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Y. Touitou E. Haus (Eds.)
Biologic Rhythms
in Clinical and Laboratory Medicine
With 347 Figures and 54 Tables
Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest
YVAN TOUITOU
Professor of Biochemistry Faculte de Medecine Pitie-Salpetriere Laboratoire de Biochimie Medicale 91, Boulevard de l'Hopital 75634 Paris Cedex 13, France
ERHARDHAUS
Professor, Department of Laboratory Medicine and Pathology University of Minnesota Chairman, Department of Anatomic and Clinical Pathology St.Paul-Ramsey Medical Center 640 Jackson Street St. Paul, MN 55101-259, USA
Cover picture: Sculpture by Arman, gare Saint-Lazare, Paris
ISBN-13: 978-3-642-78736-2 e-ISBN-13:978-3-642-78734-8
DOI:10.1007/978-3-642-78734-8
Library of Congress Cataloging-in-Publication Data Biologic rhythms in clinical and laboratory medicine / Y. Touitou, E.Haus (eds.). Includes bibliographical references and index.
ISBN 3-540-54461-5 (alk. paper) ISBN 0-387-54461-5 (alk. paper)
1. Clinical chronobiology. 2. Biological rhythms. I. Touitou, Yvan. II. Haus, Erhard. [DNLM: 1. Chronobio!ogy. 2. Circadian Rhythm--physio!ogy. QT 167 B6148j RB148.B55 1992 612 .022--dc20 DNLMlDLC
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer Verlag. Violations are liable for prosecution under the German Copyright Law.
© Springer-Verlag Berlin Heidelberg 1992
Softcover reprint ofthe hardcover 1st edition 1992
The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature.
Production Editor: Isolde Scherich Reproduction of the figures: Gustav Dreher GmbH, Stuttgart Typesetting, printing, and binding: Appl, Wemding 27/3145 - 5 4 3 2 1 0 - Printed on acid-free paper
Foreword
With the help of our European and American colleagues and friends, we have been able to prepare this book on Biologic Rhythms in Clinical and Laboratory Medicine, which includes 20 parts consisting of 47 chapters on different aspects of chronobiology and medicine.
Parts I and II present six chapters on the basic concepts and the mechanisms of biologic rhythms, followed in Part III by a review of the appropriate methodology for their study. Part IV summarizes the large amount of data accumulated on the time-dependent changes in drug effects and side effects and in toxicology. Part V presents in four chapters observations on biologic rhythms beginning in pregnancy and extending through childhood and development to old age. Part VI is dedicated to the rhythms in physical and mental performance and is followed in Part VII by the study of the adaptation of these rhythms during shiftwork and after transmeridian flights. In Part VIII is presented the physiology and pathophysiology of sleep. Parts IX-XIX discuss biologic rhythms in different organ systems in health and disease, including aspects of physiology, pharmacology, and toxicology. The clinically important rhythm alterations found in certain psychiatric conditions, i. e., in affective disorders are presented in Part IX. The eight chapters in Part X are dedicated to the rhythms of multiple frequencies found in endocrine and metabolic functions. In Part XI, the biologic rhythms in hepatic drug metabolism are discussed which determine, in part, circadian and other variations in drug effects. Part XII describes the rhythmicity of the gastrointestinal system with its implications for ulcerogenesis and timed treatment. In Part XIII are discussed rhythms of the cardiovascular system, including hypertension, and in Part XIV rhythms in the respiratory system with the clinically important application to the treatment of bronchial asthma. Part XV presents rhythms in renal function and pathology. The chronobiology of the inflammatory reaction is presented in Part XVI. Biologic rhythms in hematology and immunology are presented in Part XVII and include, in addition to the large-amplitude rhythms of some of the formed elements in the peripheral blood, new data on the rhythmicity of the human bone marrow, which will be of considerable importance for the effects and/or side effects of the numerous drugs and other agents acting upon this complex and vital tissue. This part also includes observations on biologic rhythms in cell migration, in the immune response, and of the blood coagulation system with its implications for transient risk states for thrombosis or hemorrhage. Part XVIII presents first basic data on rhythms in normal and abnormal cell proliferation, then the endocrine regulations related to the cancerogenesis in endocrine responsive tissues, i. e., the breast, the rhythms in the appearance of tumor markers in the circulation, possibly representing periodic variations in tumor metabolism and, finally, the opportunities provided by the rhythms of host and tumor to optimize chemotherapy by treatment timed according to the biologic rhythms of the host and/or the tumor. Epidemiologic aspects of chronobiology are presented in
VI Foreword
Part XIX in regard to physiologic events like birth and to chronopathology and death from numerous causes. Finally, the implication of biologic rhythms for laboratory medicine are discussed in Part XX including time-qualified reference values for high-amplitude rhythms and the tools to improve laboratory diagnosis by taking into account the principles of chronobiology.
