Marburg and Ebola virus, the two species within the family Filoviridae, are among the most pathogenic agents causing fulminant hemorrhagic fever in humans and nonhuman primates. The chronology of filovirus epidemics and epizootics proves that these viruses are prototypes of emerging/re-emerging pathogens. Since the discovery of Marburg virus in 1967 until the recent Ebola virus outbreaks in Central and West Africa filoviruses have not only raised the interest of scientists, but have also been a matter of high public concern. With the advent of recombinant DNA technology our knowledge on the genome structure and the replication strategies of these agents has significantly increased. This volumes gives an overview on many aspects of filovirus research and summarizes recent advances in the field. The topics addressed include the molecular biology of filoviruses, pathogenesis, epidemiology, immune response, as well as clinical aspects and diagnostic measures.

The translation of Blood Smears Reinterpreted was begun when the French original was still undergoing revisions. I was accorded the oppor tunity to question any statement or turn of phrase that was unclear to me or appeared liable to misinterpretation. It is my hope that as a result, ambiguities-particularly those inherent in differences between American and Eu ropean usage-have been removed and that I have at least ap proached the ultimate goal of any translation: to reflect the author's intention accurately while remaining as readable as the original. Beyond the role of translator, I was encouraged to assume the role of critic. As a result, some pages or even single sentences were hotly debated, sometimes for hours, as Marcel Bessis insisted that any inter pretations on which we could not agree should be so indicated. In fact our discussion invariably ended in agreement, though they led to changes of a sentence here or a word there and, on occasion, to the addition of a footnote or a brief paragraph.

Sarcomas represent a group of rare tumors which arise from the largest tissue compartment of the body, but account only for about 1 % of all malignancies. Among this group of tumors, soft tissue sarcomas in adults are, in addition to osteosarcomas, the most important. In the diagnostic workup of soft tissue sarcomas modern radiological investigation methods such as CT and MRI techniques are being critically evaluated. While it is widely accepted that the conventional, stained microscopic specimen is still the cornerstone for properly planned treatment stra tegies, immunohistochemistry has come to play an indis pensable role in accurate classification. Reviewing the surgical techniques, the treatment of musculo-skeletal malignancies, especially of soft tissue sarcomas, has changed considerably over the past decades. While amputation used to be the surgical treatment of choice limb-saving procedures have now become an im portant therapeutic modality in treating such lesions, particularly in combination with percutaneous or interstitial radiotherapy. Despite adequate local treatment, many patients with soft tissue sarcomas will ultimately develop metastatic disease, usually in the lungs. For this reason, effective ad juvant systemic treatment should be given simultaneously with or soon after treatment of local disease. The results of several randomized trials evaluating adjuvant chemotherapy have been reported in the meanwhile, indicating im proved, disease-free survival with a trend towards improved overall survival. In disseminated disease, drug combi- VI Preface nations or single agents are used as palliative treatment and might help to improve survival in selected subgroups."

Pathology in general is closely linked with clinical medi- cardiographic changes may be desired and therefore a cine and in cardiovascular pathology this interdepend- short section has been included on cutting the heart ence is, perhaps, greater than in most other specialities. according to conventionally used echocardiographic In recent years great advances in investigatory proce- planes. dures have taken place, including the examination of The heart can only react to physiological changes or fresh endomyocardial tissue obtained by bioptome, per- damage in a limited way and therefore a separate chapter mitting not only clinico-pathological correlation but also on hypertrophy and dilatation and another chapter deal- examination at histochemical and ultrastructural levels. ing with changes in the endocardium, which reflect hae- Angiography has gained wider usage and two-dimen- modynamic alteration and may additionally show sional echocardiography is no longer the preserve of diagnostic features, are also included. Degeneration to- specialized units. Percutaneous coronary transluminal gether with changes in connective tissue and ischaemic angioplasty is a relatively new approach to relieving heart disease are separately presented. Atherogenesis, obstructive coronary artery disease. Cardiac pathology recognition of myocardial infarction and the earliest mor- has therefore moved apace, providing not only a back- phological changes discernible at histochemical and ground to clinical manifestations but also visual proof for ultrastructural levels of investigation, which are within other investigations such as immunology and virology. the scope of modern routine laboratories, are empha- Such investigations have played an essential role in sized.

