Current problems in research and treatment of leukemias as discussed at the symposium of the International Society of Haematology on leukemias in Dresden (Germany) are dealt with in detail in this volume. The characterization of leukemic cells and the evaluation of their function are themes, with the first hints emerging of the possibility of relating them to the intensity of treatment required. The cytokines, responsible for cooperation between cells, are also of great importance, and the beginnings of therapeutic applications can be discerned here. Not only are the cytokines themselves very interesting, but also the application of cells producing cytokines according to the range of macrophages found. The emphasis on cell-to-cell relationship is thus a main topic of the book. Of course, other treatment such as bone marrow transplantation and interferon therapy play an important part, too, and the latest results of chemotherapy are reported. A further essential area covered is the diagnosis and therapy of chronic leukemic diseases, the inclusion of which suitably rounds off the book. I am very grateful to the out standing specialists from both the West and the East who contributed to the symposium and this book: an important sign of collaboration and integration for the future."

This volume contains all relevant information discussed in a Workshop on thromboplastin calibration held in Leiden, The Netherlands on July 1, 1983. The Workshop was an initiative of the Dutch foundation for a Reference Laboratory for Anticoagulant Control (RELAC) and it was organized by the Boerhaave Committee for postgraduate teaching of the Faculty of Medicine of the University of Leiden. The Workshop was held under the auspices of five organizations i. e. the European Community Bureau of Refer ence (BCR), the European Committee for Clinical Laboratory Standards (ECCLS), the International Association of Biological Standardization (lABS), the International Committee for Standar dization in Haematology (ICSH), .and the International Committee on Thrombosis and Haemostasis (ICTH). The aim of the Workshop was to discuss and develop a method for calibration of reagents, i. e. thromboplastins and/or plasmas used for the prothrombin time. During the Workshop three recent thromboplastin calibration studies were discussed, the results of which are presented in chapters 4, 7 and 9. These studies were carried out on the basis of a new calibration model developed by experts working with BCR and WHO. The usefulness of this model and the standardization system based on it is the leading thread running through this volume. Statisticians and clinicians discuss the results from a scientific point of view. Thromboplastin manufacturers, for whom especially the use of the model and the system is intended, discuss the matter also from an economic and legal point of view."

Estimates reveal that there are some 200 million heterozygous carriers of abnormal hemoglobins genes worldwide, and tens of thousands of severely affected patients. Effective application of imaging techniques is essential to combat the continuing development of the disease and to ensure risk-free follow-up of the chronically ill. This is the first book to offer complete coverage of such radiologic applications with both conventional and the most modern imaging modalities. Interventional radiology, marrow transplantation, prenatal diagnosis by ultrasonography, and radiotherapy for bone marrow heterotopia are also featured.

This book covers lymphoproliferative disorders in patients with congenital or acquired immunodeficiencies. Acquired immunodeficiencies are caused by infections with the human immunodeficiency virus or arise following immunosuppressive therapy administered after organ transplantation or to treat connective tissue diseases such as rheumatoid arthritis. It was recently discovered that various diseases or therapeutic modalities that induce a state of immunosuppression may cause virally driven lymphoproliferations. This book summarizes for the first time this group of immunodeficiency-associated lymphoproliferations.

This second volume reports on the reaction patterns of lymph nodes in neoplastic and immunodeficient diseases. Based on the contents of volume 1, it presents a detailed survey of lymph node structures and their cellular components under these conditions. The patterns of nodal reactions to the development and spread of cancer have recently been investigated and discussed by several authors. Here, the immediate interactions between tumor tissue and the regional nodes have been assessed in experimental models and in human material. Using modern morphological methods such as im munohistochemistry on the light and electron microscopic level, new insights have been gained into the stepwise process of lymphogenous metastasis. Macrophages/reticulum cells were found to playa signifi cant role in this process, which is duly emphasized. Based on appro priate animal models, one chapter focuses on various subtypes of these cellular elements and their role in the two separate phases of tumor spread and the development of true metastases. The induction of fibronectin in lymph nodes is effected by tumor cells forming a special part of the extracellular matrix. The multifunctional fibronec tin molecule serves as a mediator between tumor cells and fibroblasts, furthering the formation of tumor stroma. This volume also contains a comprehensive survey of primary im munodeficiency syndromes and their nodal manifestations, reference being made to the most recent immunological knowledge."

