major complications: diabetic ketoacidosis, hyperglycemic hyperosmolar nonketotic coma, lactic acidosis, hypoglycemia, foot problems, eye disease and blindness, kidney and heart disease, hypertension and stroke, neuropathy and vascular disease, gastrointestinal problems, skin and dental problems, psychosocial complications, and impotence and other sexual disorders. Chapters also address special concerns such as hypoglycemia and obesity. Many chapters include a case study or studies to illustrate the complications of diabetes. The book concludes with a glossary and an index. 2 appendices. 33 figures. 32 tables.
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Primer on Kidney Diseases. 2nd ed Source: San Diego, CA: Academic Press. 1998. 542 p. Contact: Available from Academic Press. Order Fulfillment Department, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 321-5068 or (407) 345-3800. Fax (800) 874-6418 or (407) 345-4060. E-mail:
[email protected]. Website: www.apnet.com. PRICE: $57.95 plus shipping and handling. ISBN: 0122990900. Summary: This comprehensive textbook on kidney diseases is designed for medical students, house staff, and practitioners. The text offers a summary of the management of renal disease and fluid and electrolyte disorders. The 79 chapters are categorized in 11 sections, covering renal function and its assessment, electrolyte disorders, glomerular disease, the kidney in systemic disease, acute renal failure, drugs and the kidney, hereditary renal diseases, tubulointerstitial diseases, the kidney in special circumstances, chronic renal disease, and hypertension. Specific chapter topics include the characteristics of kidney function in the very young and in the very old, tubulointerstitial diseases, analgesic abuse nephropathy and the effects of NSAIDs on the kidneys, hematuria (blood in the urine), proteinuria, renal imaging techniques, metabolic acidosis and alkalosis, edema and the clinical use of diuretics, immunopathogenesis, minimal change nephropathy, IgA nephropathy, Goodpasture's syndrome, renal function in congestive heart failure, renal function in liver disease, renal manifestations of systemic lupus erythematosus, diabetic nephropathy, dysproteinemias and amyloidosis, renal and urologic complications of cancer and its treatment, hemolytic uremic syndrome, the renal manifestations of HIV, interstitial nephritis, sickle cell nephropathy, Alport's syndrome, medullary cystic disease, tubulointerstitial disease, lead nephrotoxicity, lithium induced renal disease, medullary sponge kidney, obstructive uropathy, nephrolithiasis (kidney stones), urinary tract infections, the kidney in pregnancy, the uremic syndrome, hemodialysis and hemofiltration, peritoneal dialysis, nutrition and renal disease, renal osteodystrophy, renal transplantation, and the pathogenesis of hypertension. Each chapter is written by an established expert in the field. The book is illustrated with full color and black and white photographs, figures, and tables. Each chapter concludes with suggested readings. An extensive subject index concludes the text.
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Therapy for Diabetes Mellitus and Related Disorders. 3rd ed Source: Alexandria, VA: American Diabetes Association. 1998. 487 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $39.95 plus shipping and handling. ISBN: 0945448945. Summary: This handbook focuses on the treatment of problems that are of importance in the management of people with diabetes mellitus. The book attempts to help health professionals apply major advances in health care to their patients. Topics include the diagnosis and classification of diabetes mellitus, genetic counseling for type 1 diabetes, gestational diabetes mellitus, the management of pregnant women who have diabetes, antepartum and intrapartum obstetric care, neonatal problems and their management, type 1 diabetes and diabetic ketoacidosis in children, psychosocial adjustment in children who have type 1 diabetes, psychosocial aspects in adults, diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic syndrome in adults, and lactic acidosis. Other topics include the role of diabetes education in patient management; self monitoring of blood glucose; the rationale for management of hyperglycemia; medical
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nutrition therapy; pharmacological treatment of obesity; exercise; oral hypoglycemic agents such as sulfonylureas, repaglinide, metformin, alpha glucosidase inhibitors, and thiazolidinediones; insulin treatment; insulin pump therapy; combination therapy for hyperglycemia; and diabetes complications. In addition, the book discusses surgery and anesthesia in people with diabetes, geriatric patient care, hypoglycemia in patients who have type 1 diabetes, insulin allergy and insulin resistance, drugs and hormones that increase blood glucose levels, diabetic dyslipidemia, antihypertensive therapy, cutaneous disorders associated with diabetes mellitus, infections, visual loss, ocular complications, drug induced renal dysfunction, diabetic nephropathy, chronic kidney disease, painful or insensitive lower extremity, mononeuropathy and amyoradiculopathy, gastrointestinal disturbances, and bladder dysfunction. Final topics include erectile dysfunction, female sexual disorders, postural hypotension, sudomotor dysfunction and dark vision, cardiac denervation syndrome, noninvasive cardiac testing, angina and congestive heart failure, myocardial infarction, peripheral vascular disease, and foot ulcers and infections. The book includes an index. Numerous figures. Numerous tables. Numerous references. •
Manual for Management of Diabetes Mellitus: A Hong Kong Chinese Perspective Source: Hong Kong: Chinese University Press. 1998. 144 p. Contact: Available from Chinese University Press. Chinese University of Hong Kong, Sha Tin, N.T., Hong Kong. (852) 2609 6508. Fax (852) 2603 6692. E-mail: cup @cuhk.hk. PRICE: $19.00 plus shipping and handling. ISBN: 9622017576. Summary: This manual, which combines the latest international and Chinese information on diabetes, serves as a quick reference to all health care personnel involved in the management of diabetes. The manual begins with a chapter on the classification and pathogenesis of diabetes, focusing on intermediary metabolism, insulin, and counterregulatory hormones; the classification, presentation, and pathogenesis of diabetes; the overlap between type 1 and type 2 diabetes; and diabetes in Chinese people. This is followed by a chapter on the diagnosis of diabetes. Topics include the American Diabetes Association and World Health Organization diagnostic criteria and the oral glucose tolerance test. The third chapter recommends standards of medical care for patients who have diabetes, focusing on the initial visit, continuing care, the annual assessment, target values, hospital admission criteria, and referral for specialist assessment. The next chapter addresses the issue of patient education. Topics include health beliefs and affective responses, knowledge and skills, patient rights and roles, obstacles to glycemic control, self monitoring of blood glucose, insulin administration, sick day management, hypoglycemia, diabetic complications, treatment noncompliance, psychosociological problems, and finances. The fifth chapter focuses on the dietary management of diabetes and exercise in diabetes. Diet-related topics include the goals of dietary management, diet composition, healthy eating and dining out guidelines, food choices, weight control, and sweeteners. This is followed by a chapter on oral drugs for treating diabetes, including sulfonylureas, biguanides, antiabsorptive drugs, antiobesity drugs, and insulin and oral agent combinations. The next chapter discusses insulin use in terms of indications for use, actions and duration, types, regimen, dosage, adjustment of dosage, and use while travelling. The eighth chapter describes diabetic complications, including ophthalmic complications, diabetic foot, diabetic neuropathy, and microalbuminuria and renal involvement. This is followed by chapters on the treatment of hypertension and dyslipidemia. Perioperative management of people who have poorly and well controlled type 1 or type 2 diabetes is the topic of the next chapter. This is followed by a chapter on diabetic emergencies such as diabetic ketoacidosis,
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hyperosmolar nonketotic coma, and lactic acidosis. Remaining chapters discusses the diagnosis and management of gestational diabetes and the primary, secondary, and tertiary prevention of diabetes. 2 appendices. 9 figures. 1 table. •
Renal and Electrolyte Disorders, Fourth Edition Source: Boston, MA: Little, Brown and Company. 1992. 857 p. Contact: Available from Little, Brown and Company. Order Department, 200 West Street, Waltham, MA 02154. (800) 343-9204. PRICE: $57.95. ISBN: 0316774944. Summary: This medical textbook presents a pathophysiologic approach to understanding renal and electrolyte disorders. Topics in the fifteen chapters include: disorders of water metabolism; renal sodium excretion, edematous disorders, and diuretic use; the pathogenesis and management of metabolic acidosis; the pathogenesis and management of respiratory and mixed acid-base disorders; disorders of potassium metabolism; disorders of calcium, phosphorus, vitamin D, and parathyroid hormone activity; normal and abnormal magnesium metabolism; disorders of the reninangiotensin-aldosterone system; the kidney in hypertension; the pathogenesis, diagnosis and management of acute renal failure; the manifestations and pathogenesis of chronic renal failure; obstructive nephropathy; renal function in pregnancy; proteinuria and the nephrotic syndrome; and the glomerulopathies. A subject index is appended. 3862 references.
