This book provides a detailed overview of the function of the nervous system in fever and its role in antipyresis. The volume opens with an introductory account of fever, its physiology and adaptive role, and explains the mechanisms of thermoregulation. Sufficient information about bacterial pyrogens, 'endogenous' pyrogenic cytokines, body temperature regulation and survival value of fever and its ubiquity is given to enable readers to follow the central nervous system's involvement. The book should enable graduate students and researchers in neuroscience and other disciplines to understand the impact of their studies in the overall processes of fever. It will also be of benefit to pharmacologists studying anti-pyretics and the central nervous system function of these drugs. Academic clinicians will find this a more comprehensive overview of fever than other available texts. Finally, the author challenges some well-established dogmas in this area and sets an agenda for future research.

In 1960, Dr. Van R. Potter and Dr. Henry Pitot (at McCardle Laboratory in Madison, Wisconsin), Dr. Tetsuo Ono (then at McCardle Laboratory and now at the Japanese Foundation for Cancer Research in Tokyo, Japan) and Dr. Harold P. Morris (then at the National Cancer Institute and now at Howard University, Washington, D. C. ) decided that an experimental cancer model would be an invaluable tool to examine neoplastic changes in cells. Since they were study ing the various highly specific metabolic processes which are unique to liver tissues, they determined that a transplantable liver cancer model would be the ideal system to work with. This system would provide for comparison of normal liver tissue of the non-tumor bear ing animal, the tumor bearing animal's (host) liver and the liver cancer. Dr. Morris undertook a series of rat studies employing several chemicals known to cause liver cancer. Soon the first Morris hepatomas (#3683, 3924A, 5123) were being studied by several labs. During the next 18 years, Dr. Morris developed and transplanted numerous strains of hepatomas of which no two were identical. These tumors ranged from the very slowly-growing, highly differentiated cancer tissues, e. g., 96l8A which is a diploid tumor containing gly cogen and a "nearly normal" complement of enzymes, to a large group of rapidly-growing, poorly differentiated cancer tissues, e. g."

Jaundice is much more than a clinical sign of liver disease. It is also a pathophysiological disorder. Through studying it we have come to a much better understanding of how the liver functions under normal and abnormal circumstances. In spite of several important advances in this field, it has not recently been the subject of a comprehensive and interdisciplinary review. This Symposium was held in Montreal on May 31 and June 1, 1974, and the experts who participated in it came together for the purpose of reviewing the current status of Jaundice. The Editors sincerely appreciate the outstanding contribution which these experts made to the Second International Symposium of the Canadian Hepatic Foundation. They are also particularly indebted to Valerie M. Price, Executive Director, Canadian Hepatic Foundation, for her invaluable role in the preparation of this publication. Carl A. Goresky Murray M. Fisher v Contents BILIRUBIN CHEMISTRY An Overview of Bilirubin Chemistry 1 A. F. McDonagh The Conjugates of Bilirubin 19 E. R. Gordon Discussion Period. * * 39 R. Schmid, Char:imm BILIRUBIN PRODUCITON 43 Bilirubin Metabolism: An Overview * * * R. Schmid Bilirubin Production fram Non-Erythroid SoUI"Ces * * * * * * * * * * * * * * * * 57 S. H. Robinson Bilirubin Production fram Erythroid Sources 69 U. Muller-Eberhard and E. F. Johnson Induction Mechanisms for Bile Pigment Formation 85 B. A.

The practice of autologous blood collection and transfusion has been steadily increasing. The concept is not new; however, its application has been limited because of lack of interest and willingness to make the extra effort required. Also there has been concern about the safety of the procedure. Homologous blood transfusion is easy and has allo wed us to salvage lives and perform procedures which would not have been feasible without the availability of whole blood or its components. Transfusion with homologous blood products is safe; however, com plications can and do occur. The transmission of AIDS by transfusion of homologous blood products has significantly increased patient and physician awareness of the dangers one faces. This potential complica tion has promoted autotransfusion. It is now commonly used and reques ted by patients and physicians. Blood for autotransfusion is collected pre or intraoperatively by phle botomy and retrieved intra and post operatively from sites of hemor rhage. Once collected, the blood is either stored or returned to the patient as whole or processed blood. To have a successful autotransfusion program requires anticipation of its needs and coordination and training of involved personel in the blood bank, emergency room, operating room and post-surgical care units. Pre deposit and processing of collected blood requires remission of donor criteria and labeling and storage procedures."

