Free radicals appear to play a mojor role in many neurological (and non neurological) dieseases. Both acute and degenerative disorders are thought to involve free radicals reactions in tissue injury (for a list see this book page 18). This issue is very important for basic science and for therapeuthic approach as well. In order to review and discuss the place of free radicals in psychiatry and neurology, a joint meeting was initiated by the World Health Organization and the Fondation Ipsen in Paris on June 17-18,1991. This book contains the papers presented during this meeting. Although the papers included in this volume have been produced in the framework of WHO/Fondation Ipsen review of knowledge about free radicals and brain disorders, they express the views of the individual authors rather than a consensus of the participants at the meeting. They do not necessarily represent the decision or stated policy of the World Health Organiszation or the Fondation Ipsen. The editors wish to express their appreciation to Mrs Mervaillie for the organization of the meeting and Mrs M.-L. Gage for her editorial assis tance. L. Packer, L. Prilipko, Y Christen Contents Free Radical Scavengers and Antioxidants in Prophylaxy and Treatment of Brain Diseases L. Packer ........................................... 1 Reactive Oxygen Species and the Central Nervous System B. Halliwell .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 . . . . . . . . .

The proliferation of information on rotaviruses in the twenty years since their description as human pathogens has made it difficult to keep up with the latest developments in the field. Numerous aspects of rotavirus biology have been addressed in reviews, but these have been infrequent and quite selective in the material covered. The time appeared right to attempt to gather, into a single source, an overview of what we have learned. This volume is the result of that attempt. I hope that the reader will find in this single source, the core of information covering our current state of knowledge. I acknowledge my debt to the authors of the various chapters, for it is they who performed the tedious process of reviewing the literature and synthesizing and organizing it into concise works. R.F. RAMIG Contents Introduction and Overview R.F. RAMIG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Structure of Rotavirus B.V.V. PRASAD and W. CHIU .................... 9 The Rotavirus Genome U. DESSELBERGER and M.A. MCCRAE . . . . . . . . . . . 31 . . Rotavirus Protein Structure and Function G.W. BOTH, AR. BELLAMY, and D.B. MITCHELL 67 Rotavirus Replication J.T. PATTON . . . . . . . . . . . . . . . . . . . . . . .. . . . 107 . . . . . . .

In spite of a long history of intense investigation the transmissible spongiform encephalopathies remain a poorly understood family of neurodegenerative diseases. This group of diseases has been described in a wide variety of animal species and includes kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler syndrome in humans, and scrapie, bovine spongiform encephalopathy, and related syndromes in ruminants and rodents. In all cases spongiform degeneration and astrocytosis are seen in specimens of brain and a filterable transmissible agent is present in the brain and some other tissues of affected individuals. However, the precise nature of this agent remains unknown. Agent infectivity, which can so far only be assayed by serial transmission to new individuals, be remarkably resistant to inactivation has been shown to by heat, chemicals, and irradiation. These properties create significant biohazard possibilities during exposure to infected tissues. Transmission between humans was originally reco gnized in the unique epidemiology of kuru in New Guinea tribesmen, and concern about transmission from animals to humans has re-emerged as a result of the current epidemic of bovine spongiform encephalopathy in dairy cattle in Great Britain. Although interspecies transmission has often been achieved experimentally, its efficiency is highly variable. There fore, the possibility of spread of bovine spongiform encephalopathy from cattle to humans or various animal populations cannot be accurately predicted at this time. This volume presents a comprehensive update of know ledge concerning the transmissible spongiform encephalo pathies."

Der ausserordentlich grosse Zuwachs an Wissen seit der ersten Auflage dieses Handbuches vor rund 70 Jahren dokumentiert sich in den hier vorliegenden bei den Banden, die das Gebiet der klinischen Osteologie in reprasentativer Form zur Darstellung bringen. Die Gliederung in einen mehr theoretischen und in einen mehr klinischen Teil erschien aus zwei Grunden notig: Erstens sind fur das Verstandnis der Pathophysiologie der einzelnen Krankheitsbilder heute breite Kenntnisse der physiologischen Grundlagen erforderlich. So schien es ratsam auf den aktuellen Stand der diesbezuglichen endokrinologischen Forschung in Schwerpunktform einzugehen und die modernen Vorstellungen vom Knochenumbau und Kalzium- phosphatstoffwechsel darzustellen. Zweitens gibt es inzwischen eine grosse Zahl osteologischer Untersuchungsmethoden, die - um Wiederholungen bei der Ab- handlung der einzelnen Krankheitsbilder zu vermeiden - ebenfalls der Klinik vorangestellt wurden. Mit diesen Untersuchungen haben eine Reihe neuer quan- titativer Verfahren Eingang in die moderne Osteologie gefunden, die erst in neuerer Zeit eine Objektivierung von Skelettprozessen in diagnostischer und therapeutischer Hinsicht ermoglichen.