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Basic Guide for Kidney Patients: When Your Kidneys Fail, You Don't Have to Source: Washington, DC: National Kidney Foundation of the National Capitol Area. 2000. 50 p. Contact: Available from National Kidney Foundation of the National Capital Area. 5335 Wisconsin Avenue, NW, Suite 300, Washington, DC 20015-2030. (202) 244-7900. Fax (202) 244-7405. Website: www.kidneywdc.org. PRICE: Single copy free. Summary: This National Kidney Foundation (NKF) guidebook contains important information for the patient newly diagnosed with kidney disease. It is designed as a resource book to help patients understand the medical terminology, the renal (kidney) or transplant team members assigned to care for the patient, kidney failure and how it is treated, dietary considerations, medications, and resources available. The manual begins with the stories of two patients with kidney disease, including their diagnosis, coping, and treatment choices. The next part outlines how medical terms are created and helps readers understand the related root terms that are often used in nephrology (the study of the kidney). The manual then offers five sections: kidney failure and its treatment, dialysis treatment for ESRD (end stage renal disease), transplantation, nutrition, and a resource guide. Specific topics include normal kidney function, acute versus chronic kidney failure, treatment of chronic kidney failure before ESRD, hemodialysis, peritoneal dialysis, the types of transplantation, the advantages and complications of transplantation, transplant medications (to avoid rejection), how a transplant is done (the surgery itself), financial factors surrounding transplantation, hints for taking medications, nutritional factors (protein, carbohydrates and fats, calcium and phosphorus, sodium and water, potassium, iron, vitamins), medications which maintain metabolic balance, medications used to control acidosis, how to find financial help (Medicare, private insurance, Medicaid, Veterans Affairs benefits, government programs, Aid for Families with Dependent Children, Social Security Disability Income, and Supplemental Security Income), and handling major costs. The manual concludes with a glossary of terms that patients are likely to encounter. 4 figures. 3 tables.
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Renal and Electrolyte Disorders, Sixth Edition Source: Philadelphia, PA: Lippincott Williams and Wilkins. 2003. 703 p. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-3030 or (301) 223-2300. Fax (301) 223-2365. PRICE: $75.00 plus shipping and handling. ISBN: 0781737494. Summary: This textbook on renal (kidney) pathophysiology is designed for physicians in training who wish to maintain a current knowledge base and update their clinical skills. The text features clinically focused coverage of kidney pathophysiology. Fifteen chapters cover disorders of water metabolism; renal sodium excretion, edematous disorders, and diuretic use; the pathogenesis and management of metabolic acidosis and alkalosis; the pathogenesis and management of respiratory and mixed acid-base disorders; disorders of potassium metabolism; disorders of calcium, phosphorus, vitamin D, and parathyroid hormone (PTH) activity; normal and abnormal magnesium metabolism; disorders of the renin-angiotensin-aldosterone system; the kidney in hypertension (high blood pressure); the pathogenesis, diagnosis, and management of acute renal failure (ARF); the manifestations and pathogenesis of chronic renal failure (CFR); obstructive nephropathy; renal function in pregnancy; proteinuria and the nephrotic syndrome; and the glomerulopathies. Each chapter concludes with a lengthy reference list and the text concludes with a detailed subject index.
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Endocrinology. 4th ed Source: Philadelphia, PA: Harcourt Health Sciences. 2001. 3 v., 3048 p. Contact: Available from W.B. Saunders. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452 or (314) 453-7010. Fax (800) 568-5136 or (314) 453-7095. E-mail:
[email protected]. Website: customerservice.wbsaunders.com. PRICE: $495.00 plus shipping and handling. ISBN: 0721678408 (three volume set). Summary: This three volume set of books provides a complete, authoritative, up to date analysis of endocrine disease and basic endocrine physiology. This edition consists of 194 chapters that cover every aspect of endocrinology in detail by an authority in the field. About one third of the chapters are new, and the remainder have been rewritten and updated. Topics covered in volume one include the principles of hormone action; neuroendocrinology and the pituitary gland; growth and maturation; immunology and endocrinology; obesity, anorexia nervosa, and nutrition in endocrinology; and diabetes mellitus, carbohydrate metabolism, and lipid disorders. Chapters on diabetes mellitus focus on anatomy and physiology, classification, etiology, diagnosis, and treatment. Specific clinical disorders discussed include syndromes of insulin resistance, oculopathy, neuropathy, nephropathy, diabetic foot complications, ketoacidosis, hyperosmolar coma, lactic acidosis, hypoglycemia, atherosclerosis, syndrome X, and hyperglycemia. Volume two includes information on the parathyroid gland, calciotropic hormones, bone metabolism, the thyroid gland, the adrenal gland, and glucocorticoids. Topics covered in volume three include endocrine hypertension and mineralocorticoids, reproductive endocrinology and sexual development, female reproduction, endocrinology of the breast, male reproduction, endocrinology and pregnancy, endocrine tumor syndromes, and endocrine testing and treatment. Numerous figures. Numerous tables. Numerous references.
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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 “acidosis” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “acidosis” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “acidosis” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
Acidosis: Index of New Information and Medical Research Bible by Laforre; ISBN: 0788300865; http://www.amazon.com/exec/obidos/ASIN/0788300865/icongroupinterna
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Acidosis-Index of New Information and Medical Research Bible by Dr. Laforee; ISBN: 9995611953; http://www.amazon.com/exec/obidos/ASIN/9995611953/icongroupinterna
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Clinical and biochemical aspects of lactic acidosis by Robert D. Cohen; ISBN: 0632094605; http://www.amazon.com/exec/obidos/ASIN/0632094605/icongroupinterna
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Hypoxia, Metabolic Acidosis, and the Circulation (Clinical Physiology Series) by Allen I. Arieff (Editor); ISBN: 0195060628; http://www.amazon.com/exec/obidos/ASIN/0195060628/icongroupinterna
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Lactic Acidosis and Energy Metabolism: Journal of Inherited Metabolic Disease 19-4, 1996 by M. Ugarte (Editor), et al; ISBN: 0792387163; http://www.amazon.com/exec/obidos/ASIN/0792387163/icongroupinterna
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Metabolic Acidosis (Ciba Foundation Symposium, No 87) by Ciba Foundation Symposium; ISBN: 0471910562; http://www.amazon.com/exec/obidos/ASIN/0471910562/icongroupinterna
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No.87 Metabolic Acidosis (CIBA Foundation Symposium); ISBN: 0272796514; http://www.amazon.com/exec/obidos/ASIN/0272796514/icongroupinterna
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Pathophysiology - What Happens in Metabolic Acidosis: Clinical Cards; ISBN: 0874342953; http://www.amazon.com/exec/obidos/ASIN/0874342953/icongroupinterna
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The Acid Danger: Combating Acidosis Correctly by Wolfgang R. Auer; ISBN: 1591200806; http://www.amazon.com/exec/obidos/ASIN/1591200806/icongroupinterna
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The Official Patient's Sourcebook on Renal Tubular Acidosis: A Directory for the Internet Age by James N., Md. Parker (Editor), et al; ISBN: 0597832315; http://www.amazon.com/exec/obidos/ASIN/0597832315/icongroupinterna
Chapters on Acidosis In order to find chapters that specifically relate to acidosis, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book
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chapters and acidosis 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 “acidosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on acidosis: •
Hyperglycemic Emergencies: Diabetic Ketoacidosis and Nonketotic Hyperosmolar Syndrome Source: in Leahy, J.L. and Cefalu, W.T., eds. Insulin Therapy. Monticello, NY: Marcel Dekker, Inc. 2002. p. 173-192. Contact: Available from Marcel Dekker, Inc. Cimarron Road, P.O. Box 5005, Monticello, NY 12701. (845) 796-1919 or (800) 228-1160. Fax (845) 796-1772. Email:
[email protected]. Website: www.dekker.com. PRICE: $99.75. ISBN: 824707117. Summary: Ketoacidosis and nonketotic hyperosmolar syndrome are the two most serious hyperglycemic (high blood glucose) emergencies of diabetes mellitus. Diabetic ketoacidosis (DKA) is characterized by a high blood glucose level, ketonemia and ketonuria, and metabolic acidosis. The hyperosmolar syndrome entails hyperglycemia and profound dehydration without significant ketoacidosis. This chapter on hyperglycemic emergencies is from a reference book that explores the pharmacokinetics of insulin and insulin programs. The book focuses on the latest blood glucose selfmonitoring equipment and assessment strategies that can achieve optimal glycemic control and thus reduce the occurrence of complications including retinopathy (eye disease), neuropathy (nerve disease), nephropathy (kidney disease) and cardiovascular disease. In this chapter, the author discusses incidence and mortality, pathogenesis, clinical features, diagnosis and initial evaluation, treatment approaches, and general management. 1 figure. 3 tables. 27 references.