The meeting which took place in Rome on November 19th and 20th of 1982 is easily the best meeting on hepatic coma that I have ever attended, and I have attended many. It was an exceedingly we- planned meeting with prolonged opportunity for discussion, and there was genuine interplay and exchange of ideas (not the usual picture of a rushed meeting with investigators presenting their own point of view and talking past each other without a meaningful ex change) which took place in Rome. My co-editors and I hope that the published transcript, which of course can only reflect what transpired in Rome on those two days, does justice to a very intellectually exciting and gratifying ex change of ideas. L. Capocaccia, J. E. Fischer and F. Rossi-Fanelli v CONTENTS Introduction 1 SECTION 1: PATHOGENETIC PROBLEMS IN HEPATIC ENCEPHALOPATHY Ammonia: The old and the new * * . * * * . * . * * * . * . * 5 L. Zieve Role of synergism in the pathogenesis of hepatic encephalopathy * * * * . * * . . . . * 15 L. Zieve y-Aminobutyric acid receptors in experimental hepatic encephalopathy *. *. * * 25 M. L. Zeneroli, ~. Baraldi,and E. Ventura A possible role for excitatory neurotoxic amino acids in the pathogenesis of hepatic en 41 cephalopathy * * * * * * * * * * * * * * * F. Moroni, G. Lombardi, G. Moneti, D. Pellegrini and C.

The primary purpose of this book is to bridge the gap be tween the practice of clinical medicine and diagnostic radi ology. It is intended primarily for utilization by medical students in training and by nonradiologist physicians. In this world of rapidly expanding knowledge in the many specialties of medicine, it is becoming increasingly difficult for many physicians to stay abreast of the newer and constantly changing modalities of diagnosis as well as the therapeutic regimens of the common as well as the less common disease processes within their realm of practice. This book will enable the busy clinician to utilize the consultative services offered by his or her colleagues in diagnostic radiology with maximum effectiveness. The most common clinical applications of the more recent imag ing modalities (i. e. , nuclear medicine, ultrasound, comput erized tomography, and magnetic resonance imaging) have been categorized and condensed into a format that will be both comprehensible and useful on a daily basis for those physicians routinely requesting these diagnostic examina tions for their patients. For simplicity, the book is divided, whenever feasible, into organ systems and subdivided into the multiple classifications of pathologic states (i. e. , con genital, trauma or iatrogenic, inflammatory, and neo plasm). In addition, there are brief comments related to the vii specific advantages and disadvantages as well as the cost effectiveness of each modality.

The best conferences are often those where the participants are from a mixture of different disciplines. There is a cross fertilization of ideas and a wider perspective of common problems. The 6th International Meeting on Clinical Laboratory Organization and Management, held in Noordwijkerhout, The Netherlands, on 24th-28th June 1987 lived up to its promise of a stimu lating program and differing views from a wide range of international par ticipants. The theme of the conference was "Laboratory Data and Patient Care" and this provided a forum for discussion of many aspects of laboratory input into the diagnosis and monitoring of disease. The titles of the papers in this book of the proceedings will give some indication of the breadth of topics discussed, ranging from problems of laboratory management and pro fessional leadership to educating the clinician in the most cost effective testing strategies; and computer aided diagnosis to the best presentation of data and graphical displays. The backgrounds of the participants were equally wide, ranging from medical statisticians and computer experts to practising clinicians and heads of clinical laboratories. There was also a significant number of delegates from commercial companies who were able to inject a different perspective on many problems. This blend of backgrounds and disciplines promoted much discussion and new avenues for research and development."

Only quite recently has it become technically possible to record, from elec trodes attached to the scalp, the human brain's electrical responses to sensory stimulation. The core of this book is a critical survey of endeavours to use these electrical responses (called evoked potentials) as tools in attempts to discover the ways in which the brain first processes incoming sensory information and then forms internal representations of features ofthe external world. Buttressed by quantities of undeniably sloppy evoked potential research there are some who would dismiss out of hand the recording of evoked potentials as being comparable to 'holding an oscilloscope probe 6 feet in diameter up to a computer and pronouncing from the resultant waveform on the underlying structure and function'; many would contrast the scientific value of recording the activities of single nerve cells with microelectrodes. However, although it is certainly true that the brain may indeed function in a way which would not be susceptible to the approaches of the evoked potential researcher it might equally well resist the stratagems of the single-cell man. If, for example, the neural correlate of some sensation were the state of some large population of nerve cells, then the present-day researcher who records in great detail the activity of one single cell or of a very few cells would be faced with a major problem in trying to see the forest for the trees."