"De Motu animalium" is sometimes referred to in the medical literature. But who has read it? The book, originally published in Latin, seemingly constitutes the very first treatise on biomechanics. The author, Giovanni Alfonso Borelli (1608 - 1679), was professor of mathematics and physics in Pisa where he worked with Malpighi, who was professor of theoretical medicine and focused Borelli's interest on the movements of living creatures. This was the time of Galileo, Descartes, Newton and many others, when sciences exploded, sometimes leading to conflicts with religious authorities. "De Motu animalium," Borelli's life work, has two parts. In the first part, he analyses the action of the muscles, the movements of the limbs and motions of man and animals, including skating, running, jumping, swimming and flying. The second part deals with what is now called physiology, considered from the point of view of a mechanist: heart beat, blood circulation, breathing, separation of urine from the blood in the kidneys, liver function, reproduction, fatigue, thirst, hunger, fever, and so on. This work shows Borelli to be a genial precursor. He expresses his opinion as a mathematician on problems which afterwards further stimulated the curiosity and endeavours of many generations of researchers. This book will be welcomed by anybody who is interested in the working of living bodies and in the history of human knowledge.

This book is designed to be a physician's guide for those interested in diving and hyperbaric environments. It is not a detailed document for the erudite researcher; rather, it is a source of information for the scuba-diving physician who is searching for answers put to him by his fellow nonmedical divers. Following the publication of The Underwater Handbook: A Guide to Physiology and Performance for the Engineer there were frequent requests for a companion volume for the physician. This book is designed to fill the void. Production of the book has been supported by the Office of Naval Research and by the Bureau of Medicine and Surgery, Research and Development Command, under Navy Contract No. NOOOOI4-78-C-0604. Our heartfelt thanks go to the many authors without whose contributions the book could not have been produced. These articles are signed by the responsible authors, and the names a e also listed alphabetically in these preliminary pages. Every chapter was officially reviewed by at least one expert in the field covered and these reviewers are also listed on these pages. Our thanks go to them for their valuable assistance. We are grateful to Marthe Beckett Kent for editing Chapter III. Our thanks also go to Mrs. Carolyn Paddon for typing and retyping the manuscripts, and to Mrs. Catherine Coppola, who so expertly handled the many fiscal affairs.

At the beginning of the century the average life span in developed societies was less than 50 years. It is now more than 70 years and will continue to increase in the near future. Aging is a challenge to science and society. There are several theories of aging. The programmed aging hypothesis suggests that aging cannot be altered by any external influence, that aging is programmed from the beginning of life until the end of senescence. Another theory is based on genetic instability, with repair processes correcting errors in the cells that cause aging. Aging processes manifest themselves at the molecular and cellular level, in different organs, and in the whole organism. Most older persons acquire multiple diseases, primarily chronic ones. The multimorbidity of the elderly raises many questions as to nutrition, metabolism, immunity, drug therapy, and rehabilitation. Nutrition may be able to intervene in the aging process. Aging is associated with dec lining immunity and reduced resistance to many diseases, and it is pos sible that nutritional changes in old age contribute to the declining immunity in the elderly. The elderly take 40% of the prescription drugs in Germany and adverse drug reactions are more frequent in geriatric patients. There are not only problems in drug therapy for elderly pa tients, but also in their rehabilitation. The aim of rehabilitation is the restoration of geriatric patients to their former functional and environ mental status."

The application of immobilized enzymes in medicine is the main objective of this book. The author reviews natural and synthetic carriers for enzyme immobilization, chemistry of enzyme binding, and in-vitro and in-vivo properties of immobilized enzymes. Four chapters are dedicated to clinical use of immobilized enzymes.

