The aimoftheHypospadiasand Genital Symposium, held at theUniversityof California,SanFrancisco,wastoprovideaforumforauthoritativeinvestigatorswhoare activelyinvolvedinthevariousdisciplineswhichdefinetheleadingedgesofhypospadias and genital research. It is important for such investigators to continue to meet for the purpose of discussing the latest developments in their individual fields, to analyze the significanceofcurrent research, to discuss new tactics for unresolved problems and to develop new theories andapproaches asneeded. The two day conference on hypospadiasandgenitaldevelopment research was organizedintothreesections: 1)HumanStudies;2)MechanismofGenitalDevelopment; and 3) Endocrine Disruptors and Sexual Dimorphism in the Animal Kingdom. Each sessionwasintroducedbyanexpertmoderatorfollowedtheinvitedspeakerswithtimefor extensiveinteractionbetweeninvestigators. Thisbookdocumentstheproceedingsofthe HypospadiasandGenitalDevelopmentSymposium. Iwould especially like to thank Kari Gaudette for editorial assistants, Cynthia Ashe, Selcuk Yucel, Antonio Souza and the administrative staffinthe Departmentof Urology. Ihopeyoufindthisresourceuseful. Laurence S. Baskin,M. D. ProgramChair ChiefPediatricUrology UCSF vii ACKNOWLEDGEMENTS Supportforthissymposiumisgratefullyacknowledged TheNationalInstituteofHealthGrant#R13DK*HDS997 UCSFDepartmentofUrology AmericanUrologicAssociation CONTENTS Introduction...1 SECTIONI. HUMANSTUDIES EpidemiologyofHypospadias...*...*...25 J. DavidErickson EndocrineEvaluationofHypospadias...31 G. HyunandT. Kolon EndocrineAbnormalitiesinBoyswithHypospadias...45 R. I. Silver GeneticandClinicalStudiesonHypospadias...***...**...*...73 A. Nordenskjold SECTIONII. MECHANISMOFGENITALDEVELOPMENT DevelopmentofthePenileUrethra. . 87 G. CunhaandL. Baskin AnatomicalStudiesoftheMouseGenitalTubercle...103 L. Baskin,W. Liu,J. Bastacky,andS. Yucel AnatomicalStudiesoftheFibroblastGrowthFactor-l0Mutant,Sonic HedgeHogMutant,andAndrogenReceptorMutantMouseGenital Tubercle...*. **. . 123 S. Yllcel,W. Liu,DCordero,A. Donjacour,G. Cunha,andL. Baskin DevelopmentalGeneticsofHypospadias...149 M. Cohn xiii xiv Contents DevelopmentoftheMouseExternalGenitalia: UniqueModelof Organogenesis...159 K. Suzuki, K. Shiota,Y. Zhang,L. Lei,andG. Yamada NewConceptsontheDevelopmentoCtheVagina...173 E. Shapiro. H. Huang,andX. R. Wu SECTIONIII. ENDOCRINEDISRUPTORSANDSEXUAL DIMORPHISMINTHEANIMALKINGDOM EndocrineDisruptionOverview: AreMalesatRisk? 189 T. Colburn EndocrineDisruptionandHypospadias...203 G. Steinhardt Toxicant-InducedHypospadiasintheMaleRat * 217 L. E. Gray. . I. Ostby,J. Fun,C. Wolf,C. Lambright,V. Wilson, and N. Noreiga MasculinizationofFemaleMammals: LessonsfromNature...243 N. J. PI:H'candS. Glickman Index...255 SectionI Introduction HYPOSPADIAS LaurenceS. Baskin* M. D. ,FAAP 1.

