The circulatory system is usually considered to be composed of tubes of various diameters, characterized by collateral and terminal branches. There is also a tendency to treat blood vessels merely as conducting tubes in which the various structures of the wall act as mechanical pumps wlrich modify their diameter. This is, of course, not so. In fact, we know that blood vessels, and in particular arteries, are organs with personalities of their own and a particular susceptibility to several diseases. In addition, blood vessels differ in structure, according to their localization, and age at differing rates. The experimental work car ried out so far clearly confirms the data that have come from spontaneous human pathology; experimentally induced arterial lesions have a definite tendency to appear in certain arteries and not in others, depending on the experimental procedures used, and in each specific artery the lesions appear to have a specific location. We now know that the arterial wall is a metabo licallyactive structure, in which a number of enzyme activities have been clearly demonstrated. It possesses a sensitive vasa vasorum apparatus and a specific reactivity to various lesion-inducing stimuli. We must also remember that the arterial wall is in continuous contact with the blood circulating through the endothelial cells lining the vascular bed. It is obvious, therefore, that any variation in the circulating blood mass can modify the morphology as well as the function of the vessel wall.
The role of folylpolyglutamates in biosynthetic processes has gained increasing importance with the recognition that these com pounds are not only the forms of folate co-factors that accumulate within cells, but, in addition, are the preferred substrates for folate dependent reactions in eukaryotic cells. More recently attention has turned to the potential importance of the polyglutamyl derivatives of methotrexate that have been detected in normal and malignant cells both in vitro and in vivo. The biochemical trans formation of this important chemotherapeutic agent is of particular significance since polyglutamyl derivatives of methotrexate are not only potent inhibitors of the target enzyme, but have quite different cellular pharmacokinetics than the parent monoglutamate. Hence, nearly three and a half decades after 4-aminoantifolates were first applied clinically in the treatment of human neoplasms, we have begun to appreciate a new dimension in antifolate pharmaco logy which may have profound implications for our understanding of the mechanism of the cytotoxicity and selectivity of this class of agents. With the development of highly sensitive methodology for the rapid detection of folyl and antifolyl polyglutamates, it is now possible to define in depth the intracellular transformation of these agents and their role in determining antifolate action against normal and malignant cells. This information will very likely influence how regimens with methotrexate and related antifolates will be further developed and employed clinically.
Four years ago when the first European Symposium on the re lationship between alterations of blood clotting mechanisms and atherosclerosis was organized, we asked ourselves which would be the best way to obtain both scientific and practical contributions. We have been interested in cardiovascular diseases for several years now and have therefore focused our attention on the "container" (Le. the blood vessel) rather than on the "contents" (Le. the various components of blood) as considered only from a haemodynamic point of view. In recent years correlations were found between alterations of vascular wall and alteration of coagulative, fibrinolytic, and plate let factors as well as of haemorheological phenomena in the thrombo genic evolution of atherosclerotic lesions. A close cooperation between cardiologists and workers interested in atherosclerosis and thrombosis is therefore necessary. We think that the most appropriate approach to the various problems concerning correlations between thrombogenic and atherosclerotic lesions is co-operation between experts in these different fields of research. We thus decided to organize the 2nd Symposium taking into account the great progress achieved in this field during the past few years, and hope that discussions on diagnostic and therapeutical perspec' tives will yield useful elements both for the cardiologist and for the cardiologist and for the general practitioner.
These two volumes, entitled "Purine Metabolism in Man IV" con tain the paper presented at the "IV. International Symposium on Human Purine and Pyrimidine Metabolism," held in Maastricht (The Netherlands), June 1982. The proceedings of the three previous meet ings in Tel Aviv (Israel, 1973), Baden (Austria, 1976) and Madrid (Spain, 1979) were also published by Plenum Press. In the past few years interest in purine and pyrimidine metabo lism under normal and pathological conditions has been growing rapid ly. Apart from the more or less classical topics such as hyperuricae mia, clinical gout and urolithiasis, an increasing number of papers relating to other fields have been presented at successive meetings. Knowledge derived from the study of purine metabolism in relation to lymphocyte function, for instance, has opened up new possibilities for immunomodulation and leukaemia chemotherapy, with eventual conse quences for other types of cancer. At previous meetings there have been pointers implicating purine metabolism in relation to normal cardiac and skeletal muscle function. During the present meeting much new data on both issues have been re ported which indicate clear differences in the pathways of ATP metabo lism. The widening of the field of interest is also illustrated by the recent work on infectious disease: exploitation of the differences in purine metabolic pathways in certain parasites compared with those in human cells has resulted in new rationales for therapy being devel oped.
The topic of biological response modifiers has attracted the attention of many biomedical investigators, including immunologists, oncologists, pharmacologists, microbiologists, and biochemists, as well as clinical practitioners of medicine. This has occurred mainly because of the realization that the complex system of cellular and humoral interactions culminating in a productive immune response is under exquisite regulatory control for normal immune responses and that loss of control may markedly influence the capability of a host to respond in a productive manner to the numerous immunologic "insults" encountered in the environment. Furthermore, biological response modification is considered by many to be a natural offshoot of the relatively new application of "immunotherapy" to cancer. It is widely recognized that "immunotherapy" was practiced at the end of the last century and the beginning of this century when it was recognized that microbial infections were caused by distinct species of bacteria and that passive administration of serum con taining antibody to these microbes or their products could, in many cases, favorably influence the outcome of an infectious process.
We are pleased to present to our readers the Proceedings of the International Symposium "Proteases: Potential Role in Health and Disease" which was held in WUrzburg (FRG) during October 17-20, 1982. The topics discussed included those dealing with the physi ology and pathophysiology of proteases and their inhibitors, the interactions of proteases and hormones, the kallikrein-kinin system, complement and the coagulation system, the function of proteases in the kidney and the intestinal tract as well as the role of proteases in lung diseases, pancreatitis, arthritis and hypercatabolic states (multiple trauma, septicemia, acute renal failure). The papers presented answered many questions, but raised many more concerning the significance of proteases and their inhibitors in clinical medicine. It was unfortunately impossible in this volume to in clude the extended, lively and extremely stimulating discussions which were enjoyed by the participants during the conference. The meeting has provided a unique framework for close inter action between scientists from various disciplines, including bio chemistry, physiology, surgery, anaesthesiology, endocrinology, hematology, pulmonology and nephrology. We would like to express our thanks and appreciation for all those who have stimulated, encouraged and supported us to hold this symposium in WUrzburg. This endeavor could not have been possible without the generous financial support of the Paul-Martini Foundation (Mainz), Bayer AG (Leverkusen), Beiersdorf AG (Hamburg).
The study of atherosclerosis centered since the first decade of the present century on etiology and pathogenesis. In fact, the studies of the military academy of medicine in St. Petersburg have opened the way of inducing atherosclerosis in animals. Pathogenesis of atheroma has been studied since then in humans and animals naturally prone to the development of the disease and by a variety of dietary and other procedures. The various experimental studies allowed science to evaluate the relative importance of different factors (genetic, dietary, hormonal, pharmacological. mechanical, circulatory, etc.) in atherogenesis. Epidemiological studies as well as biochemical plasma lipid and lipoprotein estimations coupled with light microscopic, histo chemical and electron microscopic investigations decreased the gap between observations on the human and experimental animal research. The enormous literature covering this field allows the intelligent reader to formulate a comprehensive concept regarding etiological factors and pathogenesis of atherosclerosis. Its impact on pre ventive and curative medicine was however limited in scope.