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Metabolic Acidosis Source: in Suki, W.N.; Massry, S.G., eds. Therapy of Renal Diseases and Related Disorders, 2nd ed. Hingham, MA: Kluwer Academic Publishers. 1991. p. 177-191. Contact: Available from Kluwer Academic Publishers. P.O. Box 358, Accord Station, Hingham, MA 02018. (617) 871-6600. PRICE: $315. ISBN: 0792306767. Summary: This chapter, from a medical text on the therapy of renal disease and related disorders, discusses metabolic acidosis. The authors briefly review the pathogenesis of and diagnostic approach to metabolic acidosis, provide some general principles of treatment, and then discuss individual disorders separately. Specific topics include the calculation of the quantity of bicarbonate to administer in treating acidosis; therapeutic options; and treatment of ketoacidosis, lactic acidosis, salicylate intoxication, methanol intoxication, ethylene glycol intoxication, organic acid load from the gastrointestinal tract, and renal acidoses. 3 appendixes. 8 figures. 7 tables. 27 references.
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CHAPTER 7. MULTIMEDIA ON ACIDOSIS Overview In this chapter, we show you how to keep current on multimedia sources of information on acidosis. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.
Video Recordings An excellent source of multimedia information on acidosis is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “acidosis” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” Type “acidosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on acidosis: •
Nephrology Update Source: Cleveland, OH: Cleveland Clinic Foundation. 1992. (videocassettes, proceedings/minutes). Contact: Available from CME Video. 2000 Crawford Place, Suite 100, Mount Laurel, NJ 08054. (800) 284-8433. PRICE: $495; plus $18.25 shipping and handling; Group Practice Package $150 plus $5.25 shipping and handling. Program Number 076. Summary: This Video Education Program presents 23 hours of presentations and problem-solving workshops. Topics include the clinical applications of basic renal physiology; the biology of mesangial cell structure and function; the diagnosis and management of hypercalcemia; mechanisms of dialysis-induced hypotension; HIV nephropathy; renal artery stenosis; the pathogenesis of renal stones; glomerulonephritis; dietary treatment in chronic renal disease; drug-induced acute and chronic interstitial nephritis; issues in metabolic acidosis; prostatic disease; hypertension; systemic lupus erythematosus nephritis; and the thrombotic angiopathies. Workshops cover topics
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including: management issues in dialysis patients, access, adequacy and nutrition; complex acid-base disorders; and intensive care unit (ICU) nephrology. All tapes are indexed with Quik-Scan for fast reference to presentations of special interest to the viewer. The program is accompanied by the original course syllabus, including supplemental reference information. •
Renal Disorders: Fluids and Electrolytes Source: in Schwartz, R.S., ed. Aging and the Elderly: A Review Course of Geriatric Medicine. Seattle, WA: University of Washington School of Medicine. 1992. Tape 8, Section 29). Contact: Available from CME Conference Video, Inc. 2000 Crawford Place, Suite 100, Mount Laurel, NJ 08054. (800) 284-8433. PRICE: $549; plus $18.25 shipping and handling; Group Practice Package $150 plus $5.25 shipping and handling. Program Number 053. Summary: This videotape presentation is part of the 16th Annual Symposium on Aging and the Elderly, a continuing medical education (CME) program offered through the University of Washington School of Medicine. This program covers renal disease, notably fluid and electolytes physiology, in the elderly. Topics include anatomic changes with aging; changes in renal blood flow and glomerular filtration rate that accompany aging; changes in water homeostasis; and the diagnosis and treatment of hyponatremia, hypernatremia, sodium homeostasis, hyperkalemia, renal tubular acidosis, renal failure in the elderly, and end-stage renal disease. The proceedings include an outline of the author's comments on these topics. The videotape program includes the question-and-answer period conducted after the section.
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CHAPTER 8. PERIODICALS AND NEWS ON ACIDOSIS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover acidosis.
News Services and Press Releases One of the simplest ways of tracking press releases on acidosis 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 “acidosis” (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 acidosis. 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 “acidosis” (or synonyms). The following was recently listed in this archive for acidosis: •
Riboflavin reverses nucleoside analogue-induced type B lactic acidosis Source: Reuters Industry Breifing Date: January 25, 2002
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Simpler fluid management improves diabetic ketoacidosis therapy in children Source: Reuters Medical News Date: September 19, 2001
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Combined data fail to show link between metformin and lactic acidosis Source: Reuters Industry Breifing Date: November 26, 2003
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Amphotericin B linked to fatal lactic acidosis in AIDS patient Source: Reuters Medical News Date: May 12, 2003
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Metabolic acidosis common in HIV-infected children Source: Reuters Medical News Date: April 15, 2003
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Nucleoside-associated lactic acidosis often fatal in HIV patients Source: Reuters Industry Breifing Date: April 08, 2002
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Bristol-Myers issues second warning for potential lactic acidosis among Zerit users Source: Reuters Industry Breifing Date: April 01, 2002
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Respiratory acidosis prevalent during exacerbations of COPD Source: Reuters Medical News Date: July 10, 2000
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Lactic acidosis can develop in HIV-infected patients treated with zidovudine Source: Reuters Medical News Date: May 03, 1999
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Risk of lactic acidosis in metformin users "may be coincidental" Source: Reuters Medical News Date: October 27, 1998
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Parenteral Multivitamin Shortages Linked To Cases Of Lactic Acidosis Source: Reuters Medical News Date: June 13, 1997
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Adrenaline Infusion Associated with Lactic Acidosis Source: Reuters Medical News Date: July 30, 1996
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Positive Pressure Nasal Mask Ventilation May Reverse Respiratory Acidosis Source: Reuters Medical News Date: December 27, 1995 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 “acidosis” (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 “acidosis” (or synonyms). If you know the name of a company that is relevant to acidosis, 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 “acidosis” (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 “acidosis” (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 acidosis: •
Management of Laxative Abuse in Eating Disorders Source: SCAN'S PULSE. 18(3): 7-8. Fall 1999.
