During the last years much attention has been given to the investigation of the roles of specific growth modulators acting on liver cell populations. HGF functions as a pleotropic factor in the liver as well as in other extrahepatic tissues. The hepatic stem cell compartment is thought to play a major role in liver tissue restoration. Mechanisms of cell growth and cell death of the liver are described in detail, with particular emphasis on apoptosis. The functions of HBV-pX protein and the roles of hepatitis B virus gene expression relation to hepatocellular carcinoma are discussed. Techniques for obtaining human and nonhuman hepatocytes and other liver cell types and for efficient transfer and expression of genes in hepatocytes and liver-derived cell lines are presented.

The serene phrase, Lest I forget thee, glutathione ..., coined by the Kosowers (1) to describe the state in the 1960's, must be replaced now by something like "Inevitable GSH" in order to characterize the current situation. The surge in interest on the ubiquitous tripeptide has been ama- zing, with publications on GSH running at rates as high as one per day, so that it seemed appropriate to convene international experts for a discussion of recent develop- ments this year. Unlike the two previous meetings in this decade held in Tlibingen in 1973 (2) and in santa Ynez in 1975 (3), the scope was restricted to Functions of Gluta- thione in Liver and Kidney. Only in this way did an in-depth discussion of the current state of knowledge in a limit- ed topic appear possible. The last couple of years have seen a fascinating pro- ductivity in the fields of (a) Regulation of the Glutathione Level in the Liver, (b) Role of y-Glutamyltransferase in Gluta- thione Turnover with emphasis on the renal enzyme, and a critical appraisal of the y-Glutamyl Cycle, (c) Hyd:roperox- ide and Disulfide Metaholism, enriched by the discovery of the nonseleniurn-dependent glutathione peroxidase activ- ity and its relation to the glutathione-S-transferases, and the participation of the 2GSH/GSSG system in redox transitions in intact organ, cells and isolated mito- chondria, and (d) a multitude of Pharmacological and Toxi- cological Aspects related to glutathione, mainly centered on the events leading to liver damage and the protective

La pathologie vasculaire a ete tres marquee par les progres biologiques de ces vingt demieres annees. Le systeme arteriel est main tenant considere comme un organe a part entiere. Modelee au cours de l'organogenese par les facteurs hemodynamiques, Ie paroi arterielle maintient une structure hautement organisee et des proprietes mecaniques qui dependent directement des conditions de pression et de debit. La monocouche endotheliale developpe 2 une surface de plusieurs centaines de m a l'interface sang-tissu; elle est a la fois un organe endocrine complexe synthetisant de nombreuses proteines qui participent a l'hemostase, une surface thromboresistante et hemocompatible, une barriere de permeabilite contr6lant les echanges sang-tissus. Les cellules musculaires lisses constituent un tissu multifonctionnel, contractile, assurant la synthese des composants structuraux responsables des proprietes mecaniques de la paroi arterielle, la transmission de la force contractile, et une etonnante activite reparatrice en reponse aux agressions. Tout ceci est soumis a un ensemble complexe de communications cellulaires qui font de l'endothelium un veritable systeme recepteur pour la paroi vasculaire. Parallelement, ou a la suite de ces progres, l'angeiologie s'est progressivement affirmee comme une specialite clinique. Debordant Ie cadre de la chirurgie vasculaire, elle integre les concepts physiopathologiques au diagnostic et au traitement des maladies arterielles. De cet effort d'integration est ne cet ouvrage, cherchant a concilier les connaissances fondamentales es plus recentes et la demarche clinique.

MOTOOMI NAKAMURA As we approach the 21st century, ischemic heart disease is the major cause of death in most of the developed nations of the world. Since the 1970s, much effort and expense have led to designs of coronary thrombolytic therapy, percutaneous coronary angioplasty (PTCA), coronary artery bypass grafting, heart transplantation, automatic defibrillators, as well as to the formation of beta blockers and com pounds which block the calcium channel. Socio-educational programs directed at exercise, diet, instruction in the risk factors of smoking, hyperlipidemia and hypertension have contributed to the decrease in the rate of morbidity and mortality of patients with ischemic heart disease. However, the first clinical event of ischemic heart disease, the so-called "heart attack" and sudden cardiac death continues to present problems, as the mechanisms involved in these events are poorly understood. It has long been thought that ischemic heart disease is the sequence of an organic fixed atherosclerotic obstruction of the epicardial coronary arteries and the role of coronary vasomotion has been given much less attention. Recent clinical and laboratory animal studies revealed that increased tonus and spasm of the large epicardial coronary arteries are the cause of various stages of ischemic heart disease. The role of coronary vasospasm in the development of un stable angina, sudden cardiac death and acute myocardial infarction remains open to debate. Pharmacophysiological studies showed that the epicardial large coronary artery contributes only 5% to regulation of normal coronary flow."