The present volume contains the Proceedings of an EMBO Workshop organized in June 1983 by the Institute of Virology, Veterinary Faculty, State University of Utrecht, The Netherlands. Some 70 scientists from 11 countries followed the invitation to present and discuss their recent data on the structure, replication, genetics and pathogenesis of coronaviruses. It was the second international meeting on these viruses; the Workshop, which was held in Zeist near Utrecht followed the example of the Wuerzburg symposium of October 1980. At that time it became clear that coronaviruses are unique in many respects. Once a group of viruses that were defined merely on the basis of their characteristic peplomer morphology, Coronaviridae family members are known today - to be constructed from essentially three polypeptides - to use a "nested set" of 5-6 subgenomic mRNAs in the expression of their large, positive and single stranded RNA genome, - to generate these subgenomic RNAs through specific fusion of non contiguous sequences, - to mature by budding from intracellular membranes, - to cause persistent infection with neurological involvement and sometimes immunopathological conditons. These and many other findings have been established only very recently. The articles collected in this book reveal and/or further detail these findings. Since these Proceedings contain the combined scientific presentations of representatives from virtually all laboratories engaged in the field, they provide a fairly comprehensive review of the state of the art in corona virology.
This volume contains the proceedings of the symposium on "Ganglioside Structure, Function and Biomedical Potential" which was held at Parksville, Vancouver Island, B. C. , Canada on July 6-10, 1983. The symposium was organized ao a satellite to the ninth meeting of the International Society for Neurochemistry, held immediately afterward in Vancouver City, B. C. Close to 50 speakers from 9 countries presented papers on a wide range of topics on the ganglioside theme. These encompassed the many aspects of basic research that have evolved over the past half-century, as well as some newer topics relating to the biomedical potential of gangliosides as therapeutic agents. One of the purposes of the meeting was to encourage dialogue between investigators in these seemingly diverse areas in the hope that each would come away with fresh perspective toward his own work. Judging from the many spirited, informed discussions that took place throughout the four day meeting, this goal was achieved. The charm and beauty of Vancouver Island undoubtedly contributed to the congenial atmosphere which quickly developed among the 120 or so participants. Drawn from 13 countries of Europe (East and West), America (North and South), Asia and the Middle East, this gathering reflected the broad geographical scale on which ganglioside research is now conducted. That this field is still in its "logarithmic" stage of growth is indicated by the increasing number of citations appearing each year in the various abstracts (e. g. fig. next page).
This book addresses neoplasms of the human trophoblast. The scant literature available on the epidemiology of trophoblast neoplasms suggests that they are as much as ten times more common in Africa, Asia, India, and much of the developing world than in Western countries. The stimulus for the book evolved out of a common interest to combine Western technology with the clinical experience in the developing world in a common pursuit of the study and eradication of trophoblast neoplasia. There is substantial evidence to contend that gene derepression as seen in trophoblastic disease may be a universal prerequisite to neoplastic transformation in general. The recent discovery that the tumor markers, human chorionic gonadotropin (hCG) or its subunits, are identifiable in over 90 percent of all extracted neoplasms suggests a critical role for this common denominator of gene derepression in neoplasia. This gene derepression concept in reproductive biology and neoplasia spans many of the basic parameters of human cell replication as related to endocrinology, immunology, biochemistry, electrophysiol ogy, genetics, and pharmacology. The International Society for the Study of Trophoblastic Disease focuses on the global aspects of trophoblast neoplasms. These global aspects include epidemiology and etiology of the disease, regional variations in treatment of trophoblastic neoplasms, and potential ways to adapt and apply Western technology to effective use in developing countries. It was this perspective that formed the basis for the First World Congress on Trophoblast Neoplasms, which convened in Nairobi in October, 1982.
Naturally occurring antinutrients and food toxicants, and those formed during food processing, adversely affect the nutri tional quality and safety of foods. Because of the need to improve food quality and safety by plant breeding, fortification with appropriate nutrients, and processing methods, and because of the growing concern about possible direct relationships between diet and diseases, research is needed to: (1) evaluate the nutritive quality and safety of crops and fortified, supplemented, and processed foods; (2) define conditions that favor or minimize the formation of nutritionally antagonistic and toxic compounds in foods; and (3) define the toxicology, metabolism, and mechanisms of the action of food ingredients and their metabolites. As scientists interested in improving the safety of the food supply, we are challenged to respond to the general need for exploring: (1) possible adverse consequences of antinutrients and food toxicants; and (2) factors which contribute to the formation and inactivation of undesirable compounds in foods. Medical research offers an excellent analogy. Studies on causes and mechanisms of disease processes are nearly always accompanied by parallel studies on preventive measures and cures. Such an approach offers the greatest possible benefits to the public.
We are pleased to present to our readers the Proceedings of the Sixth International Workshop on Phosphate and Other Minerals which was held in Verona, Italy, during June 24-26, 1983. It was hosted by Professor Giuseppe Maschio, Professor of Medicine and Chief, Department of Nephrology at the University of Verona. The Sixth Workshop maintained the tradition of the previous ones. It provided a unique and outstanding opportunity for close interaction between scientist involved in the research of the overall field of Mineral Metabolism. The current Workshop was attended by 250 scientists from 15 countries including Austria, Canada, Denmark, England, France, Germany,Holland, Israel, Italy, Japan, Spain, Sweden,Switzerland, and the United States of America. The topics discussed included the renal handling of phosphate, transport of other minerals, intestinal absorption of calcium and phosphate and phosphate homeostasis in health and disease. Two symposia dealing with the recent developments of the interactions between minerals, parathyroid hormone, and blood pressure and between minerals and myopathies were included. In addition to the 15 State-of-the-Art Lectures, there were 43 oral and 63 poster presentations selected from over 200 abstracts sub mitted to the Program Committee. The Seventh International Workshop on Phosphate and Other Minerals will be held during September, 1985, in Marseille, France. It will be hosted by Professor Michel almer, Chief of the Department of Nephrology at the University of Marseille. The theme of this coming Workshop will focus on the pathophysiology of phosphate homeostasis and the metabolism of other minerals.
This book collects the Proceedings of a workshop sponsored by the European Molecular Biology Organization (EMBO) entitled "Pro teins Involved in DNA Replication" which was held September 19 to 23,1983 at Vitznau, near Lucerne, in Switzerland. The aim of this workshop was to review and discuss the status of our knowledge on the intricate array of enzymes and proteins that allow the replication of the DNA. Since the first discovery of a DNA polymerase in Escherichia coli by Arthur Kornberg twenty eight years ago, a great number of enzymes and other proteins were des cribed that are essential for this process: different DNA poly merases, DNA primases, DNA dependent ATPases, helicases, DNA liga ses, DNA topoisomerases, exo- and endonucleases, DNA binding pro teins and others. They are required for the initiation of a round of synthesis at each replication origin, for the progress of the growing fork, for the disentanglement of the replication product, or for assuring the fidelity of the replication process. The number, variety and ways in which these proteins inter act with DNA and with each other to the achievement of replication and to the maintenance of the physiological structure of the chromo somes is the subject of the contributions collected in this volume. The presentations and discussions during this workshop reinforced the view that DNA replication in vivo can only be achieved through the cooperation of a high number of enzymes, proteins and other cofactors.