The aim of Bladder Research Congress, San Francisco, California, April 23-25, 1998, was to provide a forum for authoritative investigators who are actively involved in the various disciplines which define the leading edges of bladder research. It is important for such investigators to continue to meet regularly for the purpose of discussing the latest developments in their individual fields, to analyze the significance of current research, to discuss new tactics for unresolved problems, to critically evaluate current theories, and to develop new theories and approaches as needed. The two and a half day meeting was organized into five half day sessions, with each session encompassing one of five topics: (1) Epithelial-Mesenchymal Interactions; (2) Ex tracellular Matrix and Muscle; (3) Nerves and Pharmacology; (4) Infection and Immunol ogy; and (5) Oncology. Each session was introduced by a moderator followed by five to six invited expert speakers with time for extensive interaction from the participants. Two late-afternoon poster sessions allowed further interactions between investigators. This book documents the proceedings of the Bladder Research Congress. It is organ ized into the five half-day sessions of the meeting with moderators overview and an edited transcription of discussions that followed each presentation. I would like to thank Sarah Burke and the Office of Continuing Medical Education, USCF; Joanne Hayward, Editorial Assistant; and Miriam Escamilla, Administrative Assis tant. I hope you find this resource useful. Laurence S. Baskin, M.D.

H.P. HIGER 1 In the seventeenth century people dreamed about a machine to get rid of evil spirits and obsessions, which were thought to be the main source of mis fortune and disease. I am not going to question this approach, because in a way it sounds reasonable. They dreamed of a machine that would display im ages from the inner world of men which could be easily identified and named. Somehow these are the roots of MR imaging. Of course, we now view disease from a different point of view but our objectives remain the same, namely to make diseases visible and to try to characterize them in order to cure them. This was the reason for setting up a symposium on tissue characterization. About 300 years later the clinical introduction of MRI has great potential for making this dream come true, and I hope that this symposium has con stituted another step toward its realization. When Damadian published his article in 1971 about differences in T1 relaxation times between healthy and pathological tissues, this was a milestone in tissue characterization. His results initiated intensive research in to MR imaging and tissue parameters. Actually his encouraging discovery was not only the first but also the last for a long time in the field of MR tissue characterization.

Endocrinologic investigations during pregnancy have focused in the last decades on placental hormones, the maternal endocrine system and maternal fetal interactions. Less is known about the fetus itself and the interaction of fetal hormonal response and physiological parameters. In this book physiologists, pediatricians and obstetricians active in experimental studies in both physiology and endocrinology combine both aspects of investigations. Historical remarks on the endocrine development of the fetus are followed by observations of the hormonal control of the cardiovascular system. Basic mechanisms of fetal endocrine control such as brain development, fetal growth, fetal behaviour, and thermoregulation are given particular consideration. Finally, carbohydrate metabolism and the mechanism of parturition are outlined.

The examination of excavated human bone finds is mainly the domain of anthropologists and forensic pathologists, the former working with ancient and historical specimens, the latter with modern finds. The methodological and diagnostic approaches to these skeletal finds are the same, regardless of the time of burial. For physical an thropology, bodily human relics are dealt with as historical resources which give clues to ancient population structure, population develop ment, life-style and subsistence. They are thus able to help scientists understand the present state of human populations. The identification of the finds, whether species diagnosis or the evaluation of individual parameters such as sex, age at death, body size and shape, kinship and pathology follows the same procedure used by forensic patholo gists, whose task is the identification of bodily relics in cases of crime, mass disaster and the like. However, there are other disciplines which benefit from excavated bone finds. Anatomy gains insights into the morphological variability of the skeleton in time and place. The implications for modern physi cians and pathologists are at least two-fold: pathological specimens are suitable to unravel the distribution of many diseases and the susceptibility of individuals to pathogens in pre-antibiotic populations. In addition to this epidemiological aspect, exhumed specimens often exhibit advanced states of bone disease which are no longer or only very rarely present in today's industrialized populations because of efficient surgical intervention and pharmacological treatment."

To preserve tissue by freezing is an ancient concept going back pre sumably to the practice of ice-age hunters. At first glance, it seems as simple as it is attractive: the dynamics of life are frozen in, nothing is added and nothing withdrawn except thermal energy. Thus, the result should be more life-like than after poisoning, tan ning and drying a living cell as we may rudely call the conventional preparation of specimens for electron microscopy. Countless mishaps, however, have taught electron microscopists that cryotechniques too are neither simple nor necessarily more life-like in their outcome. Not too long ago, experts in cryotechniques strictly denied that a cell could truly be vitrified, i.e. that all the solutes and macro molecules could be fixed within non-crystalline, glass-like solid water without the dramatic shifts and segregation effects caused by crystallization. We now know that vitrification is indeed pos sible. Growing insight into the fundamentals of the physics of water and ice, as well as increasing experience of how to cool cells rapidly enough have enlivened the interest in cryofixation and pro duced a wealth of successful applications."