In all these chapters, our purpose is to present to the reader, whether experienced in chronobiology or not, a general review of the role of biologic rhythms in the normal and abnormal function of different organ systems.
Each of the contributors is a known specialist in his or her field, and we would like to express our great appreciation for their participation in this didactic teamwork. We hope that this book will interest the readers who wish to extend their familiarity with chronobiology and will provide the investigators in the study of biologic rhythms a general overview of the field.
March 1992 Yvan Touitou, Paris Erhard Haus, St. Paul
Contents
Part I Bask Concepts
Biologic Rhythms from Biblical to Modern Times. A Preface Y. TOUITOU and E. HAUS
Principles of Clinical Chronobiology E. HAus and Y. TOUITOU
Part II Mechanisms of Rhythms
Cellular and Molecular Aspects of Circadian Oscillators: Models and Mechanisms for Biological Timekeeping . L.N. EDMUNDS, Jr.
The Suprachiasmatic Nucleus and Other Pacemakers. W.J.RIETVELD
Molecular and Genetic Aspects of Chronobiology D. J. LAKATUA
Seasonal and Daily Control of Enzyme Synthesis and Activity by Circadian Clocks . . . . . . . . . O. QUEIROZ and C. QUEIROZ-CLARET
Part III Data Processing
Data Processing in Chronobiological Studies. J.DE PRINS and B.HECQUET
Part rv Pbarmacology and Toxicology
Chronopharmacology . B. BRUGUEROLLE
1
6
35
55
65
78
90
114
VIII Contents
Chronotoxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 138 J.CAMBAR, B.L'Azou, and J. C. CAL
Rhythms in Drug-Induced Teratogenesis . . . . . . . . . . . . . . . . . . .. 151 I. SAUERBIER
Part hiJd De elopment and ging
Chronobiology of Pregnancy and the Perinatal Time Span . . . . . . . . .. 158 P.J.MEIS
Patterns of Growth Hormone Release During Childhood and Adolescent Development in the Human . . . . . . . . . . . . . . . . .. 167 A.D. ROGOL
Rhythms in Biochemical Variables Related to Bone and Their Regulating Hormones . . . . . . . . . . . . . . . . . . . . . . . .. 179 M. E . MARKOWITZ
Biological Rhythms and Aging . . . . . . . . . . . . . . . . . . . . . . . . .. 188 Y. TOUITOU and E . HAus
Part I Phy ical and Mental P nonnan
Chronobiology of Mental Performance . . . . . . . . . . . . . . . . . . . .. 208 T. H. MONK
Biological, Behavioral and Intellectual Activity Rhythms of the Child During Its Development in Different Educational Environments . .. 214 H. MONTAGNER, G . DE ROQUEFEUIL, and M. DJAKOVIC
Chronobiology of Physical Performance and Sports Medicine . . . . .. 230 C.M. WINGET, M. R. I. SOLIMAN, D.C.HoLLEY, and J.S.MEYLOR
Part VB hift Work and Transmeridian Flight
Night and Shift Work and Transmeridian and Space Flights ......... 243 A. E. REINBERG and M. H. SMOLENSKY
Part 1Il I P
Chronobiology of Human Sleep and Sleep Disorders . . . . . . . . . . . .. 256 B. HAYES and C. A. CZEISLER
Contents IX
Part IX Psychiatry
The Complex Circadian Pacemaker in Affective Disorders . ... .. ... 265 D.F.KRIPKE, M.D.DRENNAN, and J. A ELLIOTT
Part X Endoaine and Metabolic Functio
Rhythmic and Non-Rhythmic Modes of Anterior Pituitary Hormone Release in Man . . . . . . . . . . . . . . .. 277 J.D. VELDHUlS, M.L.JOHNSON, AIRANMANESH, and G.LIZARRALDE
Chronobiology of the Hypothalamic-Pituitary-Adrenal and Renin-Angiotensin-Aldosterone Systems . . . . . . . . . . . . . . . .. 292 A ANGELI, G. GATTI, and R. MASERA
Chronobiology of the Hypothalamic-Pituitary-Gonadal Axis in Men and Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 C. H. BLOMQUIST and J. P. HOLT, Jr.