The dramatic advances in molecular genetics are becoming incorporated into neurobiologic studies at an ever increasing rate. In developmental neurobiology, the importance of cell cell interactions for neurogenesis and gene expression is be ginning to be understood in terms of the molecular bases for these interactions. This book seeks to emphasize the importance of molecular technology in the study of neurogenetic mechanisms and to explore the possible relationships between specific cell cell interactions and regulated gene expression in the develop ing nervous ~stem. This volume consists of nineteen chapters which address ques tions of gene expression and the importance of cell-cell interac tions as key factors in the developing nervous ~stem. Rather than viewing these two processes as separate mechanisms, as the organi zation of these chapters might suggest, we would like to emphasize the interplay of these genetic and epigenetic influences in all phases of neural ontogeny, a concept which is made clear by the subject matter of the contributions themselves. The authors of these chapters were participants in selected ~mposia from the Fourth Congress of the International Society of Developmental Neuroscience held in Salt Lake City, Utah, July 3-7, 1983.
This volume contains the edited transcript of an interdisci plinary colloquium held at Totts Gap Medical Research Laboratories, Bangor, Pennsylvania on October 12-14, 1983 under the sponsorship of the Muscular Dystrophy Association. The aim was to illuminate the pathogenic mechanism of Duchenne Muscular Dystrophy through a synthesis of available data on gene expression in muscle. In the informal give and take ot the collo quium, the participants found themselves engaged in mutual education and enlightenment as they attempted to put together what is known and to highlight what is not known about the subject. Significant research into muscle as a tissue and muscle disease began only about 50 years ago although the description of muscular dystrophy by Guillaume Benjamin Amand Duchenne de Boulogne had been published in 1862. By 1943 it was clear that Duchenne muscular dystrophy was an X-linked genetic disorder. Up to the present, however, the offending gene has not been identified although its location on the short arm of the X chromosome has been approximately determined. The gene product associated with the initial disturbance in skeletal muscle has also remained elusive up to now. Moreover, investigations into the mechanisms of the muscle degeneration have been hampered by ignorance of the fundamental phenotypic expression of the genetic disorder.
The Proceedings of the Eight International Symposium on Drugs Affecting Lipid Metabolism (8th D.A.L.M.) is the subject of this volume. Since the first symposium in 1960, each successive meeting has broken new ground in the field of pharmacological control of lipid levels - offering new and stimulating insights and exposing the audience to the state of the art. The field has progressed sufficiently to permit discussion of the cellular biology of athero sclerosis. The opening session was devoted to pathology, macrophages, lipoproteins and their receptors and choles terol ester metabolism. Because of the recent emergence of new apolipoprotein technology, a workshop devoted sole ly to apolipoprotein methodology was introduced followed by a plenary session devoted to their metabolism and structure. Another rapidly developing area of atherosclerosis research is non-invasive assessment of this condition. Accordingly, a session was devoted to new techniques for this research modality. The final plenary sessions were devoted to the roles of drugs and diet in athero~ scl~rosis - cause, treatment and mechanisms of action. The meeting was summarized by Dr. O.J. Pollak, one of the "founding fathers" of this field. There were nine sessions of proffered papers whose abstracts appear in this volume. In addition, special workshops (to be reported elsewhere) were devoted to several drugs including Oiyzanol, Probucol and Etofibrate.
This symposia series, founded in 1976, is devoted to the advancement and dissemination of knowledge in the field in immunology, particularly as it relates to the immune recognition and responses to protein and peptide antigens. Leading investigators are convened every 2 or 3 years for the purpose of consolidating the research on protein and peptide antigens of defined structure and to focus on these findings in the context of contemporary immunology. Each symposium has focussed on a particular aspect of molecular and cellular immunology of proteins and peptides. It is extremely gratifying that, in the last 2-3 years, the scientific community has shown a heightened interest in the study and understanding of protein and peptide antigens. The third symposium was devoted to viral and bacterial antigens. Great advances have been made in recent years in the elucidation and synthesis of protein antigenic sites. These, together with advances in cloning, expression and sequencing of protein genes, have offered new avenues for the preparation of synthetic vaccines for viral, bacterial and other antigens. Such vaccines have been the aspiration of immunologists for over 20 years. The meeting has served to integrate and correlate the current knowledge of these systems with developing trends in immunology and to identify the most promising new directions for future investigations.
This is the proceedings of the International Conference on AIDS Associated Syndromes held at Irvine on December 7-8, 1984. The purpose of this conference was to bring together investigators who are actively engaged in AIDS research to present their most recent data with regard to etiological agent(s) of AIDS, immunological characteristics of some of the patients in early stages of AIDS and various therapeutical modalities that are available for the treatment of AIDS, early AIDS (persistent generalized lymphadnopathy) or for those who demonstrate asymptomatic acquired immunodeficiency. In the area of etiological agents, the discussions are presented dealing with the questions of whether HTLV III/LAV alone or with other co-factor(s) like EBV or CMV are responsible for AIDS. What is the relationship of these viruses to Kaposi's sarcoma, since Kaposi's sarcoma in AIDS cannot be simply explained on the basis of the underlying immune deficiency? Data are presented for HTLV III/LAV interactions with the T4 molecule on the surface of helper T cells. A paper is presented with epidemiologicai evidence for AIDS being an African disease which perhaps was brought to the United States and then to Haiti.
Montreal has had a longstanding interest in somatostatin. Two years ago when the final planning began for the International Con gress of Endocrinology in Quebec City in July 1984, we seized the op portunity for having a separate Satellite Symposium on somatostatin here in Montreal. We felt that after a decade of uniformly vigorous growth in somatostatin research, the opportune moment had arrived for a review of the most significant past developments and for setting the directions for the future. Knowing the futility of trying to cover every aspect of the burgeoning somatostatin field in a two day scientific program, we opted for a detailed analysis of selected areas which were reasonably mature and of areas of greatest new activity. To attain these objectives, 27 leading international experts actively involved in their fields were invited to present an indepth review of their work in one of five major categories of somatostatin research. Thirty minutes at the end of each session were assigned for a three way, comprehensive discussion of some of the core concepts between the session moderators, the panellists and the audience. The feedback that we have received from the particip ants leaves little doubt that the meeting was a scientific and social success. This book fulfills our final commitment towards the Meeting which was to record the proceedings in a timely publication.
Five years ago, a new system of classification of the various types of diabetes was proposed. This publication provides an inte grated picture of the latest information on the similarities and dissimilarites of two types of diabetes. It contains contributions from morphologists, physiologists, biochemists, immunologists, pathologists, geneticists, clinicians and epidemiologists. In the first section, the basis for the present classification and its limitations are discussed. In addition, there is a discussion of gestational diabetes and heterogeneity of some sub-classes of diabetes. The next section deals with genetics and immunology. The third section discusses abnormalities of insulin secretion and act ion on both the receptor and post . . . receptor levels. The role of gastrointestinal peptides in Type I and Type II diabetes is also considered. In the last section, both types of diabetes are compared with respect to diabetic complications. The closing sec tion summarizes the present status and offers a stimulating view of future development. We hope that this book will be a useful source of information for both researchers and practicing clinicians. M. Vranic G. steiner C. H. Hollenberg v ACKNOWLEDGEMENTS The symposium from which this volume arose (June 28-29, 1984) was organized by the Banting and Best Diabetes Centre, University of Toronto. We would like to express our appreciation to the following sponsors: Ames Educational Institute, Ayerst Laboratories, Becton Dickinson Canada Inc. , Canadian Soft Drink Association, Connaught Laboratories Limited, Connaught Novo Ltd. , Eli Lilly Canada Inc.