In textbooks on anatomy, radiology and stead of the normal one. An "accessory ar- surgery only the "normal" arterial blood tery" is a second artery ip addition to the one normally present, without any specifi- supply is usually described. This "nor- mality", however, is sometimes found in cation of size being made. However, there less than 30% of all cases for some arteries, is no general agreement on whether minute but in over 95% for others. Rarely men- vessels with very small diameters and hard- tioned are deviations in the individual ar- ly any significant blood flow should also be tery's origin, topographical localization and considered. the area it supplies. They can be classified The aims of this book were twofold: first, to into two groups: malformations and vari- extract the frequency of arterial anomalies from the literature (often published in inac- ations. Malformations often have a nega- tive influence on the function of the organ cessible journals) and second, to classity under normal circumstances, e.g. if both these arteries by schematic outlines of the basic types.

Our knowledge of chromaffin tissue has increased enormously since the last comprehensive treatise in this series was published in 1943, chiefly as a result of the development of new histological methods and technical improve- ments. Less than 40 years have passed since the review by MAX WATZKA, and essentially only 25 years were required to accumulate an abundance of revolu- tionizing findings: it was not until 1957 that the carotid body was first studied successfully with the electron microscope. In 1962 the technique of formalde- hyde-induced fluorescence was introduced, yielding a view of adrenergic struc- tures that was completely new and far better than that obtained with the chro- maffin reaction. Immunohistochemistry made it possible to localize enzymes responsible for catecholamine synthesis and to detect peptide hormones. Autora- diographic techniques were used at the level of the electron microscope, the method of chemical sympathectomy was introduced and still other technical improvements could be mentioned. I myself have been interested in chromaffin cells and sympathetic neurons since 1965, when I entered the Department of Histology, University of Vienna, as a medical student. Therefore I have not followed the developments mentioned above retrospectively, but have actually experienced them. Anyone who experi- ences such a development comes to believe that he is well acquainted with the various results and interpretations and is thus capable of objectivity.

If you want practical information on how to use this book please refer to "Note to the Readers" p. VII. Histochemistry and cytochemistry are essential tools in biomedical research and routine service laboratories. Most texts on histochemistry fall into one of two categories: 1. Encyclopaedic texts covering all or nearly all information available on the whole or selected parts of histochemistry. 2. Reviews or surveys of methods found to be useful by the author(s). While the former category often appeals to the more philosophically inclined reader, direct guidance on the selection of technique may be difficult to find. In contrast, the latter category are often excellent sources for details on how to perform a particular method with a reasonable chance of success. Consideration of the exact mechanism of staining, of possible reasons for failure, and of alternative techniques are, however, frequently lacking. This book is an introduction to the scientific basis of histochemistry and is intended to provide a background for the selection and development of appro priate methods. It is not a "cook book" and readers expecting exhaustive methodological descriptions will be disappointed. Although most ofthe contributors to this book would not describe themselves as histochemists, they have all at some time found it essential to develop a basic understanding of histochemistry. This book contains the information they would have greatly appreciated ready access to at that time."