Chronobiology of the Hypothalamic-Pituitary-Thyroid Axis . . . . . . . .. 330 G. Y. NICOLAU and E. HAUS
The Pineal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 348 J.ARENDT
Chronobiology of Endocrine-Immune Interactions . . . . . . . . . . . . .. 363 G. GATTI, A ANGELI, and R. CARIGNOLA
Chronobiology, Nutrition, and Diabetes Mellitus . . . . . . . . . . . . . .. 375 L. MEJEAN, M. KOLOPP, and P. DROUIN
Endocrine and Neuroendocrine Axis Testing in Clinical Medicine: Evidence for Time Dependency. . . . . . . . . . . .. 386 Y. TOUITOU and A. BOGDAN
Part XI Hepatobiliary System
Biological Rhythms in Hepatic Drug Metabolism and Biliary Systems . .. 403 P.M. BELANGER and G.LABRECQUE
Part XII Gastroinl linal System
Chronobiology of the Gastrointestinal System . . . . . . . . . . . . . . . .. 410 J.G.MOORE
X Contents
Part XIII ardiova ular y tern
Cardiovascular Chronobiology and Chronopharrnacology . . . . . . . . .. 418 B.LEMMER
Chronobiologic Blood Pressure Assessment from Womb to Tomb. . . . . . 428 G.CORNELISSEN, E.HAUS, and F.HALBERG
Part xr Re piratory y tern
Nocturnal Asthma: Mechanisms and Chronotherapy . . . . . . . . . . . .. 453 M.H.SMOLENSKY and G.E.D'ALONZO
Part V Renal Phy iology and Pathology
Renal Excretion: Rhythms in Physiology and Pathology .. . . . . . . . .. 470 J. CAMBAR, J. C. CAL, and J. TRANCHOT
Part VI Inflammatory Reaction
Inflammatory Reaction and Disease States . . . . . . . . . . . . . . . . . .. 483 G.LABRECQuE
Part II Immunolo and Hematolo
Chronobiology of Immune Functions: Cellular and Humoral Aspects. . .. 493 G.FERNANDEs
Chronobiology of Circulating Blood Cells and Platelets. . . . . . . . . . .. 504 E . HAus
Chronobiology of Human Bone Marrow . . . . . . . . . . . . . . . . . . .. 527 R.SMAALAND and O.D.LAERVM
Chronobiology of Polymorphonuclear Leukocyte Migration . . . . . . . . . 547 J.P.BuREAu and L.GARRELLY
Chronobiology in Hemostastis . . . . . . . . . . . . . . . . . . . . . . . . . . 555 H .DECOUSUS
Contents XI
Part XVIII Cell Proliferation and Cancer
Normal and Abnormal Cell Proliferation in Mice Especially as It Relates to Cancer . . . . . . . . . . . . . . . . . .. 566 L. E. SCHEVING, T. -H. TSAI, L. A. SCHEVING, R. J. FEVERS, and E. L. KANABROCKI
Chronobiology of Endocrine and Endocrine-Responsive Tumors. . . . .. 600 R. VON ROEMELlNG
Chronochemotherapy of Malignant Tumors: Temporal Aspects of Antineoplastic Drug Toxicity . . . . . . . . . . . . .. 611 W.J.M.HRvsHESKY and W.J.MARz
Immune System in Relation to Cancer . . . . . . . . . . . . . . . . . . . . . 635 C. CANON and F. LEVI
Rhythms in Tumor Markers . . . . . . . . . . . . . . . . . . . . . . . . . .. 648 Y. TOVITOV and C. FOCAN
Part XIX Epidemiology
Chronoepidemiology: Chronobiology and Epidemiology. . . . . . . . . .. 658 M. H. SMOLENSKY
Part XX Laboratory Medicine
Chronobiology in Laboratory Medicine .................... 673 E. HAVS and Y. TOVITOV
Glossary ... . 709
Subject Index . 713
Contributors
ANGELI,A.
