The first International Meeting on Apheresis was held in Dyon in 1984. At the congress it became clear that both the technical and therapeutic sides developed very rapidly and it appeared fruitful to bring together the investigators of the different countries working in the areas. At that time immunology had come to pervade many clinical specialities, and hemapheresis, especially plasmapheresis was considered a therapeutic tool in many immunological diseases which hitherto had proved to be fatal. New methods to identify certain antibodies and circulating immune complexes in the serum and the possibilities to remove them from the blood by several techniques (filtration, centrifugation, immunoabsorp tion) led to an almost uncontrolled use of plasma exchange in a variety of diseases. Since then the technical possibilities of this technique were further recognized, as was the impact of immunology on many diseases, and the possibilities to collect specific components for therapeutic pur poses. But also we became aware of the limited contributions of anec dotal data on successes or failures of apheresis as adjuvant treatment. Therefore international prospective studies were initiated to make critical assessment possible of apheresis in various diseases.

In transfusion medicine the scientific fundamentals of immunology have had a considerable clinical impact. Transfusion may suppress the immunity but some patients could suffer disadvantages including GvHD, alloimmunisation and possible cancer, where white cells (WBC) play pivotal roles in this phenomenon, presenting antigens and producing cytokines. A clinical application of this practice is LAK-cells targeted against cancer. MHC on the WBC may provide additional immunological modulations through series of secondary messengers. Thus reduction of WBC in the blood and bone marrow may be advantageous for patients. On the other hand, sharing a part of MHC or making the transplanted white cells anergic by storage may be even more advantageous for patients. CMV infection could mimic part of this MHC. UV radiation is effective in the inactivation of the WBC although filters are easy means for such removal. However, their accurate quantification requires flow cytometry that has considerable potential application in blood transfusions. Idiotypic antibody could play an important role in platelet theory. However, the potential infection risks in transfusion like HIV and HCV remain, but application of molecular biological methods like PCR or RT/PCR has great potentials in detection of infectious diseases, transplantation and genetic disorders. Immuno affinity purified concentrates, like factor IX and protein C, could reduce patients' immune functions, where in the future protein C could be derived from transgenic animals. Advances are sure to emerge through adoptive immunotherapy and gene therapies are exciting prospects when genes transferred into lymphocytes could be used to correct cell mediated immune deficiency, as in ADA.

Hematopoietic stem cell and immune cell transplantation has cont- ued as a promising therapeutic alternative and a fascinating area of cell biology as well as a field of persistent procedural problems. This - plains why substantial parts of basic research on cell growth and d- ferentiation, immune tolerance and antitumor effects, gene transfer, minimal residual disease and supportive care have settled around cli- cal transplantation in hematology and oncology. This second volume again updates the current role of allogeneic and autologous transpl- tation in leukemias, lymphomas and solid cancers, including cont- versial strategies and novel experimental approaches. In particular, cellular immune therapy, new conditioning strategies, mismatched donor transplantation, updated clinical transplantation, antiangiogenesis and strategies against fungal infections are focused upon. Outstanding representatives of leading groups guarantee fir- hand information and indicate how we can work and cooperate more effectively to the benefit of our patients. The editors are indebted to the Gesellschaft zur Bekampfung der Krebskrankheiten Nordrhein-Westfalen for a substantial support of the publication. They also acknowledge the major contribution of Beate Kosel as coordinator of the editorial work."

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."

The hematopoietic system plays roles that are crucial for survival of the host: delivery of oxygen to tissues, arrest of accidental blood leaking from blood vessels, and fending off of invading microbes by humoral, cell-mediated, and phagocytic immunity. The activity of the hematopoietic system is staggering: daily, a normal adult produces approximately 2.5 billion erythrocytes, 2.5 billion platelets, and 1 billion granulocytes per kilogram of body weight. This production is adjusted in a timely fashion to changes in actual needs and can vary from nearly none to many times the normal rate depending on needs which vary from day to day, or even minute to minute. In response to a variety of stimuli, the cellular components of the blood are promptly increased or decreased in production to maintain appropriate numbers to optimally protect the host from hypoxia, infection, and hemorrhage. How does this all happen and happen without over or under responding? There has been extraordinary growth in our understanding ofhematopoiesis over the last two decades. Occupying center stage is the pluripotent stern cell and its progeny. Hematopoietic stern cells have been characterized by their capacity for self renewal and their ability to proliferate and differentiate along multiple lineages. Few in number, the stern cell gives rise to all circulating neutrophils, erythrocytes, lymphoid cells, and platelets. In hematopoietic transplantation, the stern cell is capable of restoring long-term hematopoiesis in a lethally irradiated host.