Both functions of the mammalian ovary, the endocrine and (synthesis and secretion of steroid hormones) and exocrine (production of ova), depend upon the presence and cyclic growth of follicles, as the depletion of primordial follicles from the ovary leads to cessation of these f-unctions or female reproduction in mammals, or to postmenopausal period in humans. Actually, various fertility and sterility problems at the ovarian level are related to follicles. Therefore, a thorough understanding of the biology of ovarian follicles in mammals is of fundamental interest to a wide variety of academic and scientific disciplines. Study of their structure, function, and control involves mor phology, including ultrastructure, cell biology, physiology, endocrinology, biochemis try, immunology, neurobiology and pharmacology. Zoologists take interest in comparative and evolutionary aspects of biology of ovarian follicles in many different groups of mammals. Agricultural scientists and wildlife biologists need a thorough knowledge of the biology of follicles to control more effectively fecundity in domestic animals and endangered species of mammals. Finally, clinical scientists, toxicologists and physicians want to know the normal and pathological features of ovarian follicles in women, especially in relation to health and the regulation of fertility. Having in view the great importance of studying various aspects of biology of ovarian follicles, numerous papers and reviews on several aspects of ovarian follicles are published annually in a wide variety of scientific journals."

Life is always intimately bound up with structure and with the continuous transformation which structures undergo. Modern science and technology have now made it possible to display these structures before our eyes, right up to the frontiers of molecular dimensions. When several years ago Dr. HANS LUDWIG, while working at the First Department of Obstetrics and Gynecology of the University at Munich, demonstrated to us some micrographs showing the human oviduct's surface pattern, my immediate reaction was: This is the environment that encom passes the very onset of an individual human life. In fact, scanning electron microscopy, superimposed upon classical micro morphology, has enabled us to get insight into the landscape of living structures, their intricate organization and their delicate beauty as well. At the same time this technique opens up an entirely new perspective in our three-dimensional view and comprehension of biological events. This becomes especially evident in the realm of reproductive processes within the human female reproductive tract. In this volume the authors give - for the first time systematically - a description of the surface patterns of the inside of the human vagina, ecto and endocervix, and the human uterus and oviduct; they depict ovulatory alterations of the ovarian surface and surface changes under various endo crine conditions, as well as in relation to the menstrual cycle, pregnancy, fetal growth, and the menopausal cessation of ovarian functional activity. of the placental intervillum, the In addition they describe surface structures basal plate and the amnion."

This volume contains the Proceedings of the Serono Symposium on Pre implantation Embryo Development, held in Newton, Massachusetts, in 1991. The idea for the symposium grew out of the 1989 Serono Symposium on Fertilization in Mammals* at which preimplantation development was the predominant suggestion for a follow-up topic. This was indeed a timely subject in view of the recent resurgence of interest in this funda mental phase of embryogenesis and its relevance to basic research and applied fertility studies in humans, food-producing animals, and endangered species. The symposium brought together speakers from a broad range of disciplines in order to focus on key regulatory mechanisms in embryo development, using a wide variety of animal models, and on representative topics in human preimplantation embryogenesis. The culmination of preimplantation development is a blastocyst con taining the first differentiated embryonic tissues and capable of initiating and sustaining pregnancy. The central objective of the symposium was to throw light on the regulation of cellular and molecular events underlying blastocyst formation. It was particularly appropriate that the date of the symposium marked the 20th anniversary of the publication of the classic volume Biology of the Blastocyst, the proceedings of an international workshop held in 1970. This book, which summarized most of the information then available on this topic in mammals, was edited by the pioneer in blastocyst research, Dr. Richard B1andau, who was the guest speaker at the symposium."

The clinical acceptance of computed anatomic cross-sections. Schematic line tomography (CT) as an integral part of our drawings are also generously used to il diagnostic armamentarium was based on its lustrate particularly complex anatomic re ability to display cross-sectional anatomy gions and help the reader obtain a correct with near anatomic precision. However, perspective on these more difficult regions. the radiologist must first be knowledgeable The book successfully presents a clear per of the complexities of normal anatomy be spective on the anatomy we see daily in fore he can truly make full use of this tech using cross-sectional imaging techniques. nology. This book will prove useful as a learning Michael Farkas has truly made our task guide for the uninitiated, and as a refer as radiologists easier. As noted in the ence for the more experienced. Either preface, the book carefully correlates rep way, it is an important contribution to our resentative CT slices with corresponding literature. Elliot K. Fishman, M.D."