Physiologists have long been interested in the interaction, or coupling, between the heart and the vasculature. The early literature consists mainly of phenomenological descriptions of cardiac alterations resulting from specific interventions in the vasculature. Hundreds of studies, for example, describe functional aspects of hypertrophied myocardium associated with the excessive vascular loading produced by various types of experimental hypertension. Recently, the concepts of ventricular/vascular interaction have found important clinical application. The widespread use of vaso dilators and of intraaortic counterpUlsation balloons for unloading an ov erburdened, diseased heart is a prime example. Despite the interest in this field, until as recently as 20 years ago we were not able to describe ventricular or vascular function in a framework suitable for quantitatively expressing the interaction between these two complex systems. Three major developments-description of ventricular function in terms of both the time-varying elastance and the pump function graph and quantification of vascular function in terms of impedance have changed this. These functional descriptions now enable systems en gineers, bioengineers, physiologists, and clinicians to address very specific quantitative aspects of ventricular/vascular interaction and have resulted in a flurry of papers and symposia devoted to this subject."

Major advances have been made in the understanding of the molecular mechanisms of atherosclerosis, the disease that still affects more than 50 percent of the population in the highly industrialized countries. This volume covers the most recent advances in the treatment of hyperlipidemia. It represents a necessary update because molecular mechanisms of atherogenesis have been discovered in the past few years and their molecular mechanisms of action identified. Extensively treated are the molecular mechanisms of disease etiology of arteriosclerosis in relation to the major risk factor "hyperlipidemia," rationale for more effective treatment of this disease by dietary means, the treatment of associated or causing diseases, and the treatment using hypolipidemic drugs.

Stability of the internal environment in which neuronal elements are situated is unquestionably an important prerequisite for the effective transmission of information in the nervous system. During the past decade our knowledge on the microenvironment of nerve cells has expanded. The conception that the microenvironment of neurones comprises a fluid with a relatively simple and stable composition is no longer accepted; the microenvironment is now envisaged as a dynamic structure whose composition, shape, and volume changes, thereby significantly influencing neuronal function and the trans mission of information in the nervous system. The modern conception of the neuronal microenvironment is based on the results of research over the last 20 years. The extracellular space (ECS) is comprehended not only as a relatively stable microenvironment containing neurones and glial cells (Bernard 1878), but also as a channel for communica tion between them. The close proximity of the neuronal elements in the CNS and the narrowness of the intercellular spaces provides a basis not only for interaction between the elements themselves, but also between the elements and their microenvironment. Substances which can cross the cell membranes can easily find their way through the microenvironment to adjacent cellular elements. In this way the microenvironment can assure non-synaptic com munication between the relevant neurones. Signalization can be coded by modulation of the chemical composition of the ECS in the vicinity of the cell membrane and does not require classic connection by axones, dendrites, and synapses.

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."

Biologic System Evaluation with Ultrasound is a reference book for engineers in the field of ultrasonics and is intended to inform those unfamiliar with current methods of ultrasonic analysis. Explaining the mathematical and physical principles of ultrasound imaging of living tissue with effective precision, the book encompasses the following topics: relationships between the biological and scattering hierarchies; graphic description of scattering; class 1,2,3,4 scattering and their association with the biological hierarchy; instruments used for biologic system evaluation; computed tomographic methods of imaging. The authors have provided an effective explanation of the ultrasound scattering of image and image acquisition that will benefit engineers, physicists, and radiologists alike.

The interrelated syndromes of shock and the adult respiratory distress to attract the attention of both clinical and syndrome (ARDS) continue laboratory scientists. This reflects both the size of the problem and its unresponsiveness to current lines of treatment. Doubtless, a greater appreciation of the underlying pathophysiological disturbances during the past two decades has led to appropriate action and increased survival in the early stages but once established these syndromes have remained remarkably immune to a wide spectrum of therapeutic modalities. This observation stresses the importance of prevention but also indicates the need for continued research into the nature of the established syndromes and the means whereby they may be reversed. Drs Kox and Bihari are to be congratulated on bringing together within the covers of this volume many of the acknowledged European experts in these two fields of investigation. Each author has provided an up-to-date account of his current experimental and clinical research, and their com bined contributions makes fascinating reading. Undoubtedly, these are exciting times in the development of understanding of shock and ARDS. Inevitably, more questions are raised than answers provided, but the accumulated knowledge presented here adds significantly to our under standing of this complex biological jigsaw. From this corporate endeavour will come the clinically useful developments of the future and with them the ultimate hope that the term 'refractory' shock may be finally removed from our vocabulary.