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Contact: Available from American Dietetic Association. SCAN Office, 90 S. Cascade Avenue, Suite 1230, Colorado Springs, CO 80903. (719) 475-7751. Fax (719) 475-8748. Summary: Health professionals who treat eating disorders eventually encounter clients with anorexia nervosa or bulimia who use laxatives as a method of weight control. This article reviews the management of laxative abuse in patients with eating disorders. Women who abuse laxatives believe that taking laxatives after food consumption prevents the absorption of calories in the intestine. However, studies show that laxative use only decreases caloric absorption by 12 percent, because laxatives primarily exert their effect in the large intestine. In addition to being ineffective in weight control, chronic laxative use is also medically dangerous. Serious problems that may occur include electrolyte and fluid imbalance leading to metabolic acidosis or alkalosis, permanent structural and functional damage to the colon, interstitial renal (kidney) disease, and rectal prolapse. The successful management of chronic laxative abuse requires a team of professionals that includes a physician, nutrition therapist, and psychotherapist. The author reviews the treatment protocol for these patients, which includes adequate dietary fiber and fluids intake, limited consumption of high sodium and gas forming foods, regular exercise, and patient education. During weekly appointments, the nutrition therapist should evaluate the client's compliance with the prescribed treatment plan. The author cautions that discontinuing long term laxative abuse is extremely difficult, and some clients may require inpatient treatment to be successful. Body image issues become predominant as the client experiences severe fluid retention, often in the range of 10 to 20 pounds, until natural diuresis occurs after about 4 to 6 weeks of laxative abstinence. 9 references. •
Focus On: Renal Disease in Alagille Syndrome Source: LiverLink. 7(4): 1, 3-8. October-December 2000. Contact: Available from Alagille Syndrome Alliance. 10630 S.W. Garden Park Place, Tigard, OR 97223. (503) 639-6217. E-mail:
[email protected]. Website: www.alagille.org. Summary: Kidney (renal) disease is now recognized as a common feature of Alagille syndrome (AGS) and may be present in up to 40 percent of AGS patients. A variety of renal abnormalities that have a very wide spectrum of clinical significance (symptoms and complications) and severity have been described in AGS. This newsletter article reviews renal disease associated with AGS. AGS renal disease is a mixture of defects in the formation of the kidney, problems from lipid (fat) deposition in the kidney secondary to cholestasis (retention of bile contents in the blood stream), and vascular abnormalities. Each of these problems can lead to alteration in the normal filtration of the kidney. The article reviews the normal function of the kidney, which is to produce urine and keep the body's composition of electrolytes (sodium, potassium, bicarbonate) stable, and to filter proteins and waste products. The author describes defects in the formation of the kidney in AGS, including renal agenesis (absent kidney), duplications of the urinary tract, renal dysplasia (malformation), renal hypoplasia (small kidney with decreased ability to filter), and medullary cystic disease. Renal artery stenosis is a narrowing of the artery supplying the kidney that compromises the blood flow to the kidney. As a result of this stenosis, the kidney eventually shrinks and may lose some function. Many of these conditions lead to a functional renal condition called renal tubular acidosis (RTA); the author reviews this problem and stresses the importance of regular screening for and diagnosis of kidney problems in patients with AGS. 1 table.
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Making the Bladder Bigger Source: Pull-Thru Network News. 7(4): 4-5. November 1998. Contact: Available from Pull-Thru Network. United Ostomy Association, Inc. 4 Woody Lane, Westport, CT 06880. Summary: This article describes the surgeries used to augment the bladder (make it bigger). Surgeons have been experimenting with various forms of bladder augmentation (cystoplasty) for decades and now regularly use it in the treatment of neurogenic bladder (dysfunction of the bladder caused by problems relating to nerves supplying the bladder) and exstrophy (in which the bladder is inside out, which causes the urine to drain to the exterior). There are still a number of problems inherent in the procedure, including finding an ideal tissue to use. With bowel tissue used for augmentation, there are many documented side effects: acidosis, stone formation, growth retardation, and electrolyte imbalance. Synthetic patches have had many problems ranging from stone formation to graft rejection, and the results of their use is generally regarded as unfavorable. The author encourages parents and patients to learn about the various augmentation material choices and their associated advantages and problems. The author then briefly discusses advances in tissue engineering for bladder replacement. The author uses his own experiences with making choices for his daughter's medical care as a case study for bladder augmentation decisions. The article concludes with a brief glossary of related terms. 1 table. 8 references.
Academic Periodicals covering Acidosis Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to acidosis. In addition to these sources, you can search for articles covering acidosis 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 acidosis. 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 nonprofit 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 acidosis. 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 acidosis: Antidiabetic Agents, Sulfonylurea •
Systemic - U.S. Brands: Amaryl; DiaBeta; Diabinese; Dymelor; Glucotrol; Glucotrol XL; Glynase PresTab; Micronase; Orinase; Tolinase http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202742.html
Fludrocortisone •
Systemic - U.S. Brands: Florinef http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202244.html
Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.
Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.
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 acidosis by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/.
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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 “acidosis” (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 acidosis: •
Sodium dichloroacetate http://www.rarediseases.org/nord/search/nodd_full?code=54
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Sodium dichloroacetate http://www.rarediseases.org/nord/search/nodd_full?code=59
•
Sodium dichloroacetate http://www.rarediseases.org/nord/search/nodd_full?code=863
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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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.
NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute10: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
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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/
10
These publications are typically written by one or more of the various NIH Institutes.
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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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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.11 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:12 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
•
Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
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Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
11
Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 12 See http://www.nlm.nih.gov/databases/databases.html.
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•
Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
The NLM Gateway13 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “acidosis” (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 32749 198 535 88 1667 35237
HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.17 Simply search by “acidosis” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
13
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
14
The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17
The HSTAT URL is http://hstat.nlm.nih.gov/.
Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.
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Coffee Break: Tutorials for Biologists18 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.19 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
18 Adapted 19
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 20 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.
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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on acidosis 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 acidosis. 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 acidosis. 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 “acidosis”:
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COPD http://www.nlm.nih.gov/medlineplus/copdchronicobstructivepulmonarydisease.t ml Genetic Brain Disorders http://www.nlm.nih.gov/medlineplus/geneticbraindisorders.html Kidney Diseases http://www.nlm.nih.gov/medlineplus/kidneydiseases.html Laboratory Tests http://www.nlm.nih.gov/medlineplus/laboratorytests.html Metabolic Disorders http://www.nlm.nih.gov/medlineplus/metabolicdisorders.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on acidosis. 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: •
Renal Tubular Acidosis Source: Bethesda, MD: National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH). 2000. 4 p. Contact: Available from National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). 3 Information Way, Bethesda, MD 20892-3580. (800) 891-5390 or (301) 654-4415. Fax (301)634-0716. E-mail:
[email protected]. Website: http://www.niddk.nih.gov/health/kidney/nkudic.htm. PRICE: Full-text available online at no charge; single copy free; bulk orders available. Order number: KU-87. Summary: Renal tubular acidosis (RTA) is a disease that occurs when the kidneys fail to excrete acids into the urine, which causes a person's blood to remain too acidic. Without proper treatment, chronic acidity of the blood leads to growth retardation, kidney stones, bone disease, and progressive renal failure. This fact sheet, from the National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC), reviews the diagnosis, the subtypes of RTA, therapy, and current research activities in RTA. To diagnose RTA, the doctor will check the acid base balance in samples of the patient's blood and urine. Physicians use a three category classification system to describe the different types of RTA. Type 1, also called classic distal RTA, is an inherited disorder
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associated with diseases that affect many organ systems such as the autoimmune disorders Sjogren's syndrome and lupus erythematosus. Type 2 is called proximal RTA and occurs most frequently in children as part of a disorder called Fanconi's syndrome; it can also occur as a side effect of treatment with ifosfamide, a drug used in chemotherapy. Type 4 is caused by another defect in the kidney tubule, but is different from classic or proximal RTA because it results in high levels of potassium in the blood instead of low levels. If treated early, most people with RTA will not develop permanent kidney failure. Therefore, the goal is early recognition and adequate therapy, which will need to be maintained and monitored throughout the patient's lifetime. The fact sheet concludes with a list of organizations that can provide readers with more information and a brief description of the activities of the NKUDIC. Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •
Renal Tubular Acidosis Summary: An overview of the four types of renal tubular acidosis and its diagnosis. Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6538 The NIH Search Utility
The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to acidosis. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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Med Help International: http://www.medhelp.org/HealthTopics/A.html
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•
Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
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WebMDHealth: http://my.webmd.com/health_topics
Associations and Acidosis The following is a list of associations that provide information on and resources relating to acidosis: •
Lactic Acidosis Support Trust Telephone: (016) 068-3719 Toll-free: TTY: Fax: 0(160) 683-7198 Background: The Lactic Acidosis Support Trust is a not-for-profit voluntary health organization located in the United Kingdom. Established in 1993, the Trust works toward its goal of promoting research into the cause, treatment, and prenatal diagnosis of lactic acidosis and mitochondrial cytopathies. The Support Trust provides counseling, advice, and support to parents and caregivers of children with these rare conditions; and encourages health care professionals to become specialists in this field of medicine. The Trust seeks to provide information to parents or other relatives on a 24 hour basis and to provide physicians with financial support and grants to further their research. Fund-raising events include dances, coffee mornings, and other sponsored activities. The Lactic Acidosis Support Trust produces several educational materials including pamphlets, brochures, and a newsletter.