Histochemistry deals with the activities of chemical components in cells, and immunohistochemistry addresses the function of cell types in tissue or organs, such as those leading to acceptance or rejection of grafts or organs. This book is a methods volume focusing on antigen retrieval, particularly methods used in disease-related antigens. Because the book is a methods volume and a lab manual, it will have an audience of pathologists, biochemists, and lab technicians.

The present new version of this popular laboratory manual is at the same time the first one of this text in the English language - and this makes me even a little proud, as it reminds me of probably the first collection of monoclonal recipes in English, written by myself, which circulated for a couple of years in many laboratories. In the meantime many researchers have put enormous effort into improving methods for monoclonal antibody production. The proce dures have become more and more standardized and by this have more and more lost the character of magic secrets. Hinrich Peters and Horst Baumgarten, who had followed this good tradition already in the previous edition, written in German, suc ceeded in making laboratory tricks teachable. They had contributed their own experiences in cell culture and immunology, and were able to engage a number of experienced authors to contribute to the work. They were all willing to follow the general concept of this book, which contains a brief theoretical background for the methods described and presents the procedures in a highly organized structure. So the book has retained its shape as a "cook-book," which I especially like."

This volume is intended to cover research in the field of muscle morphology since publication of the previous edition by Haggquist in 1956. The development of new techniques, coupled with an intensified interest in muscle, has resulted in a vast literature which no single person could review, especially within the limitations of one volume. When I accepted the flattering offer to write a new edition, I quickly abandoned any hope of a comprehensive review. Instead, I tried to consider, within my limits, those lines of research which I believe to be important for the understanding of mammalian and ultimately human muscles under normal, experimental, and pathological conditions. It would be naive to suggest that muscle can be adequately described in purely morphologi cal aspects; I would characterize the results of my effort as "muscle as seen with the eyes of a morphologist." It gives me pleasure to acknowledge the help of several colleagues who read and commented on drafts of individual chapters: Dr. Brenda Eisenberg, Chicago; Dr. Else Nygaard, Copenhagen; Dr. Stefano Schiaffino, Padova; Dr. Michael Sjostrom, Umea; Dr. Lars Erik Thornell, Umea. None of these individ uals can be held responsible for any error or obscurity that persists. Indeed, without their assistance there would have been more. I also thank those col leagues who allowed me to include their published and unpublished material; their names, and also those of the publishers who kindly granted copyright permission, are given in the individual figure captions."

, Jean ANDRE Universite de Paris XI, ORSAY, France. Sperm cells have long been considered as the most highly specialized of all living cells. They surely are, being very diverse, very complex, containing organelles which do not exist in any other cell -such as acrosome or crystallized mitochondria- and being endowed with a very unique behaviour, that is to meet and recognize the ovum, pierce its protective envelopes and inject into its cytoplasm a most precious deposit, the haploid genome of the species. It is Baccio Baccetti's merit to have felt the need for a confrontation of the scientists working on sperm in order to clarify the apparent complexity of the enormous amount of knowledge accumulated on the subject. Thus, he successfully inaugurated the series of the InternationaZ Symposia on SpermatoZogy. The Seillac edition is the fourth in the series. After an initial stage during which morphology was predominant, our meetings have turned more and more towards function. It has been the will of the French Organizing Committee to devote this meeting mainly to Eutherians, and, among those, to man, in connection with the conflicting necessities to help the sterile couples and to contrul the population explosion at the surface of the world.

The idea for this treatise on the radiological anatomy of superficial and deep spinal cord vasculature evolved from daily routine neuroradiological work. This was also the reason for subdividing the monograph into a postmortem anatomical and a clinical part. The actual importance of a clear conception of radio anatomic fundamentals was made clear by many clinical conferences with neurologists, neurosurgeons and orthopedists, where a lack of knowledge about medullary syndromes of suspected vascular origin became evident. Also among neuroradiologists there is still widespread uncertainty in the interpretation of myelograms and angiographies in such cases. A study of the spinal cord's angioarchitecture is all the more justified and necessary considering the vast number of descriptions of cerebro vascular anatomy and pathology. The clinical challenge posed by patients suffering from partial or complete transverse spinal lesions has grown due to new diagnostic and therapeutic approaches. Myelography using water-soluble contrast media, X-ray computed tomography, magnetic resonance imaging and spinal angiography today allow and require both earlier and topographically and pathogenetically more exact classification of diseases of the spinal cord and its surrounding structures. Due to progress in microneurosurgery and interventional neuroradiology, even intramedullary lesions have become more and more accessible and treatable. Therefore this monograph mainly addresses those concerned with invasive therapeutic techniques and who are familiar with the interpretation of radio anatomic findings. A comprehensive description of medullary vascular syndromes would be beyond the scope of this treatise."