Cattedra di Medicina Intema, Universita degli Studi di Torino, Divisione di Clinica Medica Generale, Ospedale San Luigi Gonzaga, 10043 Orbassano, Italy
ARENDT,J.
Department of Biochemistry, University of Surrey, Guilford Surrey GU2 5XH, Great Britain
BELANGER, P. M. Universite Laval, Ecole de Pharmacie, Cite Universitaire, Quebec G1K 7P4, Canada
BLOMQUIST, C. H. Department of Obstetrics and Gynecology, Ramsey Clinic, St.Paul-Ramsey Medical Center, 640 Jackson Street, St.Paul, MN 55101, USA
BOGDAN,A.
Faculte de Medecine Pitie-Salpetriere, Laboratoire de Biochimie Medicale, 91 Boulevard de I'H6pital, 75634 Paris Cedex 13, France
BRUGUEROLLE, B. Laboratoire de Pharmacologie Medicale et Clinique, Faculte de Medecine, CHU de la Timone, 27 Boulevard Jean Moulin, 13385 Marseille, France
BUREAU, J. P. CHR de Nimes, Laboratoire de Cytologie Clinique et Cytogenetique, Faculte de Medecine, Avenue Kennedy, 30000 Nimes, France
CAL,J.C. Groupe d'Etude de Physiologie et Physiopathologie Renales, Faculte de Medecine, 91 rue Leyteire, 33000 Bordeaux, France
CAMBAR,J.
Groupe d'Etude de Physiologie et Physiopathologie Renales, Faculte de Medecine, 91 rue Leyteire, 33000 Bordeaux, France
CANON,C.
I.C.I.G., Service des Maladies Sanguine et Tumorales, H6pital Paul Brousse, 14-16 Avenue Paul Vaillant Couturier, 94800 Villejuif, France
XIV Contributors
CARIGNOLA, R. Cattedra di Medicina Interna, Universita degli Studi di Torino, Divisione di Clinica Medica Generale, Ospedale San Luigi Gonzaga, 10043 Orbassano, Italy
CORNELISSEN, G.
Chronobiology Laboratories, University of Minnesota, Minneapolis, MN, USA
CZEISLER, C. A.
Harvard Medical School, Neuroendocrinology Laboratory, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA
D'ALONZO, G.E.
School of Public Health, University of Texas, P. O. Box 20186, Astrodome Station East 442, Houston, TX 77025, USA
DECOVSVS, H. Service de Medecine Interne et TMrapeutique, H6pital de Bellevue, 42023 Saint-Etienne, France
DE PRINS, J. Stanley 7, 3080 Tervuren, Belgium
DJAKOVIC, M.
Unite 70 INSERM, 388 rue du Mas de Prunet, 34070 Montpellier, France
DRENNAN, M.D.
Department of Psychiatry, Veterans Administration Hospital, 3350 La Jolla Village Drive, San Diego, CA 92161, USA
DROUIN, P. Universite de Nancy, Departement de Nutrition et des Maladies Metaboliques, INSERM U 59, 40 rue Lionnois, 54000 Nancy, France
EDMUNDS, L.N., Jr. Division of Biological Sciences, Life Sci Bldg 370, State University of New York, Stony Brook, New York 11794, USA
ELLIOTI, J. A. Department of Psychiatry, Veterans Administration Hospital, 3350 La Jolla Village Drive, San Diego, CA 92161, USA
FERNANDES, G.