New techniques make it possible for investigators to examine and sometimes quantify various aspects of nuclear morphology and function; now they can derive clinically and biologically useful information about the nucleus. This book draws together a series of techniques which have been successfully applied to the study of the nucleus of tumour cells. These are of fundamental importance to researchers in tumour histopathology and medical oncology. Detailed reviews are given of various aspects of the morphology, ploidy and karyotypic status and function of the nuclei in the cells of tumours and preneoplastic lesions. Topics covered include nuclear morphology in tumour diagnosis, the ultrastructure of the nucleus, karyotypic analyses of solid tumours, flow cytometric assessment of nuclear ploidy and other parameters, histomorphometry of the nucleus, and in situ hybridisation.

Soft tissue tumors are a very heterogeneous group of tumors in terms of histogenesis, morphology, cytogenetics, molecular biology, clinical manifestation, and prognosis. Their spectrum is fascinating for morphologists and basic scientists alike. Yet precisely this variability in the morphologic manifestation of soft tissue tumors, specifically their histologic and cytologic patterns, presents great difficulties to any effort to categorize them. Although many soft tissue tumors are today defined not only by histology but also by immunohistochemical, cytogenetic, and molecular biological findings, the histogenesis of many soft tissue tumors, in particular malignant ones, continues to be unknown. This is associated with the fact that the actual precursor cells that lead to these tumors have frequently not yet been identified. For this reason, the customary classification of malignant soft tissue tumors is primarily not histogenetic, but actually according to the dominant phenotype, however characteristic it is. Of course, an exact morphologic examination of soft tissue tumors con tinues to be an essential prerequisite for making a diagnosis and determining a therapy. The use of a wide range of additional modern examination techniques, however, can make a substantial contribution toward more precisely defining the biological behavior of a tumor, which without doubt can have therapeutic implications.

The physiology and pathology of membrane (contact or surface) digestion of the three main components of the food of animals and man is a rapidly developing field, and there is little doubt that newer ob servations will become available as time progresses. As the dis coverer of the phenomenon of membrane digestion, Professor Ugolev is well aware of the relative infancy of this subject, and in presenting the book at this time his primary purpose was to acquaint the reader with the experimental basis for the observed phenomenon and to stimulate interest in the further work required for the elucidation of details and for proper orientation. Translations as means of communication of ideas and experimental facts are of obvious importance and they require no apologies or explanations, particularly to those who are engaged in scientific endeavors. In making this book available to those who find the Russian language an insurmountable barrier, our main efforts were directed toward preserving the author's meaning, spirit, and intent as accurately as possible. It is hoped that this objective has been attained, and that the minor unintentional errors will be forgiven by the reader and by the author. The translator wishes to express to Professor Ugolev, whom he met in Leningrad in 1965, his appreciation for the trust in the ability of the translator to make Professor Ugolev's labor oflove, the present book, available in the English language."

Medical imaging is an important topic and plays a key role in robust diagnosis and patient care. It has experienced an explosive growth over the last few years due to imaging modalities such as X-rays, computed tomography (CT), magnetic resonance (MR) imaging, and ultrasound. This book focuses primarily on model-based segmentation techniques, which are applied to cardiac, brain, breast and microscopic cancer cell imaging. It includes contributions from authors working in industry and academia, and presents new material.