An up-to-date overview of acute and chronic pancreatitis. The two authors with special interests in this field deal with the aetiology, pathophysiology, and clinical features of these diseases, as well as complications, treatment strategies, and prognostic factors. Two chapters on congenital abnormalities and hereditary pancreatic diseases round off this book. Intelligently-structured for everyday practice, this can also be used as an actual reference book. For gastroenterologists in clinic and practice.

Six members of the Herpesviridae family are human pathogens, including herpes and 2 (HSV-I and 2), Epstein-Barr virus (EBV), varicella zoster simplex virus I virus (VZV), human cytomegalovirus (HCMV), and human herpesvirus 6 (HHV 6). Each of these viruses is capable of causing distinct diseases of varying severity in children, young adults, and the aged. The diseases range from infection of epithelial tissue to the infection of internal organs and white blood cells. A common feature of the six pathogenic human herpesviruses is their ability to latently infect different cell types in which the viral DNA is not integrated and is unable to express its pathogenicity. Reactivation of the herpesviruses is a result of cellular processes which reactivate viral genes, leading to virus progeny and to signs of infection. Due to their ability to become latent after initial infection, once the pathogenic herpesviruses infect children they are maintained throughout life, having the potential of cause various diseases upon reactivation.

Nutritional support of critically ill patients is a major treatment modality which will enhance recovery and shorten convalescence. New knowledge has emphasized that much of the organ dysfunction associated with sepsis and altered blood flow is related to oxidative injury. Specific nutrients are highly effective in counteracting these effects and their early administration may attenuate cellular damage and multi-organ failure. Patient outcome may also be enhanced by the route of feeding, administration of newer nutrient combinations, utilization of evolving methods of monitoring and the use of growth factors. This new knowledge has evolved to a new area of metabolic support which is addressed for the first time by a group of international experts. The topics presented and general conclusions are of major importance to the practitioners in this field, for they show, for the first time, a departure from the more traditional approaches of nutritional support in patients with life-threatening diseases.

The Fifth World Congress of the International Society for Diseases of the Esophagus was held in the historic city of Kyoto, Japan, from August 5 through 8, 1992. Approximately 40 countries throughout the world participated and roughly 500 presentations were made. Excellent authors were selected and they were requested to send in their manuscripts for publication of this book. It is our ardent hope that this book will prove to be beneficial to the doctor interested in the esophagus and that it will provide the reader with first-hand information from leading scientists and clinicians in this field. The incidence of esophageal diseases vary greatly from country to country and in recent years, worldwide interest in these diseases has resulted in various international studies. The International Society for Diseases of the Esophagus was inaugurated by Professor Komei Nakayama in 1979 and since that time it has actively contributed to the exchange of information regarding these diseases and has made endeavors in bringing about advancement in the struggle against diseases of the esophagus in every way possible.

The clinical biochemistry ofhepatobiliary diseases is very widely studied, and publica tions abound on this topic. However, there is no recent publication that provides a comprehensive collection of the various leading aspects that go to make up this complex theme. Therefore, we thought it useful to gather together a few scientists whose work has focused on the various clinical biochemistry-aspects of these disorders in order that they might discuss their experience and expertise. The aim of the International Satellite Symposium on Clinical Biochemistry in Hepatobiliary Disease, in addition to reviewing the individual aspects, was to describe the state-of-the-art so as to provide useful data for laboratory scientists and also for physicians working in the field of hepatobiliary diseases, and these two aims are clearly reflected in the chapters of this volume. The volume opens with an introductory chapter that gives a general overview of the various aspects of the clinical biochemistry of these disorders, while the closing chapter deals with an important aspect that deserves to be increasingly emphasized in laboratory medicine, i.e., strategies to integrate information coming from the laboratory to make them more useful for clinical diagnosis.

On the occasion of a symposium in Salzburg, an international team of clinicians and pharmacologists presented recent results in profile efficacy, safety and therapeutic use of the antibiotic substance Ciprofloxacin. Of special interest for clinicians will be the clinical outcome in patients with nosocomial pneumonia and other infections of the lower respiratory tract.

