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

HYDROPS A 3-IN-1 MEDICAL REFERENCE Medical Dictionary Bibliography & Annotated Research Guide TO I NTERNET

R EFERENCES

HYDROPS 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., 1960Hydrops: 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: 0-497-00560-3 1. Hydrops-Popular works. I. Title.

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

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

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on hydrops. 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 HYDROPS .................................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Hydrops......................................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 12 The National Library of Medicine: PubMed ................................................................................ 13 CHAPTER 2. NUTRITION AND HYDROPS......................................................................................... 57 Overview...................................................................................................................................... 57 Finding Nutrition Studies on Hydrops ....................................................................................... 57 Federal Resources on Nutrition ................................................................................................... 58 Additional Web Resources ........................................................................................................... 59 CHAPTER 3. ALTERNATIVE MEDICINE AND HYDROPS .................................................................. 61 Overview...................................................................................................................................... 61 National Center for Complementary and Alternative Medicine.................................................. 61 Additional Web Resources ........................................................................................................... 64 General References ....................................................................................................................... 65 CHAPTER 4. PATENTS ON HYDROPS ............................................................................................... 67 Overview...................................................................................................................................... 67 Patent Applications on Hydrops.................................................................................................. 67 Keeping Current .......................................................................................................................... 68 CHAPTER 5. BOOKS ON HYDROPS ................................................................................................... 71 Overview...................................................................................................................................... 71 Book Summaries: Federal Agencies.............................................................................................. 71 The National Library of Medicine Book Index ............................................................................. 72 Chapters on Hydrops ................................................................................................................... 72 CHAPTER 6. MULTIMEDIA ON HYDROPS ........................................................................................ 77 Overview...................................................................................................................................... 77 Video Recordings ......................................................................................................................... 77 CHAPTER 7. PERIODICALS AND NEWS ON HYDROPS ..................................................................... 79 Overview...................................................................................................................................... 79 News Services and Press Releases................................................................................................ 79 Newsletter Articles ...................................................................................................................... 80 Academic Periodicals covering Hydrops...................................................................................... 81 APPENDIX A. PHYSICIAN RESOURCES ............................................................................................ 85 Overview...................................................................................................................................... 85 NIH Guidelines............................................................................................................................ 85 NIH Databases............................................................................................................................. 87 Other Commercial Databases....................................................................................................... 89 APPENDIX B. PATIENT RESOURCES ................................................................................................. 91 Overview...................................................................................................................................... 91 Patient Guideline Sources............................................................................................................ 91 Finding Associations.................................................................................................................... 93 APPENDIX C. FINDING MEDICAL LIBRARIES .................................................................................. 95 Overview...................................................................................................................................... 95 Preparation................................................................................................................................... 95 Finding a Local Medical Library.................................................................................................. 95 Medical Libraries in the U.S. and Canada ................................................................................... 95 ONLINE GLOSSARIES................................................................................................................ 101 Online Dictionary Directories ................................................................................................... 101

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HYDROPS DICTIONARY ........................................................................................................... 103 INDEX .............................................................................................................................................. 151

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

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

Diagnostic Testing for Endolymphatic Hydrops Source: Otolaryngologic Clinics of North America. 30(6): 987-1005. December 1997. Summary: Endolymphatic hydrops is a histologic finding consisting of dilatation of the endolymphatic spaces of the membranous labyrinth. Hydrops is a consistent finding in the temporal bones of patients with Meniere's disease. It is also found in the temporal bones of patients with syphilis, trauma, otosclerosis, infection, and other disorders. There is no way to confirm the presence of hydrops other than by histologic evaluation of the labyrinth at autopsy. This article explores other diagnostic tests that may be useful in diagnosing endolymphatic hydrops. The authors first outline the need for an objective, premortem clinical test for the presence of hydrops. They then discuss nonspecific tests, including standard audiometry, routine vestibular testing, and otoacoustic emissions. Specific tests are discussed next, including dehydration testing,

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electrocochleography (ECoG), low frequency biasing, traveling wave velocity, pressure test, and otoadmittance. The authors conclude that electrocochleography appears to have slightly greater sensitivity and reduced specificity when compared to glycerol testing. It is useful in the atypical patient, frequently to reinforce the plan for medical therapy, and occasionally to aid in surgical decision making. The other possibly specific tests for hydrops are not well-established and remain investigational at the present time. 7 figures. 2 tables. 92 references.