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.

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.

1 2 D. FITZGERALDI, I. PASTAN , and J. ROBERTUS Introduction . . . . . . . . . . . . . I 2 Toxin Structure-Function Properties 2 2. 1 Functions. . . . . . . . . . . . . . . . . . . . . . . . 2 2. 2 Binding. . . . . . . . . . . . . . . . . . . . . . . . . 3 3 Intracellular Processing - Cleavage and Reduction . . . . . . 4 3. 1 Cytosolic Activity . . . . . . . . . . . . . . . . 5 4 Immunotoxin Design and Testing. 6 5 Conclusion. . 8 References. . . . . 8 1 Introduction While various treatment approaches for cancer include reversal of the transformed phenotype, stimulation of immune responses, inhibition of metastatic spread and deprivation of key nutrients, the goal of immunotoxin treatment is the direct killing of malignant cells. Because they are enzymatic proteins that act catalytically to kill cells, bacterial and plant toxins are often employed as the cell-killing component of immunotoxins. Here we provide background information into the structure-func tion relationships of toxins and discuss how they can be combined with cell-binding antibodies or other ligands to generate immunotoxins. Bacterial and plant toxins (e. g. , diphtheria toxin, Pseudomonas exotoxin and ricin) are among the most toxic substances known. However, because they bind to cell surface receptors that are present on most normal cells, unmodified toxins are generally useless as anti-cancer agents. To convert toxins into more selective agents, their binding domains are either eliminated or disabled and replaceq with cell binding antibodies that are tumor-selective.

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."

The monograph edited by Drs. Wunder and Henon on "Peripheral Blood Stem Cell Autogtafts" is extremely useful as well as timely. It covers the "state of the arts" with respect to the use of hemopoietic stem cells collected from the peripheral blood for the reconstitution of hematopoiesis after myeloablative therapy. If is is accepted that hematopoietic function in the mammalian organism is the result of stem cell seeding of an appropriate stromal matrix, then the use of blood derived stem cells for hematopoietic reconstitution represents the "physiological form" of the (re) establishment of a hematopoietic bone marrow. All observations to date are compatible with the assumption that stem cells migrate via the blood stream from extraembryonic hematopoietic tissue to the fetal liver to establish there a first intraembryonic site of blood cell formation and especially of stem cell replication and proliferation. This fetal liver tissue appears then to be the major source for the seeding offetal bone marrow stroma as it develops sequentially in all the bones of the skeleton - in other words during most of the entire embryonic development. There is a very high concentration of stem cells in the blood of the embryo (more than 20000 CFU-GM per ml in the 22nd week) and the stem cells in cord blood seem to be the "tail end" of a dramatic "stem cell traffic" in the embryo to establish the hemopoietic as well as lymphopoietic tissue."

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.

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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."

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.

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."

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.

The idea for this volume was conceived during a discussion in the hallway at a conference in early 1990. "What is the best way to detect and define pluripotent hematopoietic stem cells?" was the question posed by Dr. Fritz Melchers. After discussing the pros and cons of the available assays for quite some time, it became apparent that this topic required a wider expertise and merited a larger forum. Thus, we decided to extend the discussion and to compile the results in this volume. Much to our delight. many of the pioneers of recent experimental and theoretical developments in stem cell research agreed to contribute their expertise to answer the question. These authors review both past findings and present insights, thus providing an overview of the evolution that has been and is occurring in the field of stem cell research. In the light of recent trailblazing developments in both experimental models and in clinical application it is indeed time to reevaluate our knowledge about stem cells. Trans plantation of hematopoietic stem cells has become more and more prevalent as a curative therapy in a variety of acquired and genetic diseases, including cancer, radiation accident, as an agent for gene therapy, and perhaps even as treatment for autoimmune diseases. Stem cells are now derived not only from bone marrow but also from peripheral blood, cord blood, and fetal liver, greatly increasing their availability for human transplantation and in some cases (fetal tissues) obliterating the need to match donors and hosts."

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.

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.

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.

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.

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