The ability to diagnose cancer by simple measurement of a serum or tissue' 'marker" has been a goal of medical science for many years. There is ample evidence that tumor cells are different from normal cells and pro duce substances that can be detected by currently available immuno chemical or biochemical methods. These "cancer markers" may be se creted proteins, enzymes, hormones, fetal serum components, monoclonal immunoglobulins, cell surface components, or cytoplasmic constituents. The purpose of this book is to present the current status of our knowledge of such cancer markers. The first tumor marker identified by laboratory means was Bence Jones protein. In a series of lectures delivered to the Royal College of Phy sicians in London in 1846, Dr. H. Bence Jones described studies on a urine sample sent to him with the following note: "Dear Dr. Jones-The tube contains urine of very high specific gravity. When boiled it becomes slightly opaque . . . . etc. " Dr. Jones found that heating of the urine after addition of nitric acid resulted in formation of a heavy precipitate; acid ad dition may have been required to bring the urine to pH 4-6 at which Bence Jones proteins are more likely to precipitate when heated. This urinary pre cipitate was associated with a bone disease termed "mollities ossium. " H. Bence Jones, Papers on Chemical Pathology, Lecture III. Lancet 2, 269-274 (1847)]."

There have been many advances in the field of gastrointestinal pa thology which are of considerable clinical significance during the 13 years since the last publication of a volume of Current Topics in Pathology devoted to this subject. Many have arisen from the app lication of new techniques of histochemistry, immunocytochemi stry, quantitative morphometry and molecular and cell biology to gastrointestinal diseases, but some, notably the recognition of the association of Campylobaeter pylori with the commonest type of chronic gastritis, have been achieved using such long established 'routine' histological procedures that one wonders how their signifi cance had escaped recognition for so long. The topics covered in this volume have been selected because they present advances of relevance to the diagnostic clinical pathologist. However, they re present the personal selection of the editor, and are in no way exhaustive. Many other examples of progress in our understanding of the pathophysiology of gastrointestinal diseases have been omit ted, either because of the confines of space or because they have been well reviewed recently in other publications. Most of the workload of the practising gastrointestinal patholo gist involves the diagnosis and assessment either of inflammation or of neoplasia in the alimentary tract, and this is reflected in the topics presented in this book."

This volume contains the proceedings of an International Symposium on `Second Messenger Systems - Molecular, Cellular and Behavioural Aspects', which was held at Tobago on June 16-17, 1994. The interaction of an extracellular agonist (First Messenger) with its plasma membrane receptor leads to the transmission of a signal across the cell membrane and results in the production and/or activation of other signalling molecules (Second Messengers). These Second Messengers control the action of many protein kinases and protein phosphatases and so lead to cellular responses. Although the biochemical basis of the transduction of signals in the main signalling systems in eukaryotic cells is probably largely known, intensified research is ongoing in the following areas: the discovery of specific substrates for many protein kinases, elucidation of the biological significance of the differential tissue expression and heterogeneity of many signalling proteins, and the unravelling of diverse interactions (such as signal potentiation, synergism, antagonism and neuronal co-transmission) between signalling systems. As knowledge from such studies accumulates, it is becoming clear that the `cross talk' interactions between signalling systems are important features of dynamic cell regulation. This volume is designed to summarize some aspects of the current work on various Second Messenger Systems and the integration of signals with respect to plasma membrane receptors. Second Messenger generation and degradation, protein kinase and phosphatase, cell cycle control, and cellular learning and memory.

W. TH. DAEMS This volume contains the papers presented at a Boerhaave Course for Post graduate Education on The cell-biological aspects of disease: the plasma membrane and lysosomes. One of the purposes of this introduction is to explain the reasons for this choice of subject. The first question which might be asked - why a postgraduate course on the cell biological aspects of disease was considered neccessary - is not difficult to answer: the impact of the basic sciences on medicine is im measurably strong, and among these sciences cell biology has contributed immensely to the advances made in medicine during recent decades. It has provided clues leading to general insights into etiology and pathogenesis as well as to the development of diagnostic tools and a basis for therapeutic methods. These insights derived mainly from the still-increasing body of knowledge about the architecture of cells. Initially, this knowledge arose from the notion that cells are either simply bags full of enzymes or complex sponge like structures in which all organelles are permanently interconnected (Fig. 1). Later, this notion was replaced by a highly schematized picture of the cell as an essentially two-compartment structure (Fig. 2) in which cell organelles are discrete units separated from each other by membranes, enabling each organelle to maintain an internal microenvironment with optimal conditions for its specific metabolic pro cesses."