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to acidosis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with acidosis. 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 acidosis. 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 “acidosis” (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 “acidosis”. 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 “acidosis” (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 “acidosis” (or a synonym) into the search box, and click “Submit Query.”
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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.21
Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.
Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of
21
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)22: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
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California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
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California: Gateway Health Library (Sutter Gould Medical Foundation)
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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
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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/
22
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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•
Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
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Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm
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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp
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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm
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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
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 acidosis: •
Basic Guidelines for Acidosis Acidosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001181.htm DKA Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000320.htm Lactic acidosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000391.htm
•
Signs & Symptoms for Acidosis Diarrhea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003126.htm Hyperventilation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003071.htm
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Vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm •
Diagnostics and Tests for Acidosis ANA Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003535.htm Arterial blood gas analysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003855.htm Blood chemistry Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003468.htm Chem-20 Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003468.htm Lactic acid Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003507.htm
•
Background Topics for Acidosis Exercise Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001941.htm Kidney disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000457.htm Respiratory Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002290.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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ACIDOSIS 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] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] 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] Actin: Essential component of the cell skeleton. [NIH] Action Potentials: The electric response of a nerve or muscle to its stimulation. [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 Diphosphate: Adenosine 5'-(trihydrogen diphosphate). An adenine nucleotide
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containing two phosphate groups esterified to the sugar moiety at the 5'-position. [NIH] Adenosine Monophosphate: Adenylic acid. Adenine nucleotide containing one phosphate group esterified to the sugar moiety in the 2'-, 3'-, or 5'-position. [NIH] Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [NIH] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a wound. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] 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] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adrenergic Antagonists: Drugs that bind to but do not activate adrenergic receptors. Adrenergic antagonists block the actions of the endogenous adrenergic transmitters epinephrine and norepinephrine. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerobic Metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, oxidative metabolism, or cell respiration. [NIH] Aerobic Respiration: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as oxidative metabolism, cell respiration, or aerobic metabolism. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]
Aetiology: Study of the causes of disease. [EU] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element,
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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] 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] Agenesis: Lack of complete or normal development; congenital absence of an organ or part. [NIH]
Aggravation: An increasing in seriousness or severity; an act or circumstance that intensifies, or makes worse. [EU] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [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] Alkalemia: Decreased acidity of blood. [NIH] 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] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on
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homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allogeneic: Taken from different individuals of the same species. [NIH] Allopurinol: A xanthine oxidase inhibitor that decreases uric acid production. [NIH] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial fibrosis or cardiac decompensation. [NIH] 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-Amylase: An enzyme that catalyzes the endohydrolysis of 1,4-alpha-glycosidic linkages in starch, glycogen, and related polysaccharides and oligosaccharides containing 3 or more 1,4-alpha-linked D-glucose units. EC 3.2.1.1. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] 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] Aluminum: A metallic element that has the atomic number 13, atomic symbol Al, and atomic weight 26.98. [NIH] Aluminum Compounds: Inorganic compounds that contain aluminum as an integral part of the molecule. [NIH] Aluminum Hydroxide: Hydrated aluminum. A compound with many biomedical applications: as a gastric antacid, an antiperspirant, in dentifrices, as an emulsifier, as an adjuvant in bacterins and vaccines, in water purification, etc. [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] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and
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many other compounds. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Ammonium Chloride: An acidifying agent that is used as an expectorant and a diuretic. [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] Amoxapine: The N-demethylated derivative of the antipsychotic agent loxapine that works by blocking the reuptake of norepinephrine, serotonin, or both. It also blocks dopamine receptors. [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] Amylase: An enzyme that helps the body digest starches. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analytes: A component of a test sample the presence of which has to be demonstrated. The
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term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]
Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Angiotensin converting enzyme inhibitor: A drug used to decrease pressure inside blood vessels. [NIH] Angiotensin-Converting Enzyme Inhibitors: A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Anode: Electrode held at a positive potential with respect to a cathode. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anorexia Nervosa: The chief symptoms are inability to eat, weight loss, and amenorrhea. [NIH]
Anovulation: Suspension or cessation of ovulation in animals and humans. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another
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living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antidiabetic: An agent that prevents or alleviates diabetes. [EU] Antidiabetic Agent: A substance that helps a person with diabetes control the level of glucose (sugar) in the blood so that the body works as it should. [NIH] 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] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] 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] Antipsychotic: Effective in the treatment of psychosis. Antipsychotic drugs (called also neuroleptic drugs and major tranquilizers) are a chemically diverse (including phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines, and diphenylbutylpiperidines) but pharmacologically similar class of drugs used to treat schizophrenic, paranoid, schizoaffective, and other psychotic disorders; acute delirium and dementia, and manic episodes (during induction of lithium therapy); to control the movement disorders associated with Huntington's chorea, Gilles de la Tourette's syndrome, and ballismus; and to treat intractable hiccups and severe nausea and vomiting. Antipsychotic agents bind to dopamine, histamine, muscarinic cholinergic, a-adrenergic, and serotonin receptors. Blockade of dopaminergic transmission in various areas is thought
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to be responsible for their major effects : antipsychotic action by blockade in the mesolimbic and mesocortical areas; extrapyramidal side effects (dystonia, akathisia, parkinsonism, and tardive dyskinesia) by blockade in the basal ganglia; and antiemetic effects by blockade in the chemoreceptor trigger zone of the medulla. Sedation and autonomic side effects (orthostatic hypotension, blurred vision, dry mouth, nasal congestion and constipation) are caused by blockade of histamine, cholinergic, and adrenergic receptors. [EU] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antispasmodic: An agent that relieves spasm. [EU] Antitussive: An agent that relieves or prevents cough. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Aphakia: Absence of crystalline lens totally or partially from field of vision, from any cause except after cataract extraction. Aphakia is mainly congenital or as result of lens dislocation and subluxation. [NIH] Apnea: A transient absence of spontaneous respiration. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aqueous: Having to do with water. [NIH] Aqueous fluid: Clear, watery fluid that flows between and nourishes the lens and the cornea; secreted by the ciliary processes. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arcuate Nucleus: A nucleus located in the middle hypothalamus in the most ventral part of the third ventricle near the entrance of the infundibular recess. Its small cells are in close contact with the ependyma. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the
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arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asymptomatic: Having no signs or symptoms of disease. [NIH] Atmospheric Pressure: The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. [NIH] Atony: Lack of normal tone or strength. [EU] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] 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] 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] Autoclave: Apparatus using superheated steam under pressure. [NIH] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH]
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Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Babesiosis: A group of tick-borne diseases of mammals including zoonoses in humans. They are caused by protozoans of the genus babesia, which parasitize erythrocytes, producing hemolysis. In the U.S., the organism's natural host is mice and transmission is by the deer tick ixodes scapularis. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [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] 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] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] 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] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Beta-Thalassemia: A disorder characterized by reduced synthesis of the beta chains of hemoglobin. There is retardation of hemoglobin A synthesis in the heterozygous form (thalassemia minor), which is asymptomatic, while in the homozygous form (thalassemia major, Cooley's anemia, Mediterranean anemia, erythroblastic anemia), which can result in severe complications and even death, hemoglobin A synthesis is absent. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Bicarbonates: Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the pH of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. [NIH] Bilateral: Affecting both the right and left side of body. [NIH]