This is the second of a number of international symposia which will, I hope, continue to be held until atherosclerosis is no longer a major problem. The first symposium was held three years ago in Athens, Greece, under the chairmanship 1 of Dr. Constantinos]. Miras , who, although he could not attend this symposium, participated actively in the deliberations of this Program Committee. Atherosclerosis together with its sequelae constitute the most important source of morbidity and mortality in civilized countries. While a major attack is being made on the consequences, the sequelae of this disease, not enough attention is being paid to the basic cause, atherosclerosis. Yet, if the basic disease were eradicated, the major concern of this symposium, the sequelae would constitute only a minor and rare disease group. The approach of the Program Committee was to bring together experts in the multiple disciplines which have a bearing on atherosclerosis. There is a great need for an exchange of ideas from various groups studying the basic process in many divergent ways. The hope we have is that those present (or those later studying the Proceedings) may be stimulated to attack the problem in new ways. Perhaps a breakthrough will be made or, at least, a brick or two added to build the structure, a rampart needed to defend against atherosclerosis. Better still, their contributions may help to confine it to a small area.

This volume contains the text of the presentations delivered at the International Symposium on Rare Diseases "Inherited Neuromuscular Diseases: Translation from Pathomechanisms to Therapies," held in Valencia, Spain, from November 16 to 18, 2008. The symposium represents a part of the continuous efforts on dif- sion of science to the society of the Catedra Santiago Grisolia and the Fundacion Ciudad de las Artes y las Ciencias -Comunitat Valenciana. More than 200 inter- tional scientists from different countries of Europe, the USA, and Australia attended the meeting. The venue was the Auditorium of the Science Museum Principe Felipe. Ten years ago Alan Emery wrote in the preface of Neuromuscular Disorders: Clinical and Molecular Genetics the following comments: "It has been estimated that more than one person in every 3,000 has a serious disabling inherited n- romuscular disorder. The suffering caused by these disorders is considerable, but, until the last decade or so, virtually nothing was known of their pathogenesis. Any rationale approach to treatment was therefore out of the question. However, matters are now changing rapidly. The genes for many of these disorders have been localised and characterised and their gene products identi ed and studied. The detection of preclinical disease, the identi cation of heterozygous carriers and prenatal di- nosis are all becoming possible, and, hopefully, effective treatments may no be too far distant."

There is an Inca incantation which stated said roughly: "Lord, give me spiritual peace so that I can acquiesce to what I cannot change, give me courage so that I can change what I can change, and give me wisdom so that I can distinguish one from the other. " Obviously, this incantation can be regularly repeated by any gerontologist, since it is very difficult to distinguish aging from the processes which enhance the organism's viability, aging from diseases, and the mechanisms of aging in various species of animals. According to N. Shock, who compiled a valuable bibliography of the works on aging, more than 43,000 works on gerontology have been published in the last decade. Why do we continue to disagree with one another and hold that the most important mechanisms are still largely unknown to us in spite of that flow of information and an enormous number of facts? What is it that we do not know? Could it be that we do not know the sole sacramental fact which can explain everything, such as the hormone of aging, the programmed triggering of a suicide gene, the appearance of a special toxic agent in the axoplasmic flow of substances, and so forth? Goethe once wrote that a scientist most often holds certain parts, but unfortunately he lacks their sacred link.