Cancer has become the most critical health problem in the United States. It is expected that 25% of the people will develop this dread disease, and many of these will die from the malady. The causes of cancer are varied, but the best estimate available is that 70--90% arise from environmental factors. These statistics have triggered widespread governmental action along two lines: (l) An effort to identify those chemicals and conditions that give rise to malignant processes has been mounted by the Carcino genesis Testing Program, the National Cancer Program, and subse quently, the National Toxicology Program. (2) Regulatory laws have been enacted that are administered by agencies such as TSCA, FIFRA, EPA, FDA, OSHA, and so on, whose mission is to minimize public ex posure to carcinogens. Since direct verification that specific chemicals induce cancer in hu of unanticipated expo mans is necessarily limited to known incidences sure and is therefore rare, most chemicals are identified as carcinogens only by laboratory experiments. At present, the only accepted procedure is long-term animal bioassay, and not only are these studies expensive and time-consuming, but current worldwide resources permit the evalua tion of only 300-400 chemicals per year, a miniscule amount compared to what is available in the commercial world: 30,000 existing chemicals, with approximately 700 new such materials being introduced every year."

A critical phase in coronary heart disease, unstable angina, is thoroughly discussed in contributions by well-known experts. Since myocardial infarction still belongs to the main causes of death, this topic is highly relevant for the present research and possible future treatment of coronary heart disease. The major recent advances made in the pathophysiology, diagnosis and therapy of unstable angina are reported in depth.

Vor die Therapie setzten die Gotter die Diagnose. Otto NiigeJi Renal biopsy has decisively enriched renal diagnostics. Kidney diseases may be monitored during their entire course, and new techniques - such as immunofluorescence and electron microscopy - may be systematically applied, resulting in novel insights into the morphogenesis, pathogenesis, and etiology of kidney lesions. These insights, in turn, have served as new starting points, in the spirit of the quotation above, for the institution of causal therapy by the clinician. This work presents our findings based on 20 years of experience in evaluating renal biopsies. As of the end of 1974, our computer-supported, systematic clinical, morphologic, and follow-up evaluation of case material consisted of over 2000 biopsies, including 679 examined by electron microscopy and 400 by immunofluorescence microscopy. The subsequent 500 biopsies (400 studied by electron microscopy and 300 by immunofluorescence) were con sidered qualitatively only. In order to enhance qualitative findings with quantitative data, it was necessary to devise new methods for quantifying electron-microscopic findings. Additionally, we attempted to correlate cyto logic and immunofluorescent observations to integrate the isolated findings of electron microscopy into a vital cytologic pattern of reactions. We also attempted to evaluate the almost overwhelming flood of publications, especially those appearing within the last 10 years. The idea for this book was conceived a decade ago. At that time, however, our own experience in renal biopsy diagnostics seemed insufficient to sup port such a major undertaking."

The first International Symposium on Brain Edema was organized by Dr. Klatzo and Dr. Seitelberger and held in Vienna in 1965. The second Symposium was held in Mainz in 1972 and organized by Dr. H. J. Reulen and Dr. K. Schiirmann, the third in Montreal in 1976 by Dr. H. M. Pap- pius, the fourth in Berlin in 1979 by Dr. J. Cervos-Navarro, and the fifth in Groningen in 1982 by Dr. K. G. Go. This volume contains the papers presented at the 6th International Sym- posium on Brain Edema, held in Tokyo, Japan, November 7-10, 1984. The invited lectures by Dr. I. Klatzo, Dr. A. Hirano, Dr. S. I. Rapoport, Dr. B. K. Siesj6, Dr. H. M. Pappi us, Dr. K. A. Hossmann, and Dr. D. M. Long are included as special chapters. On behalf of the organizing committee, I wish to express my deep ap- preciation to all the participants for their contribution toward making this meeting so fruitful and significant. Moreover, the great success of this Sym- posium depended on the high quality of the invited lectures and presen- tations by experts in various fields, as well as on the free and enthusiastic discussion. I was deeply impressed with the papers presented by all the authors, who endeavored to elucidate their subjects. The editors have made only minor corrections and rearrangements, since prompt publi- cation was considered to be important.