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Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding 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] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biogenesis: The origin of life. It includes studies of the potential basis for life in organic compounds but excludes studies of the development of altered forms of life through mutation and natural selection, which is evolution. [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] 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] Biophysics: The science of physical phenomena and processes in living organisms. [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] Biotransformation: The chemical alteration of an exogenous substance by or in a biological
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system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Biphasic: Having two phases; having both a sporophytic and a gametophytic phase in the life cycle. [EU] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [NIH] Bladder: The organ that stores urine. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Gas Analysis: Measurement of oxygen and carbon dioxide in the blood. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Glucose Self-Monitoring: Self evaluation of whole blood glucose levels outside the clinical laboratory. A digital or battery-operated reflectance meter may be used. It has wide application in controlling unstable insulin-dependent diabetes. [NIH] Blood Groups: The classification systems (or schemes) of the different antigens located on erythrocytes.The antigens are the phenotypic expression of the genetic differences characteristic of specific blood groups. [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 Preservation: The process by which blood or its components are kept viable outside of the organism from which they are derived (i.e., kept from decay by means of a chemical agent, cooling, or a fluid substitute that mimics the natural state within the organism). [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 Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [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]
Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blotting and transferred to strips of nitrocellulose paper. The blots are then detected by radiolabeled antibody probes. [NIH] Body Composition: The relative amounts of various components in the body, such as
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percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [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 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] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Hypoxia: Lack of oxygen leading to unconsciousness. [NIH] Brain Infarction: The formation of an area of necrosis in the brain, including the cerebral hemispheres (cerebral infarction), thalami, basal ganglia, brain stem (brain stem infarctions), or cerebellum secondary to an insufficiency of arterial or venous blood flow. [NIH] Brain Ischemia: Localized reduction of blood flow to brain tissue due to arterial obtruction or systemic hypoperfusion. This frequently occurs in conjuction with brain hypoxia. Prolonged ischemia is associated with brain infarction. [NIH] 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] Bronchitis: Inflammation (swelling and reddening) 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] Buffers: A chemical system that functions to control the levels of specific ions in solution. When the level of hydrogen ion in solution is controlled the system is called a pH buffer. [NIH]
Buformin: An oral hypoglycemic agent that inhibits gluconeogenesis, increases glycolysis, and decreases glucose oxidation. [NIH] Bulimia: Episodic binge eating. The episodes may be associated with the fear of not being able to stop eating, depressed mood, or self-deprecating thoughts (binge-eating disorder) and may frequently be terminated by self-induced vomiting (bulimia nervosa). [NIH] Bumetanide: A sulfamyl diuretic. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Calcifediol: The major circulating metabolite of vitamin D3 produced in the liver and the best indicator of the body's vitamin D stores. It is effective in the treatment of rickets and osteomalacia, both in azotemic and non-azotemic patients. Calcifediol also has mineralizing properties. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast
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calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcitriol: The physiologically active form of vitamin D. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption. [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 Carbonate: Carbonic acid calcium salt (CaCO3). An odorless, tasteless powder or crystal that occurs in nature. It is used therapeutically as a phosphate buffer in hemodialysis patients and as a calcium supplement. [NIH] Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools. Since they are inducers of vascular and other smooth muscle relaxation, they are used in the drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms. [NIH] Calcium Channels: Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue. [NIH] Calcium Oxalate: The calcium salt of oxalic acid, occurring in the urine as crystals and in certain calculi. [NIH] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [NIH] Caloric intake: Refers to the number of calories (energy content) consumed. [NIH] Cannula: A tube for insertion into a duct or cavity; during insertion its lumen is usually occupied by a trocar. [EU] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsaicin: Cytotoxic alkaloid from various species of Capsicum (pepper, paprika), of the Solanaceae. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU]
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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] Carbonate Dehydratase: A zinc-containing enzyme of erythrocytes with molecular weight of 30 kD. It is among the most active of known enzymes and catalyzes the reversible hydration of carbon dioxide, which is significant in the transport of CO2 from the tissues to the lungs. The enzyme is inhibited by acetazolamide. EC 4.2.1.1. [NIH] Carbonic Anhydrase Inhibitors: A class of compounds that reduces the secretion of H+ ions by the proximal kidney tubule through inhibition of carbonic anhydrase (carbonate dehydratase). [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 arrest: A sudden stop of heart function. [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] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiopulmonary Bypass: Diversion of the flow of blood from the entrance of the right atrium directly to the aorta (or femoral artery) via an oxygenator thus bypassing both the heart and lungs. [NIH] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiotonic: 1. Having a tonic effect on the heart. 2. An agent that has a tonic effect on the heart. [EU] Cardiotoxic: Having a poisonous or deleterious effect upon the heart. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular Physiology: Functions and activities of the cardiovascular system as a whole or of any of its parts. [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carotid Body: A small cluster of chemoreceptive and supporting cells located near the bifurcation of the internal carotid artery. The carotid body, which is richly supplied with
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fenestrated capillaries, senses the pH, carbon dioxide, and oxygen concentrations in the blood and plays a crucial role in their homeostatic control. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cecum: The beginning of the large intestine. The cecum is connected to the lower part of the small intestine, called the ileum. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Adhesion Molecules: Surface ligands, usually glycoproteins, that mediate cell-to-cell adhesion. Their functions include the assembly and interconnection of various vertebrate systems, as well as maintenance of tissue integration, wound healing, morphogenic movements, cellular migrations, and metastasis. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH]
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Cell Cycle Proteins: Proteins that control the cell division cycle. This family of proteins includes a wide variety of classes, including cyclin-dependent kinases, mitogen-activated kinases, cyclins, and phosphoprotein phosphatases (phosphoprotein phosphatase) as well as their putative substrates such as chromatin-associated proteins, cytoskeletal proteins, and transcription factors. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Membrane Permeability: A quality of cell membranes which permits the passage of solvents and solutes into and out of cells. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Cellular adhesion: The close adherence (bonding) to adjoining cell surfaces. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH]
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Chemoreceptor: A receptor adapted for excitation by chemical substances, e.g., olfactory and gustatory receptors, or a sense organ, as the carotid body or the aortic (supracardial) bodies, which is sensitive to chemical changes in the blood stream, especially reduced oxygen content, and reflexly increases both respiration and blood pressure. [EU] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [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] Chloride Channels: Cell membrane glycoproteins selective for chloride ions. [NIH] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [NIH]
Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chondrocytes: Polymorphic cells that form cartilage. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [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 Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Ciliary processes: The extensions or projections of the ciliary body that secrete aqueous humor. [NIH] Cinchona: A genus of rubiaceous South American trees that yields the toxic cinchona
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alkaloids from their bark; quinine, quinidine, chinconine, cinchonidine and others are used to treat malaria and cardiac arrhythmias. [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] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clathrin: The main structural coat protein of coated vesicles which play a key role in the intracellular transport between membranous organelles. Clathrin also interacts with cytoskeletal proteins. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] 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] Codeine: An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU]
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Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colectomy: An operation to remove the colon. An open colectomy is the removal of the colon through a surgical incision made in the wall of the abdomen. Laparoscopic-assisted colectomy uses a thin, lighted tube attached to a video camera. It allows the surgeon to remove the colon without a large incision. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] 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] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU]
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Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] 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] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Concretion: Minute, hard, yellow masses found in the palpebral conjunctivae of elderly people or following chronic conjunctivitis, composed of the products of cellular degeneration retained in the depressions and tubular recesses in the conjunctiva. [NIH] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congenita: Displacement, subluxation, or malposition of the crystalline lens. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH]
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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] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary Circulation: The circulation of blood through the coronary vessels of the heart. [NIH]
Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Creatine: An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. [NIH]
Creatine Kinase: A transferase that catalyzes formation of phosphocreatine from ATP + creatine. The reaction stores ATP energy as phosphocreatine. Three cytoplasmic isoenzymes have been identified in human tissues: MM from skeletal muscle, MB from myocardial tissue, and BB from nervous tissue as well as a mitochondrial isoenzyme. Macro-creatine kinase refers to creatine kinase complexed with other serum proteins. EC 2.7.3.2. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH]
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Crystallization: The formation of crystals; conversion to a crystalline form. [EU] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyanide: An extremely toxic class of compounds that can be lethal on inhaling of ingesting in minute quantities. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclin-Dependent Kinases: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with cyclins to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events. [NIH]
Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cysteinyl: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]
Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoplasmic Vesicles: Membrane-limited structures derived from the plasma membrane or various intracellular membranes which function in storage, transport or metabolism. [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.