Prior to the emergence of the sliding filament model, contraction theories had been in abundance. In the absence of the kinds of structural and biochemical information available today, it has been a simple matter to speculate about the possible ways in which tension generation and shortening might occur. The advent of the sliding filament model had an immediate impact on these theories; within several years they fell by the wayside, and attention was redirected towards mechanisms by which the filaments might be driven to slide by one another. In terms of identifying the driving mechanism, the pivotal observa tion was the electron micrographic indentification of cross-bridges extending from the thick filaments. It was quite naturally assumed that such bridges, which had the ability to split ATP, were the molecular motors, i.e., that they were the sites of mechanochemical transduction. Out of this presumption grew the cross-bridge model. in which filament sliding is presumed to be driven by the cyclic interaction of cross-bridges with complementary actin sites located along the thin filaments."

A little picture is worth a million words. Chinese proverb Prenatal human development is an extremely complicated process related to genetics, biochemistry, anatomy, and physiology. There are no developmental changes, either chemical or morphologic, without simultaneous changes in molecular organization. The astonishing buildup ofbiostructures always precedes their proper function. The development of an embryo is genetically coded and is based on interactions related to the selective switching on and off of genes. Interactions are cell-to-cell mediated, mediated by extracellular fluids, or mediated by special pathways. Every substance involved in developmental is to be recognized by its target. interactions, before triggering a metabolic or a morphogenic event, Complex physical and immunologic recognitions are involved in the process of differentiation. Small pieces of evidence are collected to create a mosaic picture elucidating the development. This picture is fascinating and represents the biggest biological puzzle: the puzzle of development. There is no doubt that analysis of human prenatal development is a basis for understanding normal and pathologic relationships between structure and function. Today, there are approximately 2000 different inborn congenital anomalies and syndromes. This book attempts to present a complete realistic account of human morphogenesis, the differentiation of structures, using direct photographs of normal specimens obtained from legal medical abortions of unwanted pregnancies. Emphasis has been placed on contemporary techniques: histochemistry and scanning electron microscopy. The text is as simple as possible; meticulous detailed anatomic descriptions have been omitted.

The new experimental tools and approaches of modern biology have allowed us to better understand many fundamental properties of the eukaryotic cells. These significant discoveries have drastically changed the diagnostic and therapeutic approaches of modern clinical practice. On April 18-22, 1988, an International Symposium on Cell Function and Disease was held in Monterrey, Nuevo Leon, Mexico, aimed at reviewing some of the most recent advances made in the following five areas: Genes and Human Diseases; Cellular and Molecular Pathology; Infectious Diseases; Brain Transplants and the New Approaches and Techniques with Potential Application to Cell Function and Disease. This book is based on the contributed papers of the symposium. To underline the importance of the clinical approach to the study of cell function and disease a section on this subject was added at the end of the book. The chapters in this volume include contributions by some of the leading scientists of the international scientific community and Mexico. During the course of this international conference, numerous discussions were held by the local and international representatives of the scientific community concerning the creation of an International Center of Molecular Medicine aimed at stimulating further interaction between molecular biologists, biochemists, biophyscists and clinicians. Such ideas received the endorsement and support of the Director General of the united Nations Educational and Scientific Organization (UNESCO), Federico Mayor, the Governor of the State of Nuevo Leon, Jorge Trevino, and the Secretary of Health of Mexico, Guillermo Soberon.