This book contains the proceedings of a symposium on the use of synthetic substrates in clinical blood coagulation assays, which was held at the University of Leuven, Belgium, on March 1st, 1980. This meeting was organized in order to exchange and discuss recent develop ments and applications in this field. Advantages and disadvantages of synthetic substrates are discussed, while expert workers report on their practical experience with the use of chromogenic substrates in routine assays for blood coagulation and fibrinolysis. The indications when to perform antithrombin III, a2-antiplasmin, factor X and factor II determinations are discussed. For each of the determinations a critical evaluation of the chromogenic assay as compared to the classical assay is presented. The clinical relevance of these assays for anticoagulated and cirrhotic patients, detection of vitamin K deficiency, monitoring heparin therapy and the fibrinolytic system are discussed. Recent developments in the use of fluorogenic substrates for the assay of low concentrations of fibrin olytic activators are presented. Taking into account all practical, medical and economical con siderations an answer is prepared to the question "Are synthetic sub strates to be recommended for routine use?." To make this symposium useful, rapid publication of the proceedings has been undertaken. We are grateful to the participants in this meeting for their co operation and for their willingness to provide manuscripts of their presentations. The manuscripts provided by C. Kluft and H.H.D.M."

This book reviews the respiratory function of vertebrate red cells. I have defined the phrase "respiratory function" broadly to include, in addition to the actual oxygen and carbon dioxide transport, erythropoiesis, haemoglobin synthesis, red cell structure, the deformability of red cells in circulation, ion and substrate transport across the cell membrane, cellular metabolism, and control of cellular volume and pH. All of these aspects of the red cell function may affect gas transport between the respiratory epithelia and the tissues. Throughout the book, I have tried to relate our current knowledge about the nucleated red cell function to the wealth of information about the function of mammalian red cells. However, whenever possible, I have placed the emphasis on the nucleated red cell function for two reasons. First, the erythro cytes of 90% of vertebrate species are nucleated, and, second, nucleated red cell function has not been reviewed earlier in a single volume. This being the case, I have tried to make the reference list as complete as I could with regard to nucleated red cells. I hope that the approach adopted is useful for both com parative and human physiologists. Many people have contributed to the making of this book directly or in directly. Antti Soivio started me in this field. Prof. Henrik Wallgren has always encouraged fresh scientific ideas in his department. My present ideas of red cell function have been influenced by work carried out with Prof. Roy E."

In June 1986 a symposium was held in Giessen on Modern Trends in Virology. It was initiated by the Deutsche Forschungsgemeinschaft, which had supported virus research for the past 18 years in the Sonderforschungsbereich 47 at the University of Giessen. The purpose of the meeting was to serve as a forum for the members of the Sonderforschungsbereich to discuss scientific topics of mutual interest with about 200 virologists that had come from various parts of Europe, the United States, and Japan. It was not by chance that the symposium took place shortly after the 60th birthday of Rudolf Rott, who had founded the Sonderforschungsbereich in 1968 and has been its speaker ever since. Without his vision and his never resting energy Giessen would not have gained the position in the field of virology that it has today. This Festschrift, which contains the contributions presented at the plenary sessions of the symposium, is therefore dedicated to Rudolf Rott. HEINZ BAuER HANS-DIETER KLENK CHRISTOPH SCHOLTISSEK Table of Contents A Genetic Approach to Determining Glycoprotein Topology: The Influenza B Virus NB Glycoprotein has an Extracellular NHz-Terminal Domain Containing two N-linked Carbohydrate Chains R. A. LAMB and M. A. WILLIAMS . . . . . . . . . . . . . . . . . . . . . . . . . 1 Paramyxovirus Metabolisms Associated with the Cytoskeletal Framework Y. NAGAI, T. ToYODA, and M. HAMAGUCHI . . . . . . . . . . . . . . . . . . . 15 Correlation of High Evolutionary Rate of Influenza A Viruses in Man with High Mutation Rate Measured in Tissue Culture: A Hypothesis P. PALESE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Few publications focus on the mysterious, genetically acquired disease paroxysmal nocturnal hemoglobinuria (PNH) and the related "intractable" disorders aplastic anemia and myelodysplastic syndromes. Now, however, the latest understanding of the clinical and molecular genetic aspects of PNH is summarized here in the proceedings of the International Symposium held in Tokyo in 2001. Major topics reviewed include the molecular mechanisms of the PIG-A gene mutation; complement activation and inhibitors; experimental animal models; pathogenesis; the history of PNH research; the natural history of the disease; the mechanism of PNH clone expansion; the emergence of PNH clones under bone marrow failure syndromes; and treatment of the disease by immunosuppressive agents and stem cell transplantation. This book provides an invaluable summary of current research on the fundamental aspects of PNH pathology, presented by renowned experts in the field.