It can honestly be said that the scope and magnitude of this meeting surpassed initial expectations with respect to the number and quality of the papers presented. Our group has grown since we last met in Dortmund in 1971. This is a good indication that a spiraling of our interests has taken place with the effects of the initial good work felt, not just in one corner of the globe, but in all four. With such a start, it was only appropriate that an international society was formed at the meeting to further coordinate our mutual undertaking. Henceforth it shall be known as the International Society of Oxygen Transport to Tissue. A final note of acknowledgement should be made to those who were in the supporting cast, not only in making the meeting in Charleston and Clemson a success, but also in the compiling of this book. Gratitude is due to Dr. Daniel H. Hunt for his efforts, the end product of which you have in your hands. Considerable service was rendered by Mr. Robert J. Adams, Mr. Buddy Bell and Mr. Nathan Kaufman during the symposium itself. Much typing, organizing and record keeping was done by our lovely secretaries, Laura B. Grove, Muff Graham and Kaye Y. Zook.
Since its inception the research area of platelet pharmacology has always been a vigorous one and it is a characteristic that new approaches to the understanding of platelet function are rapidly and thoroughly investigated. The intensity of this activity is attri butable, probably, to an appreciation by research workers in the field that a satisfactory therapeutic control of platelet function has yet to be realized. Also that if and when this problem of con trolling platelet function is achieved the benefits to clinical medicine will be immense since platelets are known to be involved in a multiplicity of events coupled within the haemostatic mechanisms and inflammatory responses. Aberrations in the behaviour of plate lets is part of the aetiology of atherosclerosis, myocardial and cerebral infarction and thrombosis. At this point in time, research in platelet function is in a particularly rapid state of flux. The recent findings of research workers active in the field and also workers investigating mechan isms of stimulus response coupling in other cells, have provided interesting insights into the generality of mechanisms involved in the function of responsive cells. One may itemize these developments as the area of cell receptor/ligand interaction, induction of cell ular response by protein phosphorylation and calcium flux. The mech anism of these latter events occurs through the activity of phospho lipase generating transient intermediates. These intermediates may act as ionophores or enzyme activators or may, in the case of eico sanoids, reinforce and make irreversible the cellular response.
The use of porphyrins for localization and photodynamic therapy of neoplastic disease has been the topic of several international symposia, reviews and books during the preceeding five years. The literature on this topic has continued to grow, as have numbers of presentations at national and international meetings relating to photobiology, chemistry, and lasers. In this volume, it is the intention of the editor to provide both information on current research projects, and detailed methodology used in such investigations. A bibliography on the subjects of porphyrin localization and therapy is included. The manuscripts contained in this volume are based on reports given at a Porphyrin Photosensitization Workshop which was held in Philadel phia, July 6-7, 1984. This Workshop was supported by NIH grant CA 36746, together with funds from the Fogarty International Center. Authors were requested to update their contributions to provide a summary of progress to mid 1985. Manuscripts containing material not presented in Philadelphia are also included, notably a series of articles describ ing current clinical and pre-clinical results from China. Since the Philadelphia Workshop, a meeting was held in Alghero, Sardinia (May, 1985), and additional conferences are now being planned; this attests to the continued interest in photodynamic therapy involving porphyrin photo sensitization.
This volume represents the first attempt to present in one place the clinical syndromes and the pathophysiologic basis for the "resistance states" to each of the classes of steroid hormones. Glucocorticoids, mineralocorticoids, androgens, estrogens, progesterone and vitamin D have widely diverse roles ranging from the control of homeostasis to reproduction and bone formation. They are similar in that they share a chemical structure and that their action is in the cell nucleus where they induce transcription of specific genes leading to synthesis of function-specific proteins. Clinical syndromes of steroid hormone resistance to androgens (complete and partial testicular feminization), aldosterone (pseudo hypoaldosteronism) and vitamin D (vitamin D-dependent rickets type II) have been known for many years. Progesterone and glucocorticoid resistance syndromes have been described only recently. Resistance to estrogens has not been reported in man or in animals. It is hoped that a detailed reexamination of what is known about each of these conditions at the clinical and molecular levels will enhance our understanding of the function of these hormones and their mechanisms of action. New insight and research initiatives should result. G.P. Chrousos D.L. Loriaus M.B. Lipsett vii ACKNOWLEDGMENTS The contents of this volume are based in part on the proceedings of an International Conference held in Bethesda in the summer of 1984. This conference was sponsored by the National Institute of Child Health and Human Development, Bethesda, Maryland.
Soybean protei ns are wi de 1 y used inhuman foods ina vari ety of forms, including baby formulas, flour, soy protein concentrates, soy protein isolates, soy sauces, textured soy fibers, and tofu. The presence of inhibitors of digestive enzymes in soy proteins impairs nutritional quality and possible safety of this impportant legume. Normal processing conditions based on the use of heat do not completely inactivate these inhibitors, so that residual amounts of plant protease inhibitors are consumed by animals and man. Inhibitors of digestive enzymes are present not only in legumes, such as soybeans, lima beans, and kidney beans, but also in nearly all plant foods, including cereals and potatoes, albeit in much smaller amounts. The antinutritional effects of inhibitors of proteolytic enzymes have been widely studied and can be ameliorated by processing and/or sulfur amino acid fortification. A more urgent concern is reports that rats fed diets containing even low levels of soybean-derived inhibitors, which are found in foods such as soy-based baby formulas, may develop over their lifespan pancreatic lesions leading eventually to neoplasia or tumor formation. On the other hand, recent stUdies suggest that certain enzyme inhibitors from plant foods may prevent cancer formation in other tissues. A key question, therefore, is whether inhibitors from plant foods constitute a human health hazard.
In this volume the policy of review by anonymous referees and minor correction by the editor has been continued, but perhaps should not be extended without an agreed policy statement by the Society. Our choice is minimal revision with rapid publication or proper review with some delay in publication. The editor wishes to express his gratitude to Ann Richardson, Joann Fish, Lance Johnson, and Philip Weinbrecht for their invaluable help in the preparation of this volume. Ian S. Longmuir v BRIEF HISTORY OF ISOTT The Society endured a long gestation period. During the 1960s its formation was discussed at a number of international meetings devoted to oxygen in biological systems. Prominent among a great number of such gatherings were those held at the Institute of Diseases of the Chest, London 1960; Bedford College, London 1963; Queen Elizabeth College, London 1963; and the Seventh Bad Oeynhausen Conference, 1967. At first, reservations were expressed about the desirability of forming a highly specialized society which might not achieve the "critical mass" necessary for its continued existence. However, the 1971 meeting in the Max Planck Institut fur Arbeitsphysiologie, Dortmund, answered these doubts, and Dr. Melvin Knisely commenced planning a very successful inaugural meeting in South Carolina. At this meeting in 1973 in Charleston and Clemson, the Society was formed with the customary remit of the promotion of scientific exchanges.