H. B. Stahelin "Under-or malnutrition is a frequent and serious problem in geriatric patients" (8). Today there is no doubt that malnutrition contributes significantly to morbidity and mortality in the aged. The immune function is impaired, the risk for falls and fractures increases, in acute illness, recovery is delayed, and complications are frequent. Acute and chronic illnesses lead to a catabolic metabolism and hence increase the signs and symptoms of malnutrition. Cytokines related to inflamma tion block the synthesis of albumin and shift protein synthesis to acute phase pro teins. The activation of the ubiquitine-proteasome pathway leads to a degradation of muscle protein, which leads to an additional loss of muscle mass which occurs as age-dependent sarcopenia, and adds to the already existing frailty (2, 4). It is often difficult to decide to what extent the metabolic alterations result from malnutrition or concomitant illness. Psychological factors contribute as a circulus vitiosus significantly to anorexia and, thus, aggravate the condition. They are the most important causes of failure to thrive in old age (7). It is evident that next to the therapy of the underlying illness, an adequate support with calorie and nutrient intake over weeks becomes essen tial under these conditions. Clear-cut improvements are often only seen after 6 or more weeks. Besides a clinical, clearly visible malnutrition, selective nutrient deficits are much more frequent. Numerous and highly different mechanisms may lead to a marginal or insufficient supply with micronutrients."

The danger of infection remains the most serious drawback to internal fixation. Prevention, using all available prophylactic measures should be the central feature in every surgical department. Though the infection rate may remain below the acceptable level of 2 %, the infected patient derives little comfort from the large number of excellent results in other people. We must discover the best way to offer these patients a favourable prognosis. This should not be based on intuition but on clear proven guiding principles. Planning the treatment for a patient whose internal fixation has become septic must decide between steps which may have advantages or disadvan tages. The disadvantage of the presence of a foreign body must be weighed against the advantage of rigidity. The authors have taken up this challenge by planned animal experiments to study the healing of internally fixed fractures which have been infected with staphylococci. They have shown that under stable conditions, even massive infection did not destroy the healing process in cortical bone. Even under these circumstances fracture union, in the form of primary bone healing, can occur even if with less regularity than in unin fected internal fixation.

The book provides a comprehensive account of ticks and tick-borne diseases occurring in tropical and subtropical areas. It begins with a complete up-to-date overview of the systematics of the Ixodida (Ixodidae, Argasidae and Nutalliellidae) and is followed by a review of the problem of ticks and tick-borne diseases of domestic animals world wide. This leads on to multi-disciplinary approaches to planning tick and tick-borne disease control and to contributions on calculating the economic impact of a tick species such as Amblyomma americanum on beef production systems. Heartwater fever (cowdriosis) and dermatophilosis are endemic in Africa and pose a threat to the North American mainland. The epidemiology of these two diseases is discussed in detail as is the role of frozen vaccines to control bovine babesiosis and anaplasmosis. The book also includes chapters on tick transmitted zoonoses such as Lyme borreliosis, tick typhus and ehrlichiosis. It concludes with a review of the acaricidal treatment of tick infestation.

Prevention of disease and injury, including early identification of risks and disease and optimal control of potentially debilitating or fatal complications of chronic conditions, is the area of clinical medicine that holds the greatest promise for improving human health. Each year a long list of major, but potentially preventable health problems exacts a terrible human and financial toll. These problems urgently need our attention, especially as major advances in curative medicine become more complex and costly. Prevention of disease and injury may well be the central health issue of our time, an issue of vital concern to every quarter of our society. Now is a very good time to promote prevention. Citizens and some social groups are increasingly aware of and interested in health and fitness issues. There is great enthusiasm about-even obsession with-health, and we are seeing an astonishing proliferation of health publications and media presentations for laymen, fitness and weight control cen ters, exercise programs, health food stores, disease support groups, health education programs, and do-it-yourself diagnostic kits. All of this betokens an increased health consciousness on the part of public and perhaps signals greater individual accountability for health."

It has been over 30 years since the first clinically important member of the quinolone class, nalidixic acid, was introduced into medical practice. The modification produced in the quinolone nucleus by introducing a fluorine at the 6-position led to the discovery of the newer fluoroquinolones with enhanced antibacterial activities as compared to nalidixic acid. By now a great deal of preclinical and clinical experience has been obtained with these agents. The intense interest in this class of antibacterial agents by chemists, micro biologists, toxicologists, pharmacologists, clinical pharmacologists, and clini cians in various disciplines encouraged us to summarize the information on the history, chemistry, mode of action and in vitro properties, kinetics and efficacy in animals, mechanisms of resistance, toxicity, clinical pharmacology, clinical experience, and future prospects in one volume of the Handbook of Experimental Pharmacology. As this series deals predominantly with "experimental" characteristics of drugs, our volume is dedicated specifically to quinolones and emphasizes principally their preclinical and clinical phar macological characteristics, despite the existence of several summaries on quinolones. The chemistry of the quinolones is described in detail. The chapter on the mode of action of quinolones reports the conclusive evidence that gyrase is the intracellular target of the quinolones; however, another enzyme, topoisomerase IV, may also be a target for quinolones, and the exact mechanisms by which quinolones act bactericidally are far from being understood."