University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7874, USA
FEVERS, R.J. Division of Genetic Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA
FOCAN,C.
Service de Medecine interne, Clinique St. Joseph - Ste. Elisabeth, Liege, Belgique
Contributors XV
GARRELLY, L. CHR de Nimes, Laboratoire de Cytologie Clinique et Cytogenetique, Faculte de Medecine, Avenue Kennedy, 30000 Nimes, France
GAITI, G. Cattedra di Medicina Interna, Universita degli Studi di Torino, Divisione di Clinic a Medica Generale, Ospedale San Luigi Gonzaga, 10043 Orbassano, Italy
HALBERG,F. 5-197 Lyons Lab, University of Minnesota, 420 Washington Avenue S. E., Minneapolis, MN 55455, USA
HAus,E. St. Paul-Ramsey Medical Center, Department of Anatomic and Clinical Pathology, 640 Jackson Street, St. Paul, MN 55101, USA
HAYES,B. Harvard Medical School, Neuroendocrinology Laboratory, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA
HECQUET, B. Centre Oscar Lambret, B.P. 307,59020 Lille, France
HOLLEY, D. C. Biomedical Research Division, 240 A-3, NASA/Ames Research Center, Moffett Field, CA 94035, USA
HOLT, J.P', Jr. Reproductive Endocrinology, St.Paul-Ramsey Medical Center, Ramsey Clinic, 640 Jackson Street, St.Paul, MN 55101, USA
HRUSHESKY, W.J.M. Division of Oncology, 47 New Scotland Avenue, Albany Medical College, State University of New York, MSX-30 Albany, NY 12208, USA
IRANMANESH, A. Division of Endocrinology and Metabolism, Department of Internal Medicine, Salem Veterans Administration Hospital, Salem, Virgina 24153, USA
JOHNSON, M.L. Division of Endocrinology and Metabolism, Department of Internal Medicine, Box 202, Health Sciences Center, University of Virginia, Charlottesville, VI, 22908, USA
KANABROCKI, E. L. Nuclear Medicine Service, Veterans Administration Hospital, Hines, Illinois 60141, USA
KOLOPp,M. Universite de Nancy, Departement de Nutrition et des Maladies Metaboliques, INSERM U 59, 40 rue Lionnois, 54000 Nancy, France
XVI Contributors
KRIPKE, D.E Department of Psychiatry, Veterans Administration Hospital, 3350 La Jolla Village Drive, San Diego, CA 92161, USA
L'Azou,B. Groupe d'Etude de Physiologie et Physiopathologie Renales, Faculte de Medecine, 91 rue Leyteire, 33000 Bordeaux, France
LABRECQUE,G. Ecole de Pharmacie, Universite Laval, Pavillon Vachon, Quebec G1K 7P4, Canada
LAERUM,O.D. Department of Oncology, Haukeland Hospital, University of Bergen, 5021 Bergen, Norway
LAKATUA, D.J. Department of Laboratory Medicine and Clinical Pathology, St. Paul-Ramsey Medical Center, 640 Jackson Street, St.Paul, MN 55101, USA
LEMMER,B. Klinikum der Johann-Wolfgang-Goethe-UniversiHit, Theodor-Stern-Kai 7, 6000 Frankfurt 70, Federal Republic of Germany
LEVI, E I. c.1. G., Service des Maladies Sanguines et Tumorales, Hopital Paul Brousse, 14-16 Avenue Paul Vaillant Couturier, 94800 Villejuif, France
LIZARRALDE, G. Division of Endocrinology and Metabolism, Department of Internal Medicine, Salem Veterans Administration Hospital, Salem, Virgina 24153, USA
MARKOWITZ, M.E. Department of Pediatrics Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USA
MARZ, w.J. Division of Oncology, 47 New Scotland Avenue, Albany Medical College, State University of New York, MSX-30 Albany, NY 12208, USA
MASERA,R. Cattedra di Medicina Interna, Universita degli Studi di Torino, . Divisione di Clinica Medica Generale, Ospedale San Luigi Gonzaga, 10043 Orbassano, Italy
MEIS, P.J. Department of Obstetrics, Bowman Gray School of Medicine, 300 South Hawthorne Road, Winston Salem, NC 27103, USA
MEJEAN,L. Universite de Nancy, Departement de Nutrition et des Maladies Metaboliques, INSERM U 59, 40 rue Lionnois, 54000 Nancy, France
Contributors XVII
MEYLOR, J. S:
Biomedical Research Division, 240 A-3, NASA/Ames Research Center, Moffett Field, CA 94035, USA
MONK, T.H. Western Psychiatric Institute and Clinic, University of Pittsburg, Pittsburg, PA, USA
MONTAGNER, H. Unite 70 INSERM, 388 rue du Mas de Prunet, 34070 Montpellier, France
MooRE,J.G.