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

Project Title: ADDUCIN ISOFORMS IN RBC AND PLATELET DIFFERENTIATION Principal Investigator & Institution: Gilligan, Diana M.; Puget Sound Blood Center 921 Terry Ave Seattle, Wa 98104 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: The goal of this research is to test the hypothesis that the membrane skeleton protein adducin is critical to the assembly of the membrane skeleton during differentiation of erythrocytes and platelets. The membrane skeleton is crucial to the red cell, providing both support and flexibility as cells move rapidly through the circulation and traverse narrow capillaries. Defects in membrane skeleton proteins cause mild to severe hemolytic anemia and even hydrops fetalis. Inherited hemolytic anemia (spherocytosis or elliptocytosis) is one of the most common inherited diseases. The membrane skeleton is also crucial to normal platelet function. The following specific aims are designed to analyze adducin's role in both erythrocyte and platelet differentiation and function: I. Determine the role of alternatively spliced adducins in erythrocyte differentiation a. complete the analysis of adducin expression patterns during normal human and mouse erythroid differentiation. b. elucidate the role of adducin in erythroid differentiation and function in vivo using two approaches: adducin null "knockout" mice and transgenic mice in which an erythroid specific promoter directs antisense mRNA production to block adducin expression. c. perform molecular dissection of the functions of the alternatively spliced isoforms in vivo by using an

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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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erythroid specific promoter to direct overexpression of tagged adducin isoforms (normal or mutant) to compete with normal adducin function in transgenic mice or to rescue knockout mice. II. Determine adducin's role in megakaryocyte differentiation and platelet function a. determine adducin expression patterns in mature platelets versus megakaryocytes b. determine the role of adducin in activation and aggregation of platelets c. elucidate the role of adducin in megakaryocyte differentiation and platelet function in vivo using two approaches: adducin null "knockout" mice and transgenic mice in which a platelet specific promoter directs antisense mRNA production to block adducin expression. d. perform molecular dissection of the functions of the alternatively spliced isoforms in vivo by using a platelet specific promoter to direct overexpression of tagged adducin isoforms (normal or mutant) to compete with normal adducin function in transgenic mice or to rescue knockout mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLINICAL DYSREGULATION

STUDIES

OF

MIDDLE

EAR

PRESSURE

Principal Investigator & Institution: Swarts, J Douglas.; Children's Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 152132583

Hosp

Timing: Fiscal Year 2002 Summary: Clinical and experimental evidences show that disruption of the mechanism for middle ear (ME) pressure regulation is associated with pathophysiological changes including the development of significant under- pressures and mucosal inflammation that if prolonged results in otitis media with effusion (OME). Adequate regulation of ME pressure requires that the intermittent transient openings of the Eustachian tube (ET) provide a sufficient quantity of gas to balance the net glasses associated with the gradient driven exchange between the ME and blood. Poor ET function causes ME under-pressures and OME by the hydrops ex vacuo mechanism, the validity of which has been convincingly demonstrated in experiments conducted under this program. Indeed, treatments for OME that bypass the ET to supply the ME with gas were shown in clinical trials to promote disease resolution. ET function tests in children and adults with concurrent diseases that predispose them to OME show changes in intraluminal congestion that present as a decreased efficiency of the muscular assisted mechanism of tubal dilation. Other studies in children "t risk" for OME and with concomitant OME, show a primary impairment of the active mechanism for tubal openings. However, the prognostic value of ET function tests with respect to disease course is limited, provoking controversy as to the role of ET dysfunction in the pathogenesis of OME. Recent studies conducted under this program show that the discordance between disease progression and test results may be explained by the failure of current test protocols to assess concurrently the functional demand placed upon the ET by the varying rates of transmucosal gas exchange. The overall objective of this project is to develop clinically applicable tests for ME pressure regulation that assess simultaneously these demand and supply functions. Also evaluated is the effect of measured test parameters associated with mucosal healing. Because histopathological studies cannot demonstrate an anatomic basis for poor ET function, new MRI imaging techniques will be used in an attempt to relate in vivo ET structure and function. The goals of this project are to develop a better understanding of ME pressure-dysregulation in the pathogenesis of OME, to evaluate the prognostic value of newly developed test protocols for assessing that function, to identify the underlying cause(s) of ET dysfunction, and to utilize this knowledge in suggesting new treatment strategies for OME. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Hydrops