Recent publications have addressed specific aspects of the endothelins, such as their roles in disease or the importance of endothelin receptors. However, in this book the entire field of endothelins is covered. This includes the pathways of endothelin production and their regulation, the local and systemic actions of endothelins, receptors for the endothelins and the signalling pathways employed, and the involvement of endothelins in a range of diseases. Attention is also paid to the development through chemistry, pharmacology and toxicology of endothelin antagonists and endothelin-converting enzyme inhibitors, with mention of all the important members of these drug classes. This leads to well-rounded discussions of the potential therapeutic benefit of endothelin inhibitors.

Looking back is a luxury for which scientists normally have little time. This XXV Anniversary Symposium, however, gives the opportunity of reminding us that in Belgium, where the risk of developing multiple sclerosis is among the highest in the world, a great man to whom we all pay tribute, I mean Dr Ludo van Bogaert, in 1957, took the initiative in founding the Belgian Research Group for Multiple Sclerosis. It may sound immodest but since that time members of the Belgian Research Group happen to have an honourable record of important contributions to MS research, quite out of proportion to the financial support they received for it. Indeed, when compared to the situation in English speaking countries, funding of MS research has always been neglected in our country in spite of the fact that in 1958, acting on the advice of the Belgian Research Group, the Belgian National MS Society was founded with the specific object of collecting money for research as well as for social care. At that time, the difficulty in raising funds for research was partly due to the fact that solving the problem of MS appeared almost impossible. Scientists could apparently only too slowly improve their ability to prevent and cure the disease. Media were indifferent to MS which was considered to have no news value, and the public remained uninformed.

Neurologists and non-neurologists alike can no longer ignore diseases of the neuromuscular system. The old dogma that these disorders are both uncommon and untreatable has lost its validity. Recent technological advances have enabled us to study more precisely muscle and nerve anatomy, physiology and biochem istry. Because of this progress, we are now recognizing new neuromuscular di seases as well as diagnosing more subtle cases of myasthenia gravis, myotonia, and metabolic myopathies. Treatment of the neuromuscular diseases has also un dergone dramatic change based on new discoveries in the fields of immunology and pharmacology. No longer are myotonia, periodic paralysis, and malignant hyperthermia untreatable medical curiosities. No longer are cases of steroid-un responsive myositis given up as hopeless. Because of all these advances, non-sur gical physicians and especially neurologists must update their knowledge regard ing the neuromuscular disorders. This book, it is hoped, will help such clinicians in dealing with this task. Emphasis has been placed on the diagnosis and management of these disorders rather than on their pathophysiology. The more uncommon diseases and those of uncertain existence have been omitted purposely and left to the larger and more encyclopedic reference works. Chapter 1 discusses the clinical symptoms and signs of muscle disease and is designed to enable the reader to formulate a differential diagnosis on the basis of the patient's history and physical examination."

Oxidative stress and aging Over the past several years there has been an extraordinarily rapid growth in our knowledge of free radical chemistry and its possible involvement in both normal essential biology and age related disease and dysfunction. Much of this growth in the traditionally separate sciences of chemistry and molecular gerontology occurred independently, with little interaction or communi cation between the scientists working in these two fields. In view of the growing maturity of the two fields and the potential importance of advancing our knowledge in the area of oxidative stress and aging, we perceived a critical need to organize an international conference the "First Inter national Conference on Oxidative Stress and Aging" in Hawaii in 1994 to bring together the world's leading scientists in the fields of reactive oxygen species and molecular gerontology. The objective of this conference was to provide a unique opportunity for scholars working in these two related and rapidly growing fields to participate in the exchange, integration, and synthesis of new concepts and ideas, to engage in constructive criticism and to initiate new collaborative research projects. The conference focused on the molecular and cellular aspects of aging as related to oxidative stress. It was one of the largest and most comprehensive international conferences held in molecular gerontology. At this conference a call was made for submission of papers to be used in the publication of a book covering the major contributions of the meeting."