Utah School of Medicine, GI Section, Department of Veterans Affairs Medical Center, 500 Foothill Blvd., Salt Lake City, Utah 84148, USA
NICOLAU, G. Y. Endocrine Rhythms Laboratory, The "c. I. Parhon" Institute of Endocrinology, Bd. Aviatorilor 34-36, 79600 Bucharest, Romania
QUEIROZ, O. 5 avenue des Bouvreuils, 78720 Cernay La Ville, France
QUEIROZ-CLARET, C. Institut National Agronomique Paris-Grignon, Chaire de Biochimie, 78850 Thiverval Grignon, France
REINBERG, A. E. URA 58 1 CNRS, Chronobiologie et Chronopharmacologie, Fondation A. de Rothschild, 29 rue Manin, 75940 Paris, France
RIETVELD, W.J.
Department of Chronobiology, University of Leiden, Wassenaarseweg 62, 2333 AL Leiden, The Netherlands
VON ROEMELING, R. Division of Medical Oncology, 47 New Scotland Avenue, Albany Medical College, State University of New York, MSX-30 Albany, NY 12208, USA
ROGOL, A.D. Department of Pediatrics, Box 386, University of Virginia, Health Sciences Center, Charlottesville, VI 22908, USA
DE ROQUEFEUIL, G.
Unite 70 INSERM, 388 rue du Mas de Prunet, 34070 Montpellier, France
SAUERBIER, I. Institut fUr Anatomie, Medizinische Hochschule Hannover, Konstanty-Gutschow-StraBe 8, 3000 Hannover 61, Federal Republic of Germany
SCHEVING, L.A. Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
XVIII Contributors
SCHEVING, L. E. University of Arkansas for Medical Sciences, Department of Anatomy, Slot 510, 4301 W. Markham, Little Rock, AR 72201, USA
SMAALAND, R. The Gade Institute, Department of Pathology, Haukeland Hospital, University of Bergen, 5021 Bergen, Norway
SMOLENSKY, M. H. School of Public Health, University of Texas, P. O. Box 20186, Astrodome Station East 442, Houston, TX 77025, USA
SOLIMAN, M. R. I. Biomedical Research Division, 240 A-3, NASA/Ames Research Center, Moffett Field, CA 94035, USA
TOUITOU, Y. Faculte de Mectecine Pitie-Salpetriere, Laboratoire de Biochimie Medicale, 91 Boulevard de l'Hopital, 75634 Paris Cedex 13, France
TRANCHOT, J. Groupe d'Etude de Physiologie et Physiopathologie Renales, Faculte de Medecine, 91 rue Leyteire, 33000 Bordeaux, France
TSAI, T.-H.
University of Arkansas for Medical Sciences, Department of Anatomy, Slot 510, 4301 W. Markham, Little Rock, AR 72201, USA
VELDHUIS, J.D. Division of Endocrinology and Metabolism, Department of Internal Medicine, Box 202, Health Sciences Center, University of Virginia, Charlottesville, VI, 22908, USA
WINGET, C. M. Biomedical Research Division, 240 A-3, NASA/Ames Research Center, Moffett Field, CA 94035, USA
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