This volume contains all the invited papers, symposium contributions and workshop reports of the 7th International Congress of Human Genetics, held in West Berlin from September 22 to 26, 1986. The organizers of this congress made sure to gain the cooperation of the leading scientists in the field from all over the world. These contributions therefore document the enormous progress made in human genetics research in recent years. The volume covers a wide range of topics, from analysis of the human genome to basic mechanisms, diagnosis and therapy of hereditary diseases, and to distribution of normal and pathological genes and DNA variation in human populations. Ethical issues raised by modern developments are discussed thoroughly. The volume is a must for all scientists and medical doctors working in human genetics research, its teaching and practical applications.

This two-volume treatise, the collected effort of more than 50 authors, represents the first comprehensive survey of the chemistry and biology of the set of molecules known as peptide growth factors. Although there have been many symposia on this topic, and numerous publications of reviews dealing with selected subsets of growth factors, the entire field has never been covered in a single treatise. It is essential to do this at the present time, as the number of journal articles on peptide growth factors now makes it almost impossible for anyone person to stay informed on this subject by reading the primary literature. At the same time it is becoming increasingly apparent that these substances are of universal importance in biology and medicine and that the original classification of these molecules, based on the laboratory setting of their discovery, as "growth factors," "lymphokines," "cytokines," or "colony stimulating factors," was quite artifactual; they are in fact the basis of a com mon language for intercellular communication. As a set they affect essentially every cell in the body, and in this regard they provide the basis to develop a unified science of cell biology, germane to all of biomedical research. This treatise is divided into four main sections. After three introductory chapters, its principal focus is the detailed description of each of the major peptide growth factors in 26 individual chapters."

Previous volumes in this series have discussed the current progression have identified a variety of targets and strategies state of our knowledge concerning the pathophysiology of to allow these goals to be realized. This volume critically cancer growth and progression. The complexity of the in reviews approaches towards cancer management in man at teraction of malignant neoplasms and the host, the the levels of: detection, diagnosis, surgery, radiology, heterogeneity of malignant cell subpopulations, and the chronobiology and endocrine treatment. existence of metastatic tumor cells resistant to drug thera Several chapters review selected methods of cancer diag pies remain as significant clinical challenges to clinical on nosis. In addition, a variety of on-going and novel ap cologists. Indeed, conventional treatment regimens of che proaches for cancer treatment are also presented in this volume. Progress in the early detection of malignant neo motherapy, surgery and radiology are often ineffective for the therapy of a large variety of established metastatic can plasms, coupled with novel approaches for the therapy of cer in patients. When one considers the insidiousness of such neoplasms, may ultimately yield safe and well-tolerated agents for the selective therapy of solid malignancies. New progressive neoplastic growth and the emergence of con tinuously more aggressive and malignant cellular subpop therapeutic approaches, directed towards the biochemical ulations one is overwhelmed with the challenges inherent in and molecular targets identified in the earlier volumes of this series, may ultimately lead to the generation of new mo attempting to control malignant neoplasms."

Human Lymphoma: The Clinical Implications of the REAL Classification is a unique volume. It is based on the recent developments in classification and overall understanding of human lymphoid neoplasms which are relatively common neoplasms and which epidemiological evidence suggests are increasing in frequency. This field has been the cause of confusion in the past as a result of conficting ideas on the classification of lymphoma and related diseases. However a new vision of the field has emerged and the is encapsulated in the pioneering REAL classification and in a forthcoming WHO scheme, both of which are covered in the book. The volume will appeal to hematologists, pathologists and oncologists and will, thanks to a diverse and expert authorship, serve to increase the working knowledge of all three groups.