This preface is addressed to the reader who wishes to inquire into the prevailing concepts, hypotheses and theories about development of sensory systems and wants to know how they are exemplified in the following chapters. I believe that science is hypothesis and theory and that the growth and evolution of any branch of science can be measured by the degree to which its theories have been reified. By that standard, one must conc1ude that developmental neuro biologie is in its infancy. The rapid accumulation of observations which has occurred in this branch of science in the past century leads to progress only to the extent that the facts validate or falsify hypotheses. The following chapters show that we have a plethora of facts but a dearth of hypotheses. Another index of the maturity of any branch of science is its level of historical self-awareness. Because the history of any branch of science is essentially the history of ideas and of the rise and fall of theories, the level of historical awareness is related to the extent to which reification of its hypothetical constructs has advanced. It is largely because few theories of development of sensory systems, or indeed, of developmental neurobiology, have progressed far in the process of reification that the his tory of developmental neurobiology remains unwritten. The subject of this volume is hardly mentioned in the many books devoted to the history of related disciplines."

Nitric Oxide (NO) an endogenous free radical, has been shown recently to mediate several important biological effects. It plays a neuro-transmitter like role in vascular endothelium, a scond-messenger role in N-methyl-D-aspartate (NMDA) responsive neurons in the central nervous system (CNS), a neurotoxic role after its release from these neurons, and a cytotoxic role after its release by macrophages.
This volume reviews among other topics the basic chemistry and physical properties of S-nitrosothiols (RS-NO) and their biochemical mechanisms of action, NO synthase isozymes, NO synthase structure, mechanisms of NO synthesis, regulation of NOS expression and posttranslational modification, and mechanisms involving NO of CNS's damage in virus infections.

With the explosion of information on autophagy in cancer, this is an opportune time to speed the efforts to translate our current knowledge about autophagy regulation into better understanding of its role in cancer. This book will cover the latest advances in this area from the basics, such as the molecular machinery for autophagy induction and regulation, up to the current areas of interest such as modulation of autophagy and drug discovery for cancer prevention and treatment. The text will include an explanation on how autophagy can function in both oncogenesis and tumor suppression and a description of its function in tumor development and tumor suppression through its roles in cell survival, cell death, cell growth as well as its influences on inflammation, immunity, DNA damage, oxidative stress, tumor microenvironment, etc. The remaining chapters will cover topics on autophagy and cancer therapy. These pages will serve as a description on how the pro-survival function of autophagy may help cancer cells resist chemotherapy and radiation treatment as well as how the pro-death functions of autophagy may enhance cell death in response to cancer therapy, and how to target autophagy for cancer prevention and therapy what to target and how to target it.

When survival is challenged by the cold, animals react by employing both behavioral and physiological solutions. Depending on the magni tude of the cold stress and the nature of the adjustment, simple avoidance or sophisticated capacity or resistance compensations may be used. Thus, migration, shelter seeking, metabolic and insulative compen sation, torpor, and freezing avoidance and tolerance are successful tac tics used by diverse groups of animals. To understand and appreciate the benefits of these tactics, it is necessary to examine not only the well being of the whole animal but also their basic underlying mechanisms. In ad dition, it is also of fundamental importance to grasp how seasonal cold affects the survivorship and reproductive success of populations when confronted by a general reduction in primary productivity and an elevated energy cost for maintenance (e. g. in endotherms). In this regard, a synthetic overview which integrates aspects of cell biology, biochem istry, physiology, neurobiology, behavior, and population biology should be a fruitful approach in providing a holistic understanding on how animals adapt to cold. The present volume is an attempt to achieve such an overview; its objective is to provide a depth and breadth of coverage that is essential to a full appreciation of animal adaptation to cold. It is the hope of the contributing authors that this book will serve as an effective reference text for all senior undergraduate and graduate students as well as research scientists with an interest in cold physiology."