Project Title: COCHLEAR AND VESTIBULAR ION TRANSPORT Principal Investigator & Institution: Marcus, Daniel C.; Professor; Anatomy and Physiology; Kansas State University 2 Fairchild Hall Manhattan, Ks 665061103 Timing: Fiscal Year 2002; Project Start 01-JUL-1983; Project End 31-DEC-2004 Summary: (provided by applicant): Meniere?s Disease is one of the pathological entities characterized by endolymphatic hydrops of the cochlear and vestibular labyrinths. Hydrops can result from an alteration of ion transport properties of the epithelial cells bordering the endolymphatic system. Little is known about the cellular basis of the pathologic processes involved because data are lacking from normal as well as pathological systems concerning active and passive mechanisms of secretion and absorption of ions. Endolymph is unique in that it is the only extracellular fluid in the body with a high potassium (K+) concentration and low sodium (Na+) and calcium (Ca2+) concentrations. It is proposed to study the ion transport processes responsible for fluxes of K+, Na+ and Ca2+ in the vestibular labyrinth and cochlea, specifically vestibular dark cells (VDC) and strial marginal cells (SMC), by further utilization of electrophysiologic techniques and in vitro preparations developed in this laboratory. Specific goals to be addressed by the proposed studies include determining a) the generator of endocochlear potential (EP) and cellular signaling pathways controlling K+ secretion by stria vascularis; b) cellular pathways mediating Ca2+ secretion and absorption; c) cellular pathways mediating control of Na+ and K+ absorption; and d) cellular pathways mediating control of Cl and HCO3 secretion and absorption. Specific parameters to be measured include transepithelial voltage and resistance with the micro-Ussing chamber, transepithelial fluxes of K+, Cl- and Ca2+ with ion- selective vibrating probes, and electrical properties of cell membranes with several configurations of the patch clamp technique. The completion of this project will further our understanding of the processes controlling secretion and absorption of medicallyimportant ions in the inner ear and may provide a foundation for the pharmacological management of inner ear disorders such as genetically-based syndromes and Meniere?s disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COCHLEAR BLOOD FLOW AND NEUROPEPTIDES Principal Investigator & Institution: Nuttall, Alfred L.; Professor; Otolaryngology Head & Neck Surgery; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 30-SEP-1995; Project End 31-JUL-2004 Summary: The migraine related inner ear symptoms for phonopobia , tinnitus, hearing fluctuation, hearing loss, and increased noise sensitivity provide evidence for a possible neurological substrate connecting basilar artery migraine and cochlear pathophysiological mechanisms. Recently we have identified a previously unreported sensory innervation of the cochlear blood vessels originating from the trigeminal ganglia. We have shown that this sensory innervation has a significant effect on cochlear blood flow (CBF) in both normal and pathological conditions (e.g., in the animal model of endolymphatic hydrops, one of the symptoms of Meniere's disease). This proposal seeks to further define the anatomical basis and mechanisms of the trigemino-sensory network around the vertebrovasilar and cochlear vascular system. The proposal offers the hypothesis that the trigemino-sensory system and its related neuropeptide system are important factors contributing to basilar migraine and vascular homeostasis of the cochlea. The study has three specific aims. Aim 1. To establish if there is a physiological basis for the cochlear symptoms in basilar artery migraine headache. Positive results

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7

will confirm a common functional basis for basilar migraine and cochlear symptoms, the basis could be neurogenic inflammation. Aim 2. To demonstrate if vanilloid receptor (VR1) and substance P (SP) are co-localized around cochlear blood vessels, the basilar artery and its related branches. Positive immunocytochemical results will demonstrate: (a) network of the VR1 and (b) SP co-labeled primary sensory neurons around the basilar artery; anterior inferior cerebellar artery (AICA), spiral modiolar artery (SMA) and radial artery; (c), Capsaicin will cause a significant reduction in the density of labeled sensory fibers. Aim 3. To determine the vasoregulatory disturbance of the trigemino-sensory neurons in endolymphatic hydrops. In this study positive results will demonstrate that endolymphatic hydrops causes a reduction in the stimulated trigeminal ganglion induced CBF change. The studies of the proposal will help clarify how trigemino-sensory neurons regulate the vertebro-basilar vascular system and cochlear fluid balance under normal and pathological conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FOXC2 IN HEREDITARY LYMPHEDEMA AND LYMPHATIC DEVELOPMENT Principal Investigator & Institution: Glover, Thomas W.; Professor; Human Genetics; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-APR-2006 Summary: (provided by applicant): The hereditary lymphedemas are developmental disorders of the lymphatic system that lead to disfiguring and often disabling edema (swelling) of the extremities together with various associated abnormalities. Most are autosomal dominant with variable expression and age of onset. The primary target tissue in these conditions is the lymphatic system, a poorly understood component of the vascular system responsible for microcirculation of fluids drained from tissues and the return to the blood vascular system, and for trafficking cells of the immune system. Despite its importance in congenital and acquired disease, including cancer, very little is known about the molecular events involved in development of the lymphatic system. As with many other developmental pathways, genes involved in hereditary lymphedema can provide important insights into the molecular events Involved in lymphangiogenesis. We recently identified the gene responsible for hereditary lymphedema-distichiasis (LD). This disorder is characterized by lymphedema and extra rows of eyelashes arising from the Meibomian glands. Associated abnormalities include tetralogy of Fallot, cleft palate, hydrops fetalis and cystic hygroma. The gene responsible for LD is the FOXC2 forkhead family transcription factor. The overall goals of this project are to determine the role of FOXC2 in hereditary lymphedema and in the development of the mammalian lymphatic system. Preliminary data indicates that Foxc2+/- mice have highly abnormal lymphatic vessels and lymph nodes analogous to those in patient's with LD. Specific aims are: (1) to fully characterize Foxc2 +/- and -/mice, and transgenic mice overexpressing the gene, for lymphatic abnormalities as a model system for lymphedema-distichiasis and abnormal lymphatic development in mammals; (2) to determine the expression patterns of Foxc2 in the lymphatic system during development to begin to assess the mechanism of Foxc2 insufficiency on lymphatic phenotype and development; (3) to begin to establish the role of Foxc2 in the pathways and hierarchy of genes controlling lymphangiogenesis in mammals; (4) to assess the timing of Foxc2 deficiency in lymphatic and other abnormalities by creating mice in which Foxc2 is conditionally expressed during development. From these studies we will learn the precise defects in the developing mouse lymphatic system caused by