"

Das ist das Schwerste von aHem, was Dir das Leichteste diinket: mit den Augen zu sehen, was vor den Augen Dir liegt. Goethe, Xenien, 1797 That is the most difficult which seems the easiest: to see with your eyes what lies there to be seen. All the diseases in question here are rare. The most common, mucopolysacchari- . dosis (MPSosis III), occurs at a rate of 1 in 160000. Consequently, anyone doctor will only encounter a few cases as a rule, and the literature offers mainly casuistic descriptions. Up till now, there has been no systematic and comprehen- sive review. We thus felt that it would be of interest and benefit to prepare a collective report on a large body of material gathered over a period of many years, the material being extensive enough to provide adequate possibilities for making comparisons. In so doing, we were also able to describe for the first time the specific, and, in some cases, the pathognomonic symptoms for each disease.

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.

Within the last few years, iron research has yielded exciting new insights into the under standing of normal iron homeostasis. However, normal iron physiology offers little protec tion from the toxic effects of pathological iron accumulation, because nature did not equip us with effective mechanisms of iron excretion. Excess iron may be effectively removed by phlebotomy in hereditary hemochromatosis, but this method cannot be applied to chronic anemias associated with iron overload. In these diseases, iron chelating therapy is the only method available for preventing early death caused mainly by myocardial and hepatic iron toxicity. Iron chelating therapy has changed the quality of life and life expectancy of thalassemic patients. However, the high cost and rigorous requirements of deferoxamine therapy, and the significant toxicity of deferiprone underline the need for the continued development of new and improved orally effective iron chelators. Such development, and the evolution of improved strategies of iron chelating therapy require better understanding of the pathophysiology of iron toxicity and the mechanism of action of iron chelating drugs. The timeliness of the present volume is underlined by several significant develop ments in recent years. New insights have been gained into the molecular basis of aberrant iron handling in hereditary disorders and the pathophysiology of iron overload (Chapters 1-5)."

Scientific and Ethical Discipline in Clinical Trials on Acute Leukemia G. MATHE Institut de Cancerologie ct d'Immunogenetique "', Hi'ipital Paul-Brousse "."", Villejuif/France Clinical research is still in an evolutionary stage. Although scientific technology was readily accepted and applied, scientific methodology has been accepted much more slowly and is very rarely properly applied. There are three reasons why this is so. First, medical ethics frequently limits the applicability of clinical research, for doctors have to be more than scientists. They must also remain moral philosophers, as they were before medicine became a science. Second, the heterogeneity of the material on which clinical researchers work in studying human diseases makes the application of scientific methodology difficult. Third, researchers must publish. This means that they must obtain publishable results, and too often this means results in accordance with established concepts, easily accepted by the editors of established journals, which are read by the establishment. It is the privilege of too many people to be able to accept "truth" and recipes from other people and confirm their truth and results. It is the mission of a very few others to accept nothing as "truth" and to consider no recipe ideal, either in concept or detail.

Volume therapy or infusion therapy is used worldwide for the treatment of hypovolemia caused by surgical blood and plasma losses, trauma, burns, or infections. Interestingly, significant differences exist between countries regarding the use of plasma substitutes. In the United States, crystalloids and albumin are more popular, whereas in Europe artificial colloids such as hydroxyethyl starch are preferred. From an international perspective, it is notable that volume therapy using hydroxyethyl starch is an established therapy for the treatment of cerebral, retinal, otogenic, and peripheral circulation disorders in Germany. In other countries, crys talloids are mostly used to treat dehydration or hypovolemia, for example in brain stroke. In recent years, new data made it possible to overcome national differences and agree on an evidence-based, international con sensus. The efficacy of different plasma substitutes for a volume therapy last ing several days has not been sufficiently studied in the past. Long-term volume therapy of patients with cerebral perfusion disorders is an excel lent model for studying the effects of artificial colloids in detail, because of the high doses of colloids that are administered. Through a compari son of commonly used plasma substitutes, we were able to show that sig nificant differences exist between different colloids, for example in their effect on coagulation. After repeated infusion, hydroxyethyl starches that are difficult to degrade lead to an accumulation of large molecules that are difficult to eliminate. These large molecules impair factor VIII/von Willebrand factor."