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

Advances in molecular biology describing important enzyme systems involved in drug conjugation and deconjugation reactions and recent work indicating the importance of drug and xenobiotic conjugates as transport forms of biologically active compounds are reviewed comprehensively. Part One describes molecular events associated with the expression and regulation of transferases and hydrolases involved in Phase II drug conjugation and deconjugation. Part Two deals with the regulation of Phase II conjugation, and Part Three reviews critically the importance of drug conjugates in pharmacology and toxicology. This volume is an up-to-date source of information on this topic and will be of broad interest to pharmacologists and toxicologists.

An insight into new advances of current interest in metal toxicology, such as mechanisms important in risk-assessment for human health. The book also has chapters on emerging conceptual problems including resistance to metal toxicity effects on gene expression, alongside principles regarding drug-chelation of metals, the potential use of prophyrins as indicators of metal exposure and toxicity. The toxicology of specific metals of major public health concern are discussed in depth, such as mercury, aluminum, arsenic, chromium, and cadmium. Of interest to basic scientists as well as public health administrators.

for the design of control programs; in extreme cases (as dis cussed below, by Fine et al., this volume, and elsewhere) it can happen that immunization programs, although they protect vaccinated individuals, actually increase the overall incidence of a particular disease. The possibility that many nonhuman animal populations may be regulated by parasitic infections is another topic where it may be argued that conventional disciplinary boundaries have retarded investigation. While much ecological research has been devoted to exploring the extent to which competition or predator-prey interactions may regulate natural populations or set their patterns of geographical distribution, few substan tial studies have considered the possibility that infectious diseases may serve as regulatory agents (1,8). On the other hand, the many careful epidemiological studies of the trans mission and maintenance of parasitic infections in human and other animal populations usually assume the host population density to be set by other considerations, and not dynamically engaged with the disease (see, for example, (1,2)). With all these considerations in mind, the Dahlem Workshop from which this book derives aimed to weave strands together -- testing theoretical analysis against empirical facts and patterns, and identifying outstanding problems -- in pursuit of a better un derstanding of the overall population biology of parasitic in fections. For the purpose of the workshop, the term "parasite" was de fined widely to include viruses, bacteria, protozoans, fungi, and helminths."

On the occasion of a research visit to Thailand in my capacity as a member of the governing board of the South Asia Institute of the University of Heidelberg, I saw for the first time the severe clinical picture of dengue with haemorrhagic symptoms among Thai children. This visit had been made possible by Profes sor Dr. med. Dr. rer. nat. Ouay Ketusinh of Bangkok, to whom I wish to express my sincere thanks in this place. In 1972 the German medical literature - the periodical Medizinische Klinik, vol. 87, pp. 152-56, to be precise - had drawn attention to this new phenomenon in the disease panorama of South East Asia, indicating a change in dengue fever from being a relatively benign tropical dis ease to a form having serious clinical and epidemiological ramifications. During the ten years following my first publication the new clinical picture, described as "dengue haemorrhagic fever," has become a standard component in the Thailand's system of notifiable diseases. So too, the World Health Orga nization publishes regular reports in its Weekly Records. On March 30/31, 1981, its Regional Office for South East Asia convened a special conference in New Delhi, thus emphasizing the significance of the diffusion of this new clini cal picture in the states of South East Asia."

The differentiation between the muscarinic and the nicotinic ef- fects of acetylcholine led to the subdivision of the cholinergic ner- vous system into two categories. Further studies showed that stimu- lating and inhibiting muscarinic effects could be demonstrated in different organs. For instance, gastric secretion and gastrointestinal motility are stimulated, while heart rate and the vascular muscula- ture are inhibited. For decades, it could not be determined whether the various ef- fects were mediated by different subgroups of muscarinic receptors, but eventually, with the availability of agonists and antagonists to muscarinic receptors, and using various techniques, the existence of at least two such subgroups could be ascertained . . Mt receptors are defined by their high affinity for the antagonist pirenzipine in comparison to M2 receptors. This subdivision of muscarinic receptors has since been proved beyond doubt by experi- ments in vivo and in vitro, by receptor binding studies, by histoauto- radiography, and by electrophysiological studies. However, these different classes of muscarinic receptors have not been found to relate to different types of effects; instead both excit- atory and inhibitory effects appear to be linked to each class. For ex- ample, excitation of gut motility and inhibition of cardiac contrac- tile activities both appear to be mediated by M2 receptors, while ex- citation of some nerves in sympathetic ganglia and inhibition of some myenteric nerves may be mediated by M receptors.