The eye has fascinated scientists from the earliest days of biological in vestigation. The diversity of its parts and the precision of their interaction make it a favorite model system for a variety of developmental studies. The eye is a particularly valuable experimental system not only because its tissues provide examples of fundamental processes, but also because it is a prominent and easily accessible structure at very early embryonic ages. In order to provide an open forum for investigators working on all aspects of ocular development, a series of symposia on ocular and visual devel opment was initiated in 1973. A major objective of the symposia has been to foster communication between the basic research worker and the clinical It is our feeling that much can be learned on both sides from community. this interaction. The idea for an informal meeting allowing maximum ex change of ideas originated with Dr. Leon Candeub, who supplied the nec essary driving force that made the series a reality. Each symposium has on a different aspect of ocular development. Speakers have concentrated been selected to approach related topics from different perspectives."

In 1974 The National Institute on Aging established a somatic cell genetic resource for aging research at the Institute for Medical Research in Camden, New Jersey. Within this program there is a yearly workshop to promote theory and concept develop ment in aging research with the specific purpose of addressing the use of genetically marked cells for aging research and to stimulate interest in aging research by workers in a variety of disciplines. This monograph, The Regulation of Cell Proliferation and Differentiation, is the result of the first workshop held May 15-17, 1975. The concept of the workshop was to consider two main areas: First, a discussion of clinical syndromes expressing as a major manifestation excessive growth, deficient growth or failure to thrive; and second, to present work in cellular and molecular biology on a model system suitable for in vitro study of regulation of cell proliferation and diff2rentiation. The model selected for this was skeletal muscle. It has been widely accepted that normal somatic cells from individual human donors display limited replicative lifespans when cultivated in vitro (1,2). That such "clonal senescence" may be related to in vivo aging is suggested by observations relating the replicative lifespans of cultures to donor age (3-5,13) donor genotype (4-7) and donor's tissue of origin (5,8). A variety of theories have been developed to explain in vitro clonal senescence (9)."

This volume documents our growing understanding of the human major histocompatibility complex. The application of this information is ever more important as the limits of transplantation continue to be reduced, including the recent success of bone marrow transplantation between unrelated but closely matched individuals. In addition, the need to transfuse platelets in the face of immunologic barriers continues to challenge transfusion services. Thus, the serologic information summarized in this volume is essential for optimal patient care. At the same time, recombinant DNA technology has led to a revolution in our understanding of many aspects of basic biology. Among the advances has been the initial characterization of the structure of some HLA loci. While this will ultimately improve clinical services, constant reference to serologic data is essential so that the powerful new techniques can be applied in the most effective ways. The timing of the First Red Cross International Histocompatibility Workshop is fortunate as it brings together experts from around the world to address the state of the art. We are all grateful to Dr. John Lee and his colleagues for organizing the workshop, and for bringing together in this volume the material to be presented in Beijing during October 17-23, 1990. Leon W. Hoyer, M.D.

In the ever-expanding field of heart research the needs of established re searchers, students and general readers can vary considerably, making it difficult therefore to cater for all types of audience within a single volume. The aim of this book has been to provide a comprehensive and up-to-date review of the structure of the heart, including its cell biology. The ultrastructure of the working myocardium and all portions of the conduction system, together with their development, is covered in detail. Also included are chapters on the morphometry of cardiac muscle, the innervation of the heart, cardiac hyper trophy and regeneration, and the development of the coronary circulation. A detailed review of cardiac muscle in cell culture is also provided. It is to be hoped that readers, whatever their background, will find the information contained herein useful for their needs. This work was supported by a grant from the National Heart Foundation of Australia. The authors wish to gratefully acknowledge the following people for their invaluable assistance in preparation of the manuscript: Professor Yasuo Uehara, D'r. Takashi. Fujiwara, Dr. Peter Baluk, Dr. Seiji Matsuda and Bill Kaegi for providing unpublished micrographs; Fabian Bowers, Patricia Murphy and Janet Bennett for typing; and Lucy Popadynec, Nella Puglisi, Maggie Mackie, Mary Delafield and Liana Butera for assistance with references and figure preparation. THE AUTHORS Contents A. General Introduction 1 Morphology of Cardiac Muscle 8 B."