This book is an edited verbatim account of the proceedings of the Second London Workshop on Red Cell Filtration and Deformability, organised jointly by the Royal Society of Medicine and the Groupe de Travail sur la Filtration Erythrocytaire. The first such London Workshop was held on the occasion of the Second European Conference on Clinical Haemorheology in 1981 and its con clusions were published in an abbreviated form. The interest in blood filtration as a technique for assessing red cell deformability has continued to increase and there are now several hundred centres around the world using some form of filtration. It was, therefore, felt that the informal detailed discussions held by a small invited group of experts from many countries would be of more general interest and therefore worth publishing. This has been made possible by the continued interest and generous support of Hoechst. Spontaneous open discussion rather than formal presentations has been the hallmark of these workshops, with precirculation of all scientific data to the participants. We have attempted to preserve this flavour in editing the transcript of the proceedings. This, together with our anxiety for rapid publication, may have resulted in a less than finely polished text which may contain some in accuracies. The topics discussed were loosely structured into eight sessions, outlined in the accompanying programme."

In the last few years a good deal of information related to the biology and treatment of malignant lymphomas has been accumulated and published in journals and monographs. There is, however, no book that gives a concise and objective update of this information or presents a general survey of the subject. The contributors to this book are international authorities, and on the basis of their personal experience and data from the literature they have written a high-level update on malignant lymphomas which will be of interest to both specialists and nonspecialists.

Recent experimental and clinical progress in the evaluation of cytokines in treatment concepts for cancer patients is the central theme of this book in the ESO Monographs series. The discussion revolves on the experimental basis as well as current clinical experience with the use of human recombinant cytokines. It gives the state of the art and, as such, puts into perspective potential areas of growth and future research.

Major epidemiologists from the UK, USA and Europe contribute to the first ever, much needed comprehensive review of the epidemiology of peripheral vascular disease in the lower limbs.

Through numerous discussions with colleagues it became apparent that the time was right to begin a series of workshop-like meetings on myeloid tumorigenesis. Myeloid tumors are the nonlymphocytic tumors of the hematopoietic system which include tumors of the neutrophilic, monocytic, erythrocytic, basophilic (mast cell) and megakaryocytic lineages. Pioneering studies in myeloid tumorigenesis were initially made in chickens with the discovery of retroviruses that induce various kinds of myeloid tumors acutely (myelocytomatosis, myeloblastosis, and erythroblastosis). These avian retroviruses were subsequently shown to contain the oncogenes v-myb, v-~, v-~, v-erbA, or v-erbB. There have been dramatic advances in studying the pathogenesis of hematopoietic tumors in genetically defined mammalian systems. Many of the well developed model systems in inbred mice, have focused on T- and B-1ymphoma development. Although myeloid tumors have been found in mice, they have not been studied as intensively as lymphoid tumors. Possibly this is because myeloid tumors are less common than lymphoid tumors. Recently, there has been renewed interest in murine myeloid tumor systems. This focus has resulted from 1) the discovery of inbred strains of mice (e. g. BXH-2, AKXD- 23, SJL/J) that are highly susceptible to spontaneous or induced myeloid tumorigenesis; 2) establishment of transplantable murine myeloid tumors (e.

The biology of solid tumor metastasis has been the subject of significant scientific and clinical interest for years and while experimental evidence reveals that metastasis is not solely a random event, very little is known about the biology of metastasis originating from prostate cancer. This is in spite of the fact that the majority of prostate cancer patients die with metastatic lesions to the bone. Progress in understanding this most important aspect of prostate cancer has been hampered by the lack of suitable animal models and an inability to accurately quantify bone metastases and their responses to therapy. Over the past decade, scientists in Japan and the United States have steadily advanced our understanding of the cellular, molecular and immunologic biology of primary and disseminated prostate cancer. It is this body of new information, combined with advances in imaging techniques and prostate cancer tumor markers, that prompted the need for an in-depth assessment of bone metastasis of prostate cancer. Accordingly, on December 12, 1990, a group of basic and clinical investigators from Japan and the United States convened in Gotenba, Japan, to hold the first conference devoted solely to the basic biology and clinical aspects of bone metastases originating from prostate cancer. The cross-fertilization of ideas that was fostered through in-depth discussion of technological advances among various basic and clinical disciplines not only further advanced our understanding of prostate metastases to the bone, but suggested approaches for precise quantitative assessment of these lesions and their treatment.