Immunology, in all its facets of immunochemistry, humoral immunity, cellular immunity, immunodiagnosis, and immunotherapy, is currently the most rapidly advancing discipline of clinical and experimental oncology. But as in most developing subjects, it is continually beset with problems of methodology and nomenclature, both of which are often intertwined. Indicative of this problem are our circular definitions of antigen and antibody. Another fre quent problem is the use of the words "specific" and "associated" when characterizing re actions to tumors or the antigenic properties of neoplasms. When applied to cancer, these terms are obviously very dependent upon the methods used to demonstrate these qualities. Indeed, the very diverse nature and multitude of types of cancer preclude our making gen eralizations or categorical statements regarding tumor "specificity. " Similar problems arise when one considers that many antigens found in malignant tumors share certain properties with embryonic or fetal tissues. First, these observations emphasize a lack of true tumor specificity, for which reason the category of oncofetal antigens has been established. Second, whether or not such antigens are truly oncofetal depends upon the method of detection used, and it has been found that here too specificity decreases as the antigen assay increases in sen sitivity. Thus, whether substances can be truly oncofetal in nature still remains a matter of debate, and such terms must therefore be used in an operational sense.

Bronchoscopy means pictures: but to comprehend an image we have to learn to see. These excellent photographs, all taken by the author himself, not only instruct us in the art of seeing just about all there is to see in the bronchial system but also illustrate many relationships between visual appearances and the clinical situation. They go even further in correlating bronchoscopic find ings with the function of the lung. Treated in this way, the image comes alive. Anyone who has come to know DE KOCK as a brilliant clini cian, or who has worked with him in the lung function labo ratory - he has made important contributions in this field also would have expected him to produce a monograph of this calibre. Now we have such a book. It contains the selected results of many years' solid work. Due attention is, of course, also accorded the merits of the various bronchoscopic techniques which provide the essential background to satisfactory results. In writing this book DE KOCK has succeeded in projecting a vivid image of the bronchi and the functional lung into our mind's eye. This work undoubtedly opens new prospects in improved care of our patients.

Experimental gerontological research is necessary to obtain optimal information and thus ensure proper drug therapy for the elderly. Most older persons acquire multiple diseases, first of all chronic diseases. They involve complex problems of a physical, social, and psychological nature. The multimorbidity of the elderly raises many questions in drug therapy. By contrast with our extensive knowledge of pharmacokinetics and pharmacodynamics in younger age groups, few facts are available in respect of the elderly. A variety of factors may influence drug therapy. Physiological and pathological age-related changes of molecules, cells, organs, and the total organism may interact to enhance or inhibit drug therapy in higher age groups. It is well known that elderly patients are overmedicated and therefore the incidence of adverse drug reactions increases with age. Elderly patients with multimorbidity often have a diminished body clearance of drugs; age-related changes of the kidney seems to be one of the most important factors in this regard. Far less important than the elimination of drugs through the kidney is their excretion in the bile. So far results have disclosed that oxidative steps in drug clearance are more likely to be disturbed than phase II reactions. Furthermore; changes in distribution volume and age-related alterations in receptor sensitivity also influence the clearance of drugs in the elderly.

H. Hafner, G. Moschel, N. Sartorius The size of the world's population aged over 65 was estimated at about 250 million in 1980; by the year 2025 it is expected to grow to about 760 million (see Hauser, this volume). This sharp increase in life expectancy at birth, in some countries amounting to almost 100% in only a hundred years, has resulted from better nutrition and improved living conditions, hygiene and medical care. Not only life expectancy at birth, but also further life expectancy in advanced age has shown a clear, though more moderate increase. This increased life expectancy, together with a simultaneous fall in birth rates, has caused the mean age of the world population and, especially, the average age of the population of industrial nations to climb substantially in recent times, a development which will reach its peak only some decades from now. For these demographic reasons alone, health care authorities will have to devote more attention to the health problems of the elderly. The main task of medical research is to develop improved methods of disease prevention and treatment. Yet, because the full benefits of such research are only realized after many years of work, researchers have already begun to respond to demographic pressures by focussing part of their efforts on the study of illnesses characteristic of old age.