Current interest in lipoprotein deficiency states stems from the growing realization of their importance in the etiology of premature coronary heart disease. While hypercholesterolemia and coronary heart disease risk are strongly correlated in their etiologic relationship, it is becoming equally clear that deficiencies in HDL, whether congenital or acquired, also enhance the risk for the future development of coronary atherosclerosis. This has led to renewed attention to the lipid hypothesis and realization of the fact that each lipoprotein class and apoprotein species has specific functions in the transport and cellular uptake of various lipids. It is a truism that a biochemical correlate of disease once identified is subsequently recognized with increasing frequency in clinical medicine. The story of HDL was no exception. Indeed hypoalphalipoproteinemia appears to be a disease of high prevalence approaching and perhaps even exceeding that of familial hypercholesterolemia. Its clinical signifi cance escaped our notice for many years largely due to a heavy emphasis on hypercholesterolemia and to difficulties in measuring HDL reliably.
The subject matter of this volume, the basis for which was a conference held in Philadelphia which focused on the subject of infections, including their diagnosis and treatment, in immunocompromised individuals. The material is of particular importance today when placed against the background of the rapid spread of acquired immunodeficiency syndrome (AIDS). The first section dealt with the general subject of the immunocompromised host. Here, reviewed in detail, were the epidemiological and clinical aspects of opportunistic infections in patients with defective immune responses. It is widely acknowledged that infections are a major complication of the neoplastic process. Cancer-bearing patients are more prone to certain kinds of infectious and cancer chemotherapy almost always increases susceptibility to such infections. Depending upon the basic disease process of the cancer, a specific array of infectious diseases can be predicted. Patients altered in thymus-derived lymphocyte populations or mononuclear phagocyte capabilities resulting in defects in cell mediated immunity or delayed hypersensitivity become highly susceptible to certain groups of organisms, whereas, profoundly neutropenic patients usually become infected with different organisms. The types of infections noted are relatively predictable for the type of immune defect, with some variations according to epidemiological factors. Major advances have been made in the early diagnosis and treatment of infectious complications with increasingly effective antimicrobial agents and increasing knowledge of their use. The application of so-called preventive procedures has had limited value to date, including immunotherapy, which appears to hold much promise.
Human epilepsy is a major public health problem affecting approximately 2 persons per 1000. It is particularly frequent in ohildren where convul sions may lead to brain damage and subsequent seizure activity in adulthood. Temporal lobe epilepsy (synonyms include limbic epilepsy. psychomotor epilepsy and complex partial epilepsy) is the most devastating form of epilepsy in the adult population since: a) it is often extremely resistant to currently available anticonvulsant drugs (i.e •• it is more resistant than tonico-clonic or grand mal seizures) and b) it includes loss of consciousness. thereby limiting performance of many normal functions and leaving the individual susceptible to bodily injury. It is also associated with nerve cell loss. in particular in the hippocampus and other structures of the temporal lobes. In order to promote an appropriate therapy it is essential to understand the etiology of seizures and its relationship to brain damage. Basic research on epilepsy also provides a very useful vehicle to learn about the way the brain functions under normal conditions. For instance. much of our present understanding of the mechanisms of action of GABA and benzo diazepines. control of neuronal activity. etc. has been derived from such stUdies.
Our understanding of the functional mechanisms relating dopamine activity to normal and abnormal behavior has been turned "upside-down" by the recent developments described in the chapters of this volume. Heretofore, it was generally agreed that all of the pharmacological and behavioral properties ascribed to dopamine systems were mediated via activation or inhibition of the subtype of dopamine receptors termed D2. The properties of these receptors were first characterized in 1975 following their identification by receptor binding techniques utilizing 3H-butyrophenones, potent antipsychotic drugs, used in the treatment of schizophrenia. Although another subtype of dopamine receptor had already been identified a few years earlier, now termed the Dl receptor, its functional properties were unknow- other than the fact that it was associated with the activation of the enzyme adenylate cyclase. Our absence of knowledge of the behavioral functions of this receptor stemmed primarily from the lack of selective agonist and antagonists for DI receptors - drugs which did not also interact with D2 receptors. Selective agents for D2 receptors did exist and hence the behavioral roles of D2 receptors were easily ascribed. The work described in this text is primarily stimulated by the development of two selective Dl receptor drugs - the antagonist SCH 23390 and the agonist SKF 38393. The studies described herein clearly show that D1 receptors do indeed have many behavioral functions, on the surface often similar to those responses mediated by D2 receptors.
Recently, considerable attention has been focused on studies of membrane structure and function--involvement of cell surface components in intercellular interaction, in translocation of ligands and receptors across cell membranes, and in the immunological properties of cells and gene expression and regulation. These investigations have led to the development of powerful technical tools which can be of immense value in the study of animal and human reproduction. The investigations of problems such as gamete interaction, fertilization, embryo implantation, and development have reached a stage where further meaningful progress in their understanding does not seem likely unless the conventional approaches are coupled with more modern molecular and cellular techniques. Furthermore, 1t is only through such basic studies that potential means of fertility regulation will emerge. The various physiological events in animal reproduction such as fertilization and implantation essentially involve an interaction between specific cell membrane components. Similarly, embryogenesis involves the expression and regulation of genes at various stages of development. Therefore, the entire Workshop was specifically devoted to two topics: 1) Structure, function, and biosynthesis of membrane components, and 2) Gene expression and regulation as related to animal reproduction. The presentations relating to each topic are presented in separate sections in this book.
An International Conference on "Therapeutic. Psychological and Research Aspects of Amyotrophic Lateral Sclerosis" was held in Varese. Italy from the 27th to the 31st March 1985. Health care professionals. scientists. patients and their families from twenty countries around the world participated in this meeting. The objectives of the Varese conference were the following: a. To provide a forum for the proponents of the various paths of research into ALS. b. To correlate the useful therapies employed regionally. for the purpose of developing a common guide for patients, families, and supporting professionals. c. To encourage self-examination by the health care professionals into the psychological barriers imposed by a diagnosis of terminal illness for which there is no known cause or cure. Not surprisingly, there were no announcements of "breakthroughs" or "miracle cures", which are nonetheless hoped for in the confrontation of a disease such as ALS. It is fair to say, however, that Varese provided the context for a thorough review of what is known about ALS and we hope that the papers will renew some of the enthusiasm which has characterized this conference. The book contains six sections: Basic Research Aspects, Diagnostic Tools, Clinical Management, Therapeutic Trials, Psychological Aspects and the Epidemiology of ALS. Certain aspects, such as pathological studies and animal models, have not been covered; these subjects were partially treated during the informal sessions. Nevertheless, the large number of papers bears evidence to the growing interest in ALS and to the success of the Varese meeting.
Atherosclerosis which accounts in Western Europe for more than 40 % of deaths, is a generalized disease that develops slowly and is symptomless until lesions have become sufficiently severe to cause myocardial or cerebral infarction. Research on specific and precocious markers of atherosclerosis and the development of non invasive techniques for their early detection represent major challenges in biomedical field. We hope that this volume of edited papers, a consequence of the third international colloquium on atherosclerosis, conducted at the University of Brussels, Belgium through the support of the "Fondation de Recherche sur l' AtherosclE,rose" will contribute to this goal. Among the topics discussed the major ones were the mechanism of action of lipolytic enzymes, the deficiency or dysregulation of cellular receptors, the genetic deficiencies of apolipoproteins, and the panoply of external factors as diet, physical exercise, drugs, which mOdify the lipoprotein metabolism. Special interest was also devoted to potent techniques as kinetic analysis of metabolic tracers and use of monoclonal antibodies. Their contribution to the detection and treatment of atherosclerosis will be obviously essential in the future.