This book is a compendium of proceedings from the Symposium on Growth Hormone II: Basic and Clinical Aspects. The intent of the sym posium was to review current aspects of the rapidly expanding science of growth hormone (GH) neuroendocrinology, especially those develop ments that occurred since our last meeting in 1985. The meeting was timely since there have been many new and exciting developments in basic research on the GH axis, and several new clinical applications for GH other than growth have been identified. For example, significant strides have been made into use of the bioengineered hormone as an anabolic in debilitated states and as an immunorestorative agent. Both these areas have received most attention as they relate to geriatric popu lations. Furthermore, recent focus on a novel family of GH secretagogues that complement the action of GHRH has shown that in animal models, these compounds have the potential to restore GH secretion in deficient or insufficient states, including growth retardation, obesity, and aging. Accordingly, these xenobiotics may have significant potential as drug products to stimulate physiological GH secretion and, thus, resist or reverse some of the maladaptive changes in form and function resulting from GH insufficiency. The importance of these agents as drug candidates is underscored by the diversity of molecules that have been studied by various pharmaceutical companies and the recent discovery that non peptide analogs with high oral bioavailability can be synthesized."

This book is the compilation of papers presented at the International Symposium on in vivo Body Composition Studies, held at the University of Toronto, Ontario, Canada, June 20 - 23, 1989. The purpose of this conference was to report on advances in techniques for the in vivo measurement of body composition and to present recent data on normal body composition and changes during disease. This conference was the most recent of several meetings on body composition studies, and follows two successful such meetings, one at Brookhaven National Laboratory in 1986, and at Edinburgh in 1988. The large number of excellent research papers and posters presented at these conferences demonstrates the rapid growth of the field and the broad interest in the subject of in vivo body composition studies. The proceedings of the Brookhaven meeting "In Vivo Body Composition Studies", is published by The Institute of Physical Sciences in Medicine, London. Both the Brookhaven and the current Toronto meeting emphasized the clinical applications, together with the techniques employed. The Edinburgh meeting placed more emphasis on the methodological problems and design of instrumentation. Because of the number of papers presented at the meeting it was necessary to ask the authors from the same institution to combine their presentations into a single paper where appropriate. The editors wish to thank the authors for their cooperation and for graciously accepting the minor revisions made to each manuscript.

Man has always been curious about himself, a curiosity that began centuries ago with an examination of the soul, and that extended in the period of the Renaissance to his anatomy and certain functions such as the circulation of the blood. Chemical science entered the scene in the 18th century, and burst into prominence in the 19th century. As the various chemical elements were discovered, many were found to be present in body fluids and tissues. Organic compounds were recognized; it became known that body heat was produced by the combustion of food; chemical transformations such as the production of fat from carbohydrate were recognized; and in the 1850s it was determined that young animals differed from adults in certain aspects of body composition. As methods for chemical analysis evolved, they were applied to samples of body fluids and tissues, and it became apparent that life depended on chemical normality; and most importantly it was realized that given the necessary amount of food and water the body had the ability to maintain a degree of constancy of what Claude Bernard called the milieu interieur, in other words its interior chemical en vironment."

This book is concerned with a quantitative analysis of dynamic behavior of various enzymatic reaction systems by computer simulation. The authors and coworkers have been engaged in cooperative research since 1975, seeking to clarify the catalytic and regulatory characteristics of enzymatic reactions in vivo and control mechanisms suitable for enzyme technology. Rather than "enzyme kinetics" generally known in enzymol. ogy, this research has employed an approach called "enzyme dynamics" which concentrates on the exact schematic representation of an actual reac tion mechanism, derivation of rate equation on the basis of the scheme, and computer simulation of its dynamic behavior (numerical solution of the rate equation and explanation of kinetic and regulatory properties of the enzymatic reaction). A rate equation representing the behavior of enzymatic reactions is gen erally expressed by a set of nonlinear differential equations. The analytic solution of rate equations is therefore impossible in general, making it necessary to introduce some approximations in order to analyze the exper. imental data in enzyme kinetics. For example, under an assumption of excess substrate against enzyme in a closed system, we commonly use the linear approximation for the early period of reaction, the quasi-steady state approximation based on putative maintenance of steady state in en zyme species, and the rapid-equilibrium approximation assuming instantane ous equilibration in complex formation and between complexes. The kinetic characteristics obtained by these approximations do not always reflect the dynamic behavior of actual enzymatic reactions."