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[NIH]
Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decompression: Decompression external to the body, most often the slow lessening of external pressure on the whole body (especially in caisson workers, deep sea divers, and persons who ascend to great heights) to prevent decompression sickness. It includes also sudden accidental decompression, but not surgical (local) decompression or decompression applied through body openings. [NIH] Decongestant: An agent that reduces congestion or swelling. [EU] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dentifrices: Any preparations used for cleansing teeth; they usually contain an abrasive, detergent, binder and flavoring agent and may exist in the form of liquid, paste or powder; may also contain medicaments and caries preventives. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] 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] Desensitisation: Gradually increasing the dose of a medicine in order to overcome severe allergic reactions. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU]
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Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Dextrans: A group of glucose polymers made by certain bacteria. Dextrans are used therapeutically as plasma volume expanders and anticoagulants. They are also commonly used in biological experimentation and in industry for a wide variety of purposes. [NIH] Dextroamphetamine: The d-form of amphetamine. It is a central nervous system stimulant and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetes, Gestational: Either symptomatic diabetes or impaired glucose tolerance induced by pregnancy but resolved at the end of pregnancy. It does not include previously diagnosed diabetics who become pregnant (pregnancy in diabetics). [NIH] Diabetic Foot: Ulcers of the foot as a complication of diabetes. Diabetic foot, often with infection, is a common serious complication of diabetes and may require hospitalization and disfiguring surgery. The foot ulcers are probably secondary to neuropathies and vascular problems. [NIH] Diabetic Ketoacidosis: Complication of diabetes resulting from severe insulin deficiency coupled with an absolute or relative increase in glucagon concentration. The metabolic acidosis is caused by the breakdown of adipose stores and resulting increased levels of free fatty acids. Glucagon accelerates the oxidation of the free fatty acids producing excess ketone bodies (ketosis). [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialysate: A cleansing liquid used in the two major forms of dialysis--hemodialysis and peritoneal dialysis. [NIH] Dialysis Solutions: Solutions prepared for exchange across a semipermeable membrane of solutes below a molecular size determined by the cutoff threshold of the membrane material. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diaphoresis: Perspiration, especially profuse perspiration. Called also sudoresis. [EU] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Dichloroacetate: A derivative of acetic acid which increases the activity of pyruvate dehydrogenase and rate of lipogenesis. It is used in organic synthesis, pharmaceuticals, and medicine. [NIH]
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Didanosine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. Didanosine is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA by binding to reverse transcriptase; ddI is then metabolized to dideoxyadenosine triphosphate, its putative active metabolite. [NIH] Dideoxyadenosine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is an inhibitor of HIV replication, acting as a chain-terminator of viral DNA by binding to reverse transcriptase. Its principal side effect is nephrotoxicity. In vivo, dideoxyadenosine is rapidly metabolized to didanosine (ddI) by enzymatic deamination; ddI is then converted to dideoxyinosine monophosphate and ultimately to dideoxyadenosine triphosphate, the putative active metabolite. [NIH] Dietary Fiber: The remnants of plant cell walls that are resistant to digestion by the alimentary enzymes of man. It comprises various polysaccharides and lignins. [NIH] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Digitalis: A genus of toxic herbaceous Eurasian plants of the Scrophulaceae which yield cardiotonic glycosides. The most useful are Digitalis lanata and D. purpurea. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dihydroxyacetone: A ketotriose compound. Its addition to blood preservation solutions results in better maintenance of 2,3-diphosphoglycerate levels during storage. It is readily phosphorylated to dihydroxyacetone phosphate by triokinase in erythrocytes. In combination with naphthoquinones it acts as a sunscreening agent. [NIH] Dihydroxyacetone Phosphate: An important intermediate in lipid biosynthesis and in glycolysis. [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] 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] Dipeptides: Peptides composed of two amino acid units. [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] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important
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determinant of therapy and prognosis. [NIH] 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] 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] Diving: An activity in which the organism plunges into water. It includes scuba and bell diving. Diving as natural behavior of animals goes here, as well as diving in decompression experiments with humans or animals. [NIH] Dobutamine: A beta-2 agonist catecholamine that has cardiac stimulant action without evoking vasoconstriction or tachycardia. It is proposed as a cardiotonic after myocardial infarction or open heart surgery. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] 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] Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. [NIH]
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Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dyslipidemia: Disorders in the lipoprotein metabolism; classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high-density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol predispose to premature atherosclerosis. [NIH] Dyspepsia: Impaired digestion, especially after eating. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Eating Disorders: A group of disorders characterized by physiological and psychological disturbances in appetite or food intake. [NIH] Echinacea: A genus of perennial herbs used topically and internally. It contains echinacoside, glycosides, inulin, isobutyl amides, resin, and sesquiterpenes. [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] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU]
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Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] 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]
Electroretinogram: The electrical effect recorded from the surface of the eyeball and originated by a pulse of light. [NIH] Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] 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] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [NIH] 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] 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] Emergency Treatment: First aid or other immediate intervention for accidents or medical conditions requiring immediate care and treatment before definitive medical and surgical management can be procured. [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said
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of a disease or agent. Called also endemial. [EU] Endocrine Glands: Ductless glands that secrete substances which are released directly into the circulation and which influence metabolism and other body functions. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [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] 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] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enterocytes: Terminally differentiated cells comprising the majority of the external surface of the intestinal epithelium (see intestinal mucosa). Unlike goblet cells, they do not produce or secrete mucins, nor do they secrete cryptdins as do the paneth cells. [NIH] 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]
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Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Ependyma: A thin membrane that lines the ventricles of the brain and the central canal of the spinal cord. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] 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] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythrocyte Membrane: The semipermeable outer portion of the red corpuscle. It is known as a 'ghost' after hemolysis. [NIH] Erythrocyte Volume: Volume of circulating erythrocytes. It is usually measured by radioisotope dilution technique. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] 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] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethylene Glycol: A colorless, odorless, viscous dihydroxy alcohol. It has a sweet taste, but is poisonous if ingested. Ethylene glycol is the most important glycol commercially available and is manufactured on a large scale in the United States. It is used as an antifreeze and coolant, in hydraulic fluids, and in the manufacture of low-freezing dynamites and resins.
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[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] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excrete: To get rid of waste from the body. [NIH] Exercise Test: Controlled physical activity, more strenuous than at rest, which is performed in order to allow assessment of physiological functions, particularly cardiovascular and pulmonary, but also aerobic capacity. Maximal (most intense) exercise is usually required but submaximal exercise is also used. The intensity of exercise is often graded, using criteria such as rate of work done, oxygen consumption, and heart rate. Physiological data obtained from an exercise test may be used for diagnosis, prognosis, and evaluation of disease severity, and to evaluate therapy. Data may also be used in prescribing exercise by determining a person's exercise capacity. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Expander: Any of several colloidal substances of high molecular weight. used as a blood or plasma substitute in transfusion for increasing the volume of the circulating blood. called also extender. [NIH] Expectorant: 1. Promoting the ejection, by spitting, of mucus or other fluids from the lungs and trachea. 2. An agent that promotes the ejection of mucus or exudate from the lungs, bronchi, and trachea; sometimes extended to all remedies that quiet cough (antitussives). [EU]
Expiration: The act of breathing out, or expelling air from the lungs. [EU] Extender: Any of several colloidal substances of high molecular weight, used as a blood or plasma substitute in transfusion for increasing the volume of the circulating blood. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the
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relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extracorporeal: Situated or occurring outside the body. [EU] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extravascular: Situated or occurring outside a vessel or the vessels. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] Failure to Thrive: A condition in which an infant or child's weight gain and growth are far below usual levels for age. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]
Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Artery: The main artery of the thigh, a continuation of the external iliac artery. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Fetal Blood: Blood of the fetus. Exchange of nutrients and waste between the fetal and maternal blood occurs via the placenta. The cord blood is blood contained in the umbilical vessels at the time of delivery. [NIH] Fetal Growth Retardation: The failure of a fetus to attain its expected growth potential at any gestational stage. [NIH] Fetal Heart: The heart of the fetus of any viviparous animal. It refers to the heart in the postembryonic period and is differentiated from the embryonic heart (heart/embryology) only on the basis of time. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrillation: A small, local, involuntary contraction of muscle, invisible under the skin, resulting from spontaneous activation of single muscle cells or muscle fibres. [EU]