Pancreatic a-cell biophysics has undergone a veritable informa tion explosion in the past two years. Single channel and macroscopic currents have become easily accessible following the introduction of the patch clamp technique. In addition to this new approach, further development of techniques for optical measurements, ion-sensitive microelectrodes, permeabilized cells and mathematical modelling have recently added to the now classical techniques of membrane potential recording and tracer flux measurement. The International Workshop on Biophysics of the Pancreatic a-Cell held in Alicante (Spain) on Sep tember 30 - October 1, 1985, has now given us the opportunity to share experiences with these new techniques applied to the a-cell. Further more this was the first occasion for most of the groups doing patch clamp studies of the a-cell to decide on appropriate nomenclature and to debate the different characteristics of the a-cell ionic channels. To make this information available to the larger scientific community a record of the meeting has been assembled in this book. It is a collection of research papers by leading scientists at the meet ing working on biophysical, biochemical and physiological aspects. of secretion. We grouped their contributions in seven sections, includ ing new experimental approaches, K-channels, Ca-channels, role of ionic channels, intracellular ionized calcium, neural regulation and mechanisms of insulin release. Each section gives an account of the state of the problem at the time of the meeting, and the subjects are analyzed from the different perspectives of the various contributors.
During the past 5 years rapid progress has been made in the understanding of biochemical pathways for signal transduction in lymphocyte activation. Gene cloning technology has been instrumental in defining and making available in pure form of a number of growth and differentiation factors, in the characterization of their receptors, and in the delineation of genes for the T cell receptor. This book is divided into 6 sections. Section 1 deals with the molecular structure of the T cell receptor. Section 2 discusses the role of the T cell receptor, membrane ion channels and biochemical pathways of signal transduction in T cell activation. The molecular structures and biological and immunological effects of interleukin 1, interleukin 2 and interleukin 3 are presented in Section 3. This section also details the structure of interleukin 2 receptor and its use as a target for therapy for certain leukemias. Section 4 includes the biochemical events which occur following the delivery of the signal for B cell activation, proliferation, and differentiation by antigen, growth/differentiation factors. The molecular structure of B cell stimulating factors is also discussed. The role of oncogene expression in cellular activation and differentiation is included in Section 5. The cellular and molecular basis of natural killing and the molecular basis of cyc1osporin A-mediated immunosuppression are discussed in detail in Section 6. We hope this book will serve as a reference work on basic mechanisms of lymphocyte activation, proliferation, and differentiation for immunologists and molecular biologists.
The International Symposium on The New Dimensions of Warfarin Prophylaxis held on October 16-18, 1986 in New York City was conceived as a forum to bring together physicians and other scientists knowledgeable about the pharmacological effects of warfarin on the hemostatic mechanism and the clinical usefulness of this compound in the prevention of thromboembolic phenomena. The coumarin compounds have commanded a striking breadth of interest among members of the biomedical research community for almost one-half century. Aspects of its effects on the vitamin K-dependent proteins, on the laboratory recognition of the drug's pharmacologic action and its use as a therapeutic agent in a variety of disease states have been actively studied with increasing intensity in the past several decades. Thus, the present state of these studies seemed to be a timely subject for discussion, not only to gather together in one place representative samples of the myriad of data on warfarin, but also to underscore the ever increasing necessity for communication between basic research and clinical practice. The content and organization of this monograph reflect the scope and importance of warfarin prophylaxis. One of the unique aspects of this publication is that it spells out in one place the warfarin story from molecular biology through clinical trials to future directions of research and patient care.
The International Society on Oxygen Transport to Tissue (ISOTT) was founded in 1973 "to facilitate the exchange of scientific information among those interested in any aspect of the transport and/or utilization of oxygen in tissues". Its members span virtually all disciplines, ex tending from various branches of clinical medicine such as anesthesiology, ophthalmology and surgery through the basic medical sciences of physiology and biochemistry to the physical sciences and engineering. The fifteenth annual meeting of ISOTT was held in 1987 for three days, from July 22 to 24, at Hokkaido University in Sapporo, Japan. Previously, all ISOTT meetings had been held in Europe or the USA alternatively. This time, however, the meeting was held for the first time in an Asian country. When we first started preparing for this meeting some of our members were afraid that the number of those attending would not exceed '30. Fortunately the results were quite different. We had more than 60 participants from abroad and an even greater number from Japan. In addition to three special lectures and two symposia there were a total of 88 posters presented over the three days of the meeting. These covered all aspects of physiological oxygen transport including convection, diffusion, chemical reaction, and control of oxygen demand in blood and various tissues as well as the methods, models and instrumentation for their study. The 92 papers which comprise this volume encompass all of these areas.
This book is the outcome of the Symposium held in Firenze-San Miniato (PI), October 6-9, 1986. The symposium was entitled "Sulfur Amino Acids, Peptides and Related Compounds" and was the 7th international symposium on taurine and associated substances. It is always difficult to introduce, with the right brevity and emphasis, a topic which has been studied in depth by numerous experts. Nevertheless, I shall do my best to give a historical perspective of the subjects of the meeting which I consider to be very important for the frontiers of research on taurine. The following topics have also become coherent areas of study during the development of research on taurine: metabolism, nutrition, neurochemistry, cardiovascular regulation. Although taurine was isolated in 1827 by Tiedman and Gmelin, its only biochemical role known at the time was the synthesis of bile salts in mammalian tissue. There has been an increasing interest in the biological action of taurine from metabolic aspects to other biological aspects (nutrition, development, etc.). In 1975 it was first demonstrated that taurine deprivation product retinal degeneration that taurine deprivation produced retinal degeneration in cats: more recent studies showed that a taurine-free diet or the administration of taurine transport inhibitors caused retinal degeneration in other mammlas. More recent studies have pointed out the role of taurine in development, and the first part of this book is dedicated to these topics. From the pioneer work of Read and Welty, which showed the antiarrhythmic action of taurine, particular attention has been focussed on the effect of taurine on cardiovascular regulation. One important issue is inotropism and the cardioprotective effect of taurine. Although pharmacological studies are in progress on structure-action relationships, there are few electrophysiological studies, and thus the action of taurine on ion currents has yet to be clarified. Neurochemistry, with neuropharmacology, is widely represented in this book. The data are interesting although the classical question "Is taurine a neurotransmitter?" is still without reply, at least for mammadlian tissue. Is should like to point out the multidisciplinary approach of the symposium and consequently of the book, a fact also demonstrated by the different methodological approaches represented. In the symposium a taurine antagonist was introducted and in the interests of research, I hope that it will be very selective. Although much progress has been made in discovering the biological role of taurine no insight on its mechanisms is available, although the unifying hypothesis of Ryan Huxtable is a good point at which to start new research. I hope that this book will be good guide to the state of the art of research on taurine and related compounds.
Coronaviruses have emerged during the past ten years from being a group of viruses causing a variety of minor veterinary and human diseases to a major virus group of both clinical significance and molecular biological interest. Against this background, two international coronavirus symposia were held in 1980 and 1983. In recent years, the pace of coronavirus research has been quickened even more by infusion of recombinant DNA technology and establishment of various animal model systems to study the pathogenesis and immunology of coronavirus infections. We therefore organized the Third International Coronavirus Symposium held at Asilomar, California in September 1986, which was attended by more than 120 participants representing a cross section of both academia and industry. This symposium provided an exciting and stimulating forum for assessing the progress made since the last triennial symposium in Netherlands and to suggest the directions for future efforts. This volume collects the scientific papers presented in this symposium. Three loosely defined areas, Molecular biology, Virus-Cell Interaction and Viral Pathogenesis, are separated. These papers very nicely summarize the current status of coronavirus research. They contain a large amount of sequence data, including the complete sequence of a 27 Kb coronavirus genome, a novel mechanism of mRNA synthesis that is unique to coronviruses, and many exciting aspects of coronavirus pathogenesis and immunology. Reflecting the growing interest in the preparation of vaccines, several papers also address the issues related to coronavirus vaccines, which is an area new to this symposium. Dr.