The publication of Platelet-Vessel Wall Interactions, the second monograph in the Bloomsbury Series in Clinical Science, is particu larly welcome as its appearance signifies the further development of the Series and its potential for the future. The theme of this monograph is the pathophysiology of atherosclerosis, a topic that symbolises the aim of the Series, namely to highlight the important interfaces between basic medical science and clinical practice. Our congratulations to the Editors and contributors. London, December 1987 lack Tinker Preface In the Western world, atherosclerosis causes more illness and death than any other disease. Despite its devastating effects, the pathogenesis of the disease remains a matter for hypothesis and con jecture. This monograph owes its conception to a programme of work directed towards understanding the basic pathophysiology of atherosclerosis. The circulatory system is lined by vascular endothelium which has a central role in maintaining the integrity of the vessel wall and prevent ing thrombosis. The natural equilibrium existing between normal en dothelium which supports blood flow, and platelets which serve to re pair damaged endothelium, is explored in the first two chapters. Atherosclerosis developing as a response to endothelial injury is one hypothesis which has stimulated widespread interest, and re search has largely been directed towards finding the injurious agent."

Written by a team of world-leading experts in the field, who have published extensively

For primary care physicians, haematologists, surgeons and other healthcare professionals with an interest in thromboprophylaxis

Discusses both medical and surgical thromboprophylaxis and includes all relevant guidelines for thromboprophylaxis in pregnancy

Thoroughly revised and updated new edition

This second edition of the Handbook of Thromboprophylaxis expands upon the role of anticoagulants in clinical practice. In addition, it summarises key papers in the field and provides evidence-based guidelines for the use of anticoagulants in routine day-to-day practice.

"

While the enzyme cascade that allows coagulation is well known physiologically, its elegant practical examples are vividly demonstrable in the clinical application of blood and components for the treatment of bleeding problems in surgery, trauma or in congenital deficiency in patients. This volume provides the fundamental and recent understanding relating to coagulation pathways, recombinant technology and other methods for coagulation factor production, up to date laboratory assay, preservation of cellular and plasma components, and their clinical use in surgery and medicine, including the immuno response to repeated challenge to contaminating protein in coagulation factor concentrates. The interrelated but multi-disciplinary chapters have been integrated in four sections: Principles and Fundamentals: Mechanism of thrombin formation; structure -- function relationship of coagulation proteins, role of calcium and anticoagulant: blood collection on haemostatic potential of plasma proteins and platelets; Factor VIII yields from anticoagulant exchanged plasma. Preservation Aspects: Platelet function preservation, platelet interaction with vessel wall; trends in the use of coagulation factor concentrate; immuno purification of Factor VIII; structural and fundamental properties of recombinant coagulation factors. Laboratory Aspects: Platelets counting and function testing; platelet crossmatch predictive value; clinical efficacy of platelet concentrate; protein C and protein S; principle of coagulation factor assay; standardisation of clotting factor assays; clinical efficacy of clotting factor concentrates. Clinical Consequences

Between 1950 and 1960, remarkable advances were made in the develQpment Qf antihypertensive drugs, but since then, prQgress has been less rapid. This dQes nQt mean that no. new drugs have been intrQduced: Qn the cQntrary, their number has increased sharply; but since the advent Qf the beta-adrenergic blQckers no. new pharmacQdynamic principle has been discQvered that CQuid be applied widely as an antihypertensive. This has nQt been fQr want Qf effQrts, because many attempts have been made to. find new ways and means Qf influencing blQQd- pressure regulatiQn Qr the mechanisms invQlved in the pathQgenesis Qf hypertensiQn. HQwever, the results Qf these endeavQrs have mQstly been disapPQinting. Even thQugh high blQQd pressure can be treated mQre satisfactQrily tQday than many Qther diseases, the success achieved in cQmbating Qne Qf man's mQst frequent ailments shQuld nQt induce cQmplacency, but rather stimulate research tQwards further imprQvements. The present standstill affQrds an QPPQrtunity to. review the field Qf antihy- pertensive agents, fQr it is unlikely that fundamentally new drugs will appear in the near future. AlthQugh greater knQwledge has been gained Qf the mechanisms Qf blQQd-pressure regulatiQn and Qf the pathQgenesis Qf hypertensiQn, these ad- vances have had no. direct cQnsequences in the search fQr new therapeutics.

J.J. Van Loghem Previously to this symposium, five others have taken place in Groningen. The first one in 1976. This yearly scientific happening has continued. It has greatly stimulated the in terest in blood transfusion and all allied disciplines in our country. It is clear that these meetings are organized not only by a good scientist, but at the same time by a gifted or ganizer who, as director of the Red Cross Blood Bank Gro ningen-Drenthe, has shown that the heavy load of daily routine work can very well be combined with a large amount of experimental and clinical research in blood component therapy, coagulation disorders, blood group genetics and serology, the latter in cooperation with the Blood Group laboratory of the University Hospital Groningen under the directorship of Dr. Van Dijk. All these activities show how much a well-organized blood bank can contribute to a national blood transfusion orga nization."