This volume is based on a series of lectures delivered at a one-day teach ing symposium on functional and metabolic aspects of NMR measure ments held at the Middlesex Hospital Medical School on 1st September 1985 as a part of the European Nuclear Medicine Society Congress. Currently the major emphasis in medical NMR in vivo is on its poten tial to image and display abnormalities in conventional radiological im ages, providing increased contrast between normal and abnormal tissue, improved definition of vasculature, and possibly an increased potential for differential diagnosis. Although these areas are undeniably of major importance, it is probable that NMR will continue to complement con ventional measurement methods. The major potential benefits to be de rived from in vivo NMR measurements are likely to arise from its use as an instrument for functional and metabolic studies in both clinical re search and in the everyday management of patients. It is to this area that this volume is directed."

ARCHIVE COpy DO NOT REMOVE The public in industrialized countries shows a mounting concern about biological effects of electrical and magnetic fields. As a result, experimental studies on this subject are being published in increasing numbers throughout the world. Prof. H. L. Konig, of the Technical University of Munich, West Germany, a leading expert and pioneer in this field, has written an authoritative text in a lucid style which makes the material also accessible to lay readers. The book describes the effects of natural as well as artificial electromagnetic energies covering the en tire measurable frequency range from the highest frequencies, x-rays, through microwaves, radio waves, and finally extremely low frequency (ELF) waves. Cit ing the evidence from scientific studies in various countries, Konig also appraises the biologic effects of microwaves and high tension power lines, which have become controversial issues in recent years. Other contributions to the book have been made by Prof. Albert P. Krueger, University of California, Berkeley, on air ionization effects and by the mete orologist Walter Sonning on biometeorology, documenting the influence of atmo spheric electrical currents on health and disease. Moreover, the late Dr. Siegnot Lang, a former coworker of Dr. Konig, has contributed to this book."

Cardiovascular dynamics is a field in which modelling and systems analysis have formed an extremely important discipline. For example, understanding of even such a fundamental function of the circulation as the relationship between central venous pressure apd cardiac output has required evolution of a pertinent model based on years of exhaustive ex perimental investigations by Starling, Starr, and Guyton. Hemodynamic analyses of pulsatile pressures and flows in the arteries and veins have been a continuing challenge taken up by champions of fluid dynamics such as Frank, Wetterer, Taylor, and Wormersley, just to mention a few names, and some kind of model was always proposed as a conceptual framework. An even greater challenge to cardiovascular dynamicists was how to analyze the intermittent coupling of the ventricle and the arterial or venous vasculature through the valve. The availability of numerical solutions by computer and the recently evolved ventricular model with a time-varying elastance and a pressure-dependent internal resistance opened the way to analysis of this coupling. The ever increasing speed of computers has also facilitated trips between the fre quency and the time domain, even on-line for some experimental studies. This book contains many analyses dedicated to the interactions between the heart and the vasculature, providing the reader with findings at the cutting edge of current research in this field."

The recent surge of interest in designing, validating, and implementing short-term tests for carcinogens has been spurred by the fairly convincing correlation be tween the carcinogenicity and mutagenicity of chemicals and physical agents and by the assumption that DNA alteration, mutations, and chromosome aberrations are somehow involved in neoplastic transformation. Moreover, it has been tacitly assumed that the mutagenic capacity alone of compounds would induce regulatory agencies to pass rules for their removal from the environment and would lead the public to avoid them. The actual response, however, is quite different. Governmental departments shy away from making any decisions on the basis of in vitro test systems. The public at large is becoming irritated by daily an nouncements that many of their cherished habits could adversely affect their health. Industry appears to feel threatened and may reduce its search for new beneficial chemicals. The reluctance to accept wholeheartedly the mutagenicity tests for the detection of carcinogens is partly due to uncertainty about the in volvement of mutations in neoplastic transformation, partly due to the present difficulty of extrapolating results from various endpoints obtained on numerous organisms to man, and partly due to a multitude of complex events that lead in vivo to the evolvement of benign or malignant tumors."

The objective of this book is to provide information that will be useful to people in a variety of disciplines who wish to learn more about normal aging processes in the human body. Although gerontologists in the biological sciences are making great strides in research on human aging and documenting this work in mono graphs, texts, and review chapters, this information is generally not easily acces sible nor is it comprehensible to nonprofessionals in these fields. This book is intended to provide a summary of this work, along with its implications for psy chological functioning of the aging individual. The majority of the book is devoted to describing the results of research on the physiological changes in the human body with aging and to seeking explana tions for these age effects. This description has been approached in such a way as to make it readable for the nonspecialist, but also to focus on research issues that will be useful reading for those who are currently working in these parti cular areas. In addition, throughout the book, I have tried to develop some themes regarding physiological and psychological adaptation during adulthood."