Spinal Cord Injury or disease can happen to anyone at any time and the effects can be devastating. I found this out personally when I was thrown from the back of a pick up truck at age 15 was left paralyzed from the waist down. It was during my recuperation as a young teenager that I first gained insight into the importance of rehabilitation. My family, doctors, nurses, fellow patients and researchers who were dedicated to helping me over come my personal tragedy helped me pull through. Today, rehabilita tion medicine is taking great strides and empowering the person with the injury to take control of their future, overcome their setbacks and, through collaborative support, reach their personal goals and potential. Since 1987 the Legacy raised by my Man in Motion World Tour (24901 miles wheeled around the world March 1985-May 1987) has pro $13 million dollars to research and rehabilitation in the areas vided over of spinal cord injury. I hope that in some small way this funding has contributed to the development of the vital programmes that supported me and many others. The effects of spinal cord injury are traumatic and life-shattering and require a skilled interdisciplinary approach. I congratulate those who have contributed to this book and challenge each one of you to never give up on your dreams to find the answers to the optimum treatment of spinal cord injury and disease."

1. Concepts on the Causal Genesis of Human Intestinal Tumors The action of chemical substances has a significant role in the genesis of human tumors. It is assumed that most human tumors are induced by exogenous chemical noxae (Schmahl, 1970;Heidelberger, 1975; and others). In the course of intensive efforts to discover the principles of tumor etiology, important insights have resulted in recent years. These are that chemical carcinogens do not only arise as products of our tech nological civilization, but that they also occur in nature as potent solitary carcinogens and cocarcinogens (e. g., as plant products). For review, see Hecker (1972) and Preuss mann (1975). Not only "complete" carcinogens are significant for the genesis of tu mors, but also substances which are first transformed to the actual carcinogenic com pound in the organism (Schmahl, 1975). The causal significance of exogenous noxae in carcinogenesis is indicated by the fact emphasized by Bauer (1963) that malignant tumors occur predilectively at those sites in the body which are in direct or indirect contact with the environment. This applies especially to the intestinal tract."

During the past few years, a considerable number of monographs on bone tumors have been published. They are mainly restricted to bone tumors as clinical-pathological entities, since their diagnosis, more than that of other tumors, requires the interdisciplinary cooperation between orthopedic specialist, radiologist, and pathologist. However, investiga tions concerning the histogenesis of bone tumors are rather limited, although they might be helpful in explaining the unique morphological heterogeneity of tumors of the skeletal system. Furthermore, the histo genetic approach in the study of bone tumors may facilitate the inter pretation of the advanced cytobiological methods available for improv ing classification and diagnosis. Therefore, this volume presents recent pathological advances in the biological characterization of bone tumors. A major chapter deals with the differential diagnosis of Ewing's sarcoma as regards its demarcation from the so-called neuroectodermal tumor of bone. The analysis of the ground substances in bone-forming tumors may be helpful for their classification. Therefore the volume includes a chapter on the biochemical and histochemical analysis of different osteosarcoma types. Recently it has become clear that in addition to different collagen types which are not specific for bone tissue, several bone-specific proteins occur, one of which is osteonectin. Its distribu tion is obviously important for the classification and diagnosis of osteo blastic tumors. Proliferative behavior is of major importance for the diagnosis of malignant tumors.

It is difficult for a teacher to accept the fact that not all of the information in his or her field is a necessary part of the armamentarium of the student. This holds for histologists, and for that matter, pathologists, biochemists, and ophthalmologists. It may especially hold for those who were trained during exciting periods in the history of their discipline. In the past two decades, information in every basic medical science has increased greatly, perhaps exponentially, and the basic science curriculum has been compressed to the point where the medical student can reasonably be expected to acquire only a superficial knowledge of anyone of these sciences. Hence the information provided must be carefully selected, effectively presented in retainable doses, and useful for understanding material to be presented later in the curriculum and for the solution of clinical problems. In the compact courses of today, the presentation of only enough data to support basic working concepts of structure and function is appropriate. Additional factual information consti tutes trivia, which in our opinion interferes with effective development, reten tion, and use of the concepts. This philosophy has been the basis for the preparation of this book. Consistent with this philosophy, the text is brief, and the content has been carefully examined for its appropriateness to the needs of the medical student."