Rapid advances have taken place in various aspects of reproductive biology during the last decade. These advances have centered around several organ systems that comprise the reproductive system and encompass molecular events and structure-function relationships. It becomes important to review these advances in knowledge, at periodic intervals, with respect to feedback systems and regulatory loops that control reproductive processes in vivo. Towards this end, a workshop entitled "Functional Correlates of Hormone Receptors in Reproduction" sponsored by the National Institute of Child Health and Human Development and the Reproductive Biology Study Section of the Division of Research Grants, National Institutes of Health was held in October 1980. The proceedings of the workshop were published by Elsevier Biomedical/New York. This workshop was followed by two workshops sponsored by the Reproductive Biology Study Section of the Division of Research Grants, National Institutes of Health entitled "Role of Peptides and Proteins in Control of Reproduction" in February 1982 and published by Elsevier Biomedical and "Molecular and Cellular Aspects of Reproduction" in October 1985 and published by Plenum Press. It was, therefore, timely to review the current state of knowledge regarding the regulation of ovarian and testicular function by bringing together scientists working in separate and discrete aspects of reproduction to review the functional implications of their research on the regulation of function within the same tissue and also in relationship to feedback systems and regulatory loops with other tissues.
The theme of this volume--risk analysis in the private sector--reflects a changing emphasis in risk analysis. Until re cently, attention has been focused on risk analyses conducted in support of federal regulatory decision making. Such analyses have been used to help set safety standards, to illuminate issues of regulatory concern, and to evaluate regulatory alternatives. As this volume indicates, however, risk analysis encompasses a broader set of activities. Analyses performed by private sector institutions aimed at preventing or reducing potential adverse health or environmental effects also play an important part in societal risk management. In virtually all societies, there have been strong incentives for the private sector to conduct such analyses. These incentives range from moral or altruistic norms and values to simple self-interest based on fear of monetary loss, possible civil or criminal litigation, or punitive or restrictive government action. The papers in this volume address the overall theme from a variety of perspectives. Specifically, the papers represent con tributions from such diverse fields as toxicology, epidemiology, chemistry, biology, engineering, statistics, decision analysis, economics, psychology, philosophy, and the law.
The interaction of neurotransmitters, neuromodulators and neuroactive drugs with receptors localized at the cell surface initiates a chain of molecular events leading to integrated neuronal responses to the triggering stimuli. Major advancements in the characterization and isolation of recep tor molecules have answered many quest ions regarding the nature of the ele ments that determine the specificity in these interactions. At the same time, recent studies have provided evidence that delicate regulation by intracellular enzymatic systems determines the efficiency of the stimulus response coupling process, mediates the interaction between receptors, operates in feedback control mechanisms and transduces signals from the receptors to various effector sites in a highly coordinated fashion. These studies are at the focus of the present volume, which is an outcome of a symposium held at the University of Vermont College of Medicine on March 21-23, 1986, in conjunction with the seventeenth annual meeting of the Amer ican Society for Neurochemistry. The symposium has demonstrated clearly that the concerted efforts of investigators in neurophysiology, biochemis try, pharmacology, cell-biology, molecular genetics, neurology, and psy chiatry are required to achieve better understanding of the processes under lying neuronal responsiveness. This volume includes contributions provided by prominent investigators in all these research areas. We hope that the readers will find here a useful source of information and ideas for stimu lating further studies which may serve to narrow the gap between basic neuroscience research and its clinical implications.
The present book contains the Proceedings of a two day Symposium on Uremic Toxins organized at the University of Ghent in Belgium. A series of guest lectures, free communications and posters have been presented. An international audience of 163 scientists from 16 nationalities listened to and discussed extensively a spectrum of topics brought forward by colleagues and researchers who worked for many years in the field of Uremic Toxins. There is a striking contrast between all the new dialysis strategies available in the work to "clean" the uremic patients and the almost non-progression of our knowledge on uremic toxins in the past decade. In this sense the symposium was felt by all participants as a new start for the research in the biochemical field of the definition of uremia. If the present volume would stimulate new work in this field in order to define uremia, or identify the uremic toxins, the purpose of the organizers would be maximally fulfilled.
The purpose of this annual symposium of the Eastern Pennsylvania Branch of the American Society for Microbiology was to organize a panel of scientists to review the many newer aspects of urogenital infections (UGI). From the onset it was recognized that the subject of UGI is a broad one and that it would not be possible to do justice to all aspects in a two day program. Therefore, it was agreed not to attempt an extensive review of the many recognized sexually transmitted diseases (STD), in that these have been the subject of other recent scientific symposia either individually or collectively. The major goal of this meeting was to review the many newer aspects of UGI relating to the pathogenesis of infections, newer treatment modalities, and newer approaches to the laboratory diagnosis of the respective diseases. The sessions were organized primarily along the lines of different etiologic agents of UGI. The opening session presented an overview of UGI, with major emphasis on new therapeutic modalities. This area has expanded greatly in recent years because of a better understanding of the etiology of such infections as well as the availability of newer effective chemothera peutic agents.
This symposium was established in 1976 for the purpose of bringing to gether once every two or three years, active investigators in the fore front of contemporary immunology, to present their findings and to discuss their significance in the light of current concepts and to identify important new directions of investigation. The founding of the symposium was stimulated by the achievement of major breakthroughs in the under standing of the immune recognition of proteins and peptides. We believed that these breakthroughs will lead to the creation of a new generation of peptides which should have enormous potential in biological, therapeutic and basic applications. This anticipated explosion has finally occurred and many applications of these peptides are now being realized. The main symposia topics of the fourth symposium were: T-cell recognition of proteins, structure and function of the T-cell receptor, presentation of protein antigens, recycling and activation of membrane receptor molecules, Ir-gene control of T-cell responses and methods of cell separation. The molecular features recognized by antibodies on proteins were the first immune recognition sites to be local ized and confirmed by synthetic peptides. The complete antigenic structures of several proteins have been defined, and individual antigenic sites have been described on many more proteins. More recently, major breakthroughs have been reported in the immune recognition of proteins by T cells.
The papers in this volume were presented at the Symposium on Cell Biology of the Uterus held December 12, 1986, on the NIH campus, Bethesda, MD. This was the first of a series of meetings that will be held in con junction with the annual meeting of the American Society for Cell Biology. The uterus is now recognized as an extremely complex organ whose nor mal function is orchestrated by a delicate procession of cellular and molecular events that investigators are beginning to unravel for the first time. Powerful new analytical methods and the tools of molecular biology are now providing exciting breakthroughs in our basic understanding of uterine structure and function. Thus, the program of this meeting was or ganized to cover recent developments in uterine cell biology including the mechanism of hormone action, control of gene expression by nuclear acceptor sites and nuclear receptors, role of growth factors, endometrial cell kine tics during the menstrual cycle, regulation of specific protein synthesis and secretion, decidual cell function, and the role of early pregnancy pro teins. The material presented in this volume is concerned not only with how hormones and growth factors prepare the endometrium for implantation of the blastocyst, but it also details the recent characterization and identification of specific marker proteins secreted in response to hormone action and early pregnancy.