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Foxc2 deficiency, whether Foxc2 expression in lymphatic or other cell types is correlated with these defects, the timing of Foxc2 insufficiency on phenotype, and will begin to determine the role of Foxc2 in the complex biochemical pathways involved in lymphangiogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INNER EAR FLUID INTERACTIONS Principal Investigator & Institution: Salt, Alec N.; Professor; Otolaryngology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-JAN-1992; Project End 28-FEB-2005 Summary: (Adapted from the Investigator's Abstract) Cochlear fluid disturbances are a major facto in a number of pathologies affecting the inner ear, such as Meniere's disease. The goal of our studies is to provide a scientific basis for the diagnosis and treatment of endolymph volume disturbances. A direct approach is used, based on sensitive techniques, which measure endolymph volume and flow in vivo. Using these measures, we will establish a number of methods, which influence endolymph volume, including infrasonic, and low frequency tones and pressure pulses delivered to the cochlear fluids or ear canal. Ossicular movements induced by some of these stimuli are comparable to those induced by middle middle muscle contractions which have been shown to generate endolymph movements. Mechanisms underlying volume disturbance and those contributing to volume recovery will be investigated. During volume manipulations, indirect methods for quatifying endolymph volume changes will be correlated with direct measurements of endolymphatic cross-sectional area. These studies will lead to improved diagnostic tests for endolymphatic hydrops. A second project will examine physiologic changes occurring in the endolymphatic sac during manipulations of endolymph volume in the cochlea. The magnitude and time course of electrolyte changes in the sac will be measured during disturbances. The time course and spatial distribution of induced anatomical changes of the sac will be documented and quantified using 3-D magnetic resonance microscopy, light and electron microscopy. The functional role played by the endolymphatic sac will be incorporated into quantitative mathematical models of solute dispersion in the inner ear. These studies will identify possible mechanisms by which the sac regulates endolymph volume and will lead to more sophisticated methods for treating endolymph volume disturbances. They will also direct future studies to the tissues and processes underlying specific aspects of volume regulation. The project as a whole will establish the fundamental physiological processes contributing to endolymph volume regulation and will have relevance to the clinical diagnosis and treatment of cochlear fluid disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISM-BASED MEASURES OF OTOLOGIC PATHOLOGY Principal Investigator & Institution: Don, Manuel; Professor; House Ear Institute Los Angeles, Ca 90057 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Adapted from the Investigator's Abstract) The project's long-term goal is to understand the effects of otologic pathology on mechanisms underlying human cochlear and brainstem processes. It proposes a mechanism-based approach that will provide (1) critical neuro-patho-physiological information, and (2) a scientific framework for early diagnoses of difficult-to-identify otologic diseases. In this approach, it uses newlydeveloped non-invasive measures of the auditory brainstem response (ABR) to

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investigate known and hypothesized pathological changes in the mechanisms underlying specific processes in the peripheral auditory system caused by small acoustic tumors and Meniere's disease. The specific aims are (1) to demonstrate that small (