This volume contains the proceedings of a symposium held in Marseille on April 6, 1992, on the topic "Heterogeneity of Alzheimer's disease. " This was the eighth of a continuing and very successful series of meetings related to Alzheimer's disease organized by the Fondation Ipsen pour la Recherche Therapeutique. These symposia, known as "Colloques medecine et recherche," started in 1987 and have dealt with widely different aspects of the disease such as immunology, genetics, neuronal grafting, biological markers, imaging, growth factors, and last year's less conventional topic of Neurophilo- sophy and Alzheimer's disease. The next IPSEN symposium dedicatet to Alz- heimer's disease will take place in Lyon on June 21, 1993, and will deal with "Amyloid protein precursors in development, aging, and alzheimer's disease. " It is being organized by Konrad Beyreuther, Colin Masters, Marc Trillet, and Yves Christen. Until a few years ago, several names were used to refer to the most common cause of dementia in the elderly. They included such terms as "senile psycho- sis," "organic brain syndrome," and "senile dementia. " Following Kraepelin, the term "Alzheimer's disease" was often restricted to an uncommon condition starting at a younger age (before 60 or 65 years of age).

The International Skeletal Society is now fifteen years old and as measured in human terms has outgrown its childhood. During this time the ISS has earned worldwide respect and praise for successful work. The International Skeletal Society is an interdisciplinary working group concerned with skeletal diseases, their pathogenesis, diagnosis, and treatment at all ages. At the Annual Closed Meetings of the ISS prominent scientists representing many countries from all over the world gather to exchange ideas in the fields of radiology, pathology, orthopedic surgery, nephrology, and endocrinology. Follow ing these meetings Refresher Courses are offered for students, physicians in train ing, and interested collegues from the various medical specialities. The purpose of these courses is to present the latest developments in clinical practice and research with regard to skeletal diseases. The Society's internationally well-known journal "Skeletal Radiology," which is published by Springer-Verlag, Heidelberg, adds in exchanging updated developments in the field of skeletal disorders. The hereby presented first Book of Members contains a record summarizing the most important milestones and events of the history of the International Skeletal Society up to 1987 in the form of short biographies regarding the members of the Society. The task of gathering all important informations for this book was accom plished by one of the members during his term as President of the ISS. The other one - honorary member - took upon himself the tasks related to publication."

The Yearbook compiles the most recent developments in experimental and clinical research and practice in one comprehensive reference book. The chapters are written by well recognized experts in the field of intensive care and emergency medicine. It is addressed to everyone involved in internal medicine, anesthesia, surgery, pediatrics, intensive care and emergency medicine.

Almost 50 million persons visit another continent each year. It is mainly those 15-18 million travelers from industrialized nations who visit or reside in developing countries that are at increased health risk. To develop effective health protection advice, the health risks of travel and the benefits of prophylaxis (vaccines, new and old drugs, behaviour modification, etc.) should be assessed systematically. The purpose of this book is to improve the protection of the travelers' health by more effective and more uniform recommendations. It contains many data on recent research and represents the first comprehensive account on travel medicine for professionals.

The Second Meeting of the International Society for Trace Element Research in Humans (ISTERH) was held in Tokyo from August 28 through September 1,1989. On August 27, the day preceding the opening of the meeting, a typhoon made a direct attack on Tokyo, welcoming guests from all over the world in a rather violent way. To our great relief, the weather during the week of the meeting turned out to be exceptionally agreeable for that time of year in Tokyo. We were also pleased to see the entire scheduled course of the meeting, including the social activities, carried out smoothly and the contents of the program favorably appraised. The meeting was attended by 518 scientists from 30 countries. Recent unrest following steps toward democratization in the Communist bloc gave rise to some apprehension; therefore, we were particularly pleased to see attendants from China, Eastern Europe, and the Soviet Union. No one could possibly have predicted the drastic change in Eastern Europe that followed, but again, we were relieved to learn (by a subsequent letter) of the safety of an attendant from Rumania, who had been our greatest concern. A total of 384 papers were contributed to the meeting. The abstracts for all have been published in the Journal of Trace Elements in Experimental Medicine, vol 2, No. 2/3 (1989). This proceedings carries 64 subjects introduced in the Special Session.