This book arose from a meeting held at the University of Washington, Seattle, in July of 1986. The meeting was a satellite symposium of the XXXth International Congress of Physiological Sciences which occurred in Vancouver, canada, at that time. 2 Adjustments in the cytoplasmic Ca + concentration of cells occur in response to a variety of external signals. These fluctuations are a cen tral component of one mechanism by which cells adapt their activities to changes in the external environment and to the requirements of whole body 2 homeostatic mechanisms. It is now clear that redistribution of Ca + within 2 intracellular compartments, as well as changes in the rates of Ca + influx and extrusion at the whole cell level, occur during signal-dependent 2 changes in the cytoplasmic Ca + concentration. In summarizing current research in this area, this volume considers first the properties of indi vidual cation transporting activities located in various cell membranes. It then moves to the cellular level, where the consequence of individual transporting activities acting in concert is examined. l!D.phasis is also 2 p1 aced on pa tho1 ogica1 conditions which resu1 t in loss of cell Ca + regu1 a tion as a part of the disease process. We hope that this approach will help the reader to integrate developments in this large and rapdi1y changing fie1 d.
Growth factors are elaborated to control the growth of cells in such physiological processes as wound healing, tissue regeneration and the immune response. Abnormal production of these growth factors, their receptors or intracellular med!ators of their action may lead to disease states including oncogenesis. This volume will focus on exciting developments in defining the precise molecular lesions that permit the conversion of controlled proliferative signals to neoplasia, on the possible involvement of growth factors in the development of blood vessel diseases as seen in diabetes and atherosclerosis, on the altered immune surveillance that leads to autoimmunity and on the fundamental mechanisms by which growth factors signal their target cells. We expect that the contents of this volume will help promote understanding of the role of these fundamental biological processes and their alterations in a wide variety of disease states and stimulate new investi gations in this important area of biomedical research. The Editors v CONTENTS PERSPECTIVES ON THE CONTROL OF GROWTH AND DIFFERENTIATION Perspectives on the Biology of Growth Factors . . . •. . . . . . . . . . . . . . . • I. B. Fritz Platelet-Derived Growth Factor- Its Role in Health and Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 R. Ross and E. W. Raines Molecular and Developmental Biology Aspects of Fibroblast Growth Factor. • . . . . . . . . . . . . . . • . . . . . . . . . • • . . . . . . . . . . . . . . . . . . • 23 D. Gospodarowicz Chemical and Biochemical Properties of Human Angiogenin. . . . . . . . . . 41 B. L. Vallee and J. F. Riordan GROWTH FACTOR - ONCOGENE RELATIONSHIPS Structure - Function Relationships in Cellular and Viral fps/fes Cytoplasmic Protein-Tyrosine Kinases. . . . . . . . . . . . . . . . . . . . . . . . 55 T. Pawson. P. Greer, M. Moran, K.
In recent years there has been rapid progress in research on vascular endothelium. This has led to significant advances in our understanding of the structure and function of vascular endothelium in health and disease, including such aspects as the permeability of endothelium in relation to its ultrastructural correlates, theoretical basis, regulatory factors, and role in atherogenesis; the interaction between endothelium and blood cells; the endothelial release and processing of a number of important physiological agents, such as eicosanoids, hemostatic factors, and histamine; the cell biology of endothelium with respect to the cytoskeletal apparatus, cell activation, and cell locomotion; and the role of endothelium in microcirculatory regulation in normal and pathophysiological circumstances. A Symposium on "Vascular Endothelium in Health and Disease" was held on August 5-6, 1987, at the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China, following the 4th World Congress for Microcirculation in Japan. Experts working on various aspects of vascular endothelium came from allover the world to participate in this two-day Symposium and gave excellent presentations. This volume, embodying the proceedings of that Symposium, is a collection of the papers given by the speakers with, in many cases, further updating and new information added subsequent to the Symposium. The Institute of Biomedical Sciences (IBMS), the site of this Symposium, is a newlJl established research institution, which has vascular endothelium as one of its areas of research emphasis.
Plasma lipoproteins constitute a unique macromolecular system of lipid-protein complexes responsible for the transport of lipids from their sites of origin to their sites of utilization either as metabolic fuel or as structural components of cell membranes. Although studies on the role of lipoproteins in the mechanism of lipid transport are meritorious in their own right, the ever-increasing interest in chemical and functional properties of this remarkable class of conjugated proteins stems from the impressive evidence of their direct involvement in the genesis and develop ment of atherosclerotic lesions. The initial emphasis on neutral lipids and phospholipids as the most characteristic constituents of operationally defined lipoprotein classes has shifted in recent years to their protein moieties or apolipoproteins. The discovery of a number of apolipoproteins and characterization of familial hypolipoproteinemias as apolipoprotein deficiency disorders indicated that apolipoproteins play an essential role in maintaining the structural stability and integrity of lipoprotein particles. In addition to their role in the formation of lipoproteins, apolipoproteins were shown to perform a variety of functions in metabolic conversion of lipoproteins and their interactions with cellular surfaces. Results from several laboratories have demonstrated that the chemical and metabolic heterogeneity of operationally-defined lipoprotein classes is due to the presence of several discrete lipoprotein particles with similar physical properties but different and characteristic apolipoprotein composition. Thus, the apolipoproteins have emerged not only as essential structural and functional constituents of lipoproteins but also as unique chemical markers for identifying and classifying lipoprotein particles.
The time seems ripe for a critical compendium of that segment of the biological universe we call viruses. Virology, as a science, having only recently passed through its descriptive phase of naming and num bering, has probably reached that stage at which relatively few new~ truly new~viruses will be discovered. Triggered by the intellectual probes and techniques of molecular biology, genetics, biochemical cytology, and high-resolution microscopy and spectroscopy, the field has experienced a genuine information explosion. Few serious attempts have so far been made to chronicle these events. This comprehensive series, which will comprise some 6000 pages in a total of about 22 volumes, represents a commitment by a large group of active investigators to analyze, digest, and expostulate on the great mass of data relating to viruses, much of which is now amorphous and disjointed and scattered throughout a wide literature. In this way, we hope to place the entire field in perspective as well as to develop an invaluable reference and sourcebook for researchers and students at all levels. This series is designed as a continuum that can be entered anywhere but which also provides a logical progression of developing facts and integrated concepts.
It has been over 50 years since Hans Selye formulated his concept of stress. This came after the isolation of epinephrine and norepinephrine and after the sympathetic system was associated with Walter Cannon's "fight or flight" response. The intervening years have witnessed a number of dis coveries that have furthered our understanding of the mechanisms of the stress response. The isolation, identification and manufacture of gluco corticoids, the identification and synthesis of ACTH and vasopressin, and the demonstration of hypothalamic regulation of ACTH secretion were pivotal discoveries. The recent identification and synthesis of CRR by Willie Vale and his colleagues gave new impetus to stress research. Several new concepts of stress have developed as a result of advances in bench research. These include the concept of an integrated "stress sys tem", the realization that there are bi-directional effects between stress and the immune system, the suggestion that a number of common psychiatric disorders represent dysregulation of systems responding to stress, and the epidemiologic association of stress with the major scourges of humanity.