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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] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibronectins: Glycoproteins found on the surfaces of cells, particularly in fibrillar structures. The proteins are lost or reduced when these cells undergo viral or chemical transformation. They are highly susceptible to proteolysis and are substrates for activated blood coagulation factor VIII. The forms present in plasma are called cold-insoluble globulins. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fluid Therapy: Therapy whose basic objective is to restore the volume and composition of
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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 be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Foot Ulcer: Lesion on the surface of the skin of the foot, usually accompanied by inflammation. The lesion may become infected or necrotic and is frequently associated with diabetes or leprosy. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fourth Ventricle: An irregularly shaped cavity in the rhombencephalon, between the medulla oblongata, the pons, and the isthmus in front, and the cerebellum behind. It is continuous with the central canal of the cord below and with the cerebral aqueduct above, and through its lateral and median apertures it communicates with the subarachnoid space. [NIH]
Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Free Radical Scavengers: Substances that influence the course of a chemical reaction by ready combination with free radicals. Among other effects, this combining activity protects pancreatic islets against damage by cytokines and prevents myocardial and pulmonary perfusion injuries. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Fructose: 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] Fructose Intolerance: An autosomal recessive fructose metabolism disorder due to deficient fructose-1-phosphate aldolase (EC 2.1.2.13) activity, resulting in accumulation of fructose-1phosphate. The accumulated fructose-1-phosphate inhibits glycogenolysis and gluconeogenesis, causing severe hypoglycemia following ingestion of fructose. Prolonged fructose ingestion in infants leads ultimately to hepatic failure and death. Patients develop a strong distaste for sweet food, and avoid a chronic course of the disease by remaining on a fructose- and sucrose-free diet. [NIH] Fungistatic: Inhibiting the growth of fungi. [EU] Fura-2: A fluorescent calcium chelating agent which is used to study intracellular calcium in
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many tissues. The fluorescent and chelating properties of Fura-2 aid in the quantitation of endothelial cell injury, in monitoring ATP-dependent calcium uptake by membrane vesicles, and in the determination of the relationship between cytoplasmic free calcium and oxidase activation in rat neutrophils. [NIH] Furosemide: A sulfamyl saluretic and diuretic. It has a fast onset and short duration of action and is used in edema and chronic renal insufficiency. [NIH] Gadolinium: An element of the rare earth family of metals. It has the atomic symbol Gd, atomic number 64, and atomic weight 157.25. Its oxide is used in the control rods of some nuclear reactors. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] 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 Emptying: The evacuation of food from the stomach into the duodenum. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gavage: Feeding by a tube passed into the stomach; called also tube feeding. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] 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]
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Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]
Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geriatric: Pertaining to the treatment of the aged. [EU] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]
Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and kidney failure. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] 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
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ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glucose-6-Phosphatase: An enzyme that catalyzes the conversion of D-glucose 6-phosphate and water to D-glucose and orthophosphate. EC 3.1.3.9. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] 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] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycogen Storage Disease: A group of inherited metabolic disorders involving the enzymes responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement. [NIH] Glycogen Synthase: An enzyme that catalyzes the transfer of D-glucose from UDPglucose into 1,4-alpha-D-glucosyl chains. EC 2.4.1.11. [NIH] Glycolysis: The pathway by which glucose is catabolized into two molecules of pyruvic acid with the generation of ATP. [NIH] Glycophorin: The major sialoglycoprotein of the human erythrocyte membrane. It consists of at least two sialoglycopeptides and is composed of 60% carbohydrate including sialic acid and 40% protein. It is involved in a number of different biological activities including the binding of MN blood groups, influenza viruses, kidney bean phytohemagglutinin, and wheat germ agglutinin. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Goats: Any of numerous agile, hollow-horned ruminants of the genus Capra, closely related to the sheep. [NIH] Goblet Cells: Cells of the epithelial lining that produce and secrete mucins. [NIH] Gonadal: Pertaining to a gonad. [EU]
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Gonads: The gamete-producing glands, ovary or testis. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Government Programs: Programs and activities sponsored or administered by local, state, or national governments. [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] Grafting: The operation of transfer of tissue from one site to another. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] 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] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Haemodialysis: The removal of certain elements from the blood by virtue of the difference in the rates of their diffusion through a semipermeable membrane, e.g., by means of a haemodialyzer. [EU] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] 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] Heartburn: Substernal pain or burning sensation, usually associated with regurgitation of
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gastric juice into the esophagus. [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] Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Hematuria: Presence of blood in the urine. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [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 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 C: A commonly occurring abnormal hemoglobin in which lysine replaces a glutamic acid residue at the sixth position of the beta chains. It results in reduced plasticity of erythrocytes. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocyte: A liver cell. [NIH] Hepatorenal Syndrome: Renal failure in those with liver disease, usually liver cirrhosis or obstructive jaundice. Historically called Heyd disease, urohepatic syndrome, or bile nephrosis. [NIH]
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Hepatotoxicity: How much damage a medicine or other substance does to the liver. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] 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]
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] Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hydration: Combining with water. [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] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperammonemia: Metabolic disorder characterized by elevated level of ammonia in blood. [NIH] Hyperbaric: Characterized by greater than normal pressure or weight; applied to gases
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under greater than atmospheric pressure, as hyperbaric oxygen, or to a solution of greater specific gravity than another taken as a standard of reference. [EU] Hyperbaric oxygen: Oxygen that is at an atmospheric pressure higher than the pressure at sea level. Breathing hyperbaric oxygen to enhance the effectiveness of radiation therapy is being studied. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hypercalciuria: Abnormally large amounts of calcium in the urine. [NIH] Hypercapnia: A clinical manifestation of abnormal increase in the amount of carbon dioxide in arterial blood. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperglycemic Hyperosmolar Nonketotic Coma: A syndrome consisting of extreme hyperglycemia, serum hyperosmolarity and dehydration in the absence of ketosis and acidosis. [NIH] Hyperlipidaemia: A general term for elevated concentrations of any or all of the lipids in the plasma, including hyperlipoproteinaemia, hypercholesterolaemia, etc. [EU] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperoxia: An abnormal increase in the amount of oxygen in the tissues and organs. [NIH] Hyperphagia: Ingestion of a greater than optimal quantity of food. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hyperventilation: A pulmonary ventilation rate faster than is metabolically necessary for the exchange of gases. It is the result of an increased frequency of breathing, an increased tidal volume, or a combination of both. It causes an excess intake of oxygen and the blowing off of carbon dioxide. [NIH] Hypoglycemia: Abnormally low blood sugar [NIH] Hypoglycemic: An orally active drug that produces a fall in blood glucose concentration. [NIH]
Hypoglycemic Agents: Agents which lower the blood glucose level. [NIH]
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Hypogonadism: Condition resulting from or characterized by abnormally decreased functional activity of the gonads, with retardation of growth and sexual development. [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypotension: Abnormally low blood pressure. [NIH] Hypotensive: Characterized by or causing diminished tension or pressure, as abnormally low blood pressure. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypothermia: Lower than normal body temperature, especially in warm-blooded animals; in man usually accidental or unintentional. [NIH] Hypotonic Solutions: Solutions that have a lesser osmotic pressure than a reference solution such as blood, plasma, or interstitial fluid. [NIH] Hypoventilation: A reduction in the amount of air entering the pulmonary alveoli. [NIH] Hypovolemia: An abnormally low volume of blood circulating through the body. It may result in hypovolemic shock. [NIH] Hypoxemia: Deficient oxygenation of the blood; hypoxia. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Ibotenic Acid: Neurotoxic isoxazole substance found in Amanita muscaria and A. pantherina. It causes motor depression, ataxia, and changes in mood, perceptions and feelings, and is a potent excitatory amino acid agonist. [NIH] Ifosfamide: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [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] Immaturity: The state or quality of being unripe or not fully developed. [EU] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH]
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Immunoblotting: Immunologic methods for isolating and quantitatively measuring immunoreactive substances. When used with immune reagents such as monoclonal antibodies, the process is known generically as western blot analysis (blotting, western). [NIH]
Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Indigestion: Poor digestion. Symptoms include heartburn, nausea, bloating, and gas. Also called dyspepsia. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins,
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intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]
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] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insecticide Resistance: The development by insects of resistance to insecticides. [NIH] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insufflation: The act of blowing a powder, vapor, or gas into any body cavity for experimental, diagnostic, or therapeutic purposes. [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]
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Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]
Intensive Care Units: Hospital units providing continuous surveillance and care to acutely ill patients. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or 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] Interindividual: Occurring between two or more individuals. [EU] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestinal Obstruction: Any impairment, arrest, or reversal of the normal flow of intestinal contents toward the anus. [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: Po
