This volume contains the papers which were presented at the Third International Symposium on Oxygen Transport to Tissue together with the discussions at the end of each Session. The meeting was held at Churchill College, Cambridge from July 4th-7th 1977. Our special thanks are due to Mrs. Valerie Jeal and Mr. Charles Drown of the Department of Pathology, Bristol, who were invaluable in ensuring the smooth running of the meeting and the preparation of this book. We are very grateful to Dr. Marian Silver for proof-reading and helping to disentangle the "discussion". We would also express our thanks for the general help received from Janet and Fiona Silver and Steven James and our appreciation of the cheerful assistance of Miss Sadie Williams in putting the finishing touches to the manuscript. August, 1977 I. A. Silver M. Erecinska H. I. Bicher Contents Session 1 - OXYGEN ELECTRODES AND BLOOD MONITORING DEVICES The Bitumen P0 Electrode - A New Method to 2 Manufacture P0 Needle Electrodes 3 2 H. Acker, D. Sylvester, E. Dufau, and H. Durst A Working Equation for Oxygen Sensing Disk Electrodes * * * * * * 9 T. E. Tang, R. E. Barr, V. G. Murphy, and A. W. Hahn Variations on the Response Characteristics of Oxygen Electrodes **** 17 R. E. Barr, T. E. Tang, and A. W. Hahn Directly Heated Transcutaneous Oxygen Sensor 25 H. P. Kimmich, J. G. Spaan, and F.

Extensive research into the molecular mechanisms of cancer disease has heralded a new age of targeted therapy. In malignant cells, key proteins that are crucial to tumor growth and survival are now being targeted directly with rationally designed inhibitors. Apart from monoclonal antibodies, small molecule therapeutics such as oncogenic protein kinase inhibitors are attracting a vast amount of investigational attention. This textbook, written by acknowledged experts, provides a broad overview of the small molecules currently used for the treatment of malignant diseases and discusses interesting novel compounds that are in the process of clinical development to combat cancer.

An up-to-date overview of blood and marrow transplantations, the book discusses in detail Indication to transplantation and pre-transplant considerations. An outlook on the latest developments and their future aspects is included, while problems and pre- and post-transplant complications are fully explored.

Hemorrhage and thrombosis are major hazards for pregnant women and their newborn infants. This book is concerned with the developmental mechanisms, the diagnosis and treatment, as well as the prevention of these hemorrhagic and thrombotic disorders. The topics discussed in this volume, (1) perinatal hemorrhage in mothers and their offspring; (2) coagulation disorders complicating pregnancy; (3) neonatal intracranial hemorrhage; and, (4) vitamin K deficiency in the neonate, will help bridge the gap between basic scientists and clinicians and between the pediatri- cian and the obstetrician. Hopefully, all those concerned with preventing these disorders will be stimulated by the information and questions raised in the fol- lowing presentations. Acknowledgements We wish to thank Professors Takeshi Abe (Vice President, Teikyo University), Nobuyoshi Shinagawa (Hirosaki University), Hiroaki Soma (Tokyo Medical College), Tamotsu Miyazaki and Keisuke Sakurada (Hokkaido University) for their helpful advice. SHIGENORI SUZUKI WILLIAM E. HATHAWAY JOHN BONNAR ANTON H. SUTOR SHIGENORI SUZUKI. * 1936 in Sapporo, Japan. M.D., Uni- 'versity of Hokkaido, 1963. Lecturer, Hokkaido Univer- sity, 1974. Alexander Humboldt-Foundation Scholarship, Free University of Berlin. University of Munich, 1974- 1976. Foriner President, Japanese Society of Obstetrical, Gynecological, and Neonatal Hematology. President of International Symposium on Perinatal Thrombosis and Hemostasis (1989 Sapporo). Professor, College of Medi- cal Technology affiliated with Hokkaido University since 1983. WILLIAM E. HATHAWAY. * 1929 in Oklahoma, USA.

A variety of metabolic processes are known to be intimately involved in the maintenance of cellular structure and function. It has also become clear that metabolic events involved in the synthesis and hydrolysis of ATP as well as for the synthesis of proteins and phospholipids are essential for cellular health. The regulation of cell function is generally achieved through participation of a wide variety of hormones and different signal transduction mechanisms for the activation/deactivation of some specific metabolic processes. In this regard cyclic AMP and calcium seem to play a crucial role. Various hormones are also known to affect the genetic machinery of all the cell; however, the exact signals for genetic control of cellular function are not well defined. In particular, the sequence of events concerned with remodelling of different types of cells under various pathological situations is poorly understood. In this book we have therefore dealt with some of these issues from biochemical, molecular biological, physiological, and pharmacological viewpoints. Special emphasis has been laid on understanding heart function and metabolism in health and disease in general, and cardiac hypertrophy, heart failure, and ischemic heart disease in particular. It is hoped that this multidisciplinary information will be of value to basic scientists and clinical investigators.

This book offers a description of current and recently developed laboratory assays in the field of haemostasis and thrombosis. It is the result of a unique cooperation between experts from more than 60 institutes in 12 European countries, brought together by the ECA T (European Concerted Action on Thrombosis and Disabilities) under the auspices of the Commission of the European Communities in Brussels, Belgium. The ECAT, which was initiated in 1981, designed and performed three prospective clinical studies to establish haemostatic factors as risk indicators of thrombosis. Included were patients with angina pectoris at risk from myocardial infarction, patients undergoing angioplasty at risk from re-stenosis, and patients receiving hip replacement at risk from deep venous thrombosis. Assay procedures were chosen, training courses for technicians held, and essential reagents were supplied from a central source. A quality control assessment scheme served to compare assay results both within and between laboratories. In the angina pectoris study, centres determined most of the assays locally; in the other two studies assays were performed centrally. The need for further quality assessment in Europe Dr J. F. Davidson in Glasgow, led to a separate activity coordinated by including coagulation inhibitors and plasminogen as risk factors for familial venous thrombosis. The Editors hope the ECA T Assay Procedures book will contribute to further harmonization ofhaemostasis assays, and ultimately to their standardization.

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.

Coronary heart disease remains the leading cause of death for men and women in the United States and other industrialized nations. Acute myocardial infarction accounts for a majority of these deaths, approaching 750,000 yearly. Thrombolytic therapy has revolutionized the treatment of myocardial infarction, saving lives to a greater extent than any treatment developed to date. The identification of patients best suited for thrombolytic therapy has been a challenging task, as has the ideal adjuvant strategy. Further, the noninvasic diagnosis of treatment successes and failures, as well as the expeditious triaging of patients requiring mechanical/surgical revascularization have been difficult to define, but progress has been made recently. The emergence of information vital for patient care has appeared at an extraordinary pace, with hundreds of articles being published yearly. Unfortunately, a resource devoted to the area of thrombolysis does not exist, making the dissemination of information to physicians, scientists and health care providers problematic. The Modern Era of Coronary Thrombolysis is designed to bring the medical and scientific communities up to date. It will serve as a foundation for future investigation, as well as a resource which can be referred to for many years to come.

This monograph covers the entire field of blood group serology, with its main emphasis on the chemical and biochemical basis of blood group specificity. Full consideration is given to molecular biology investigations, in particular to studies on the structure of blood group genes and the molecular biological basis of alleles and rare blood group variants, whereby relevant literature up to the year 2000 is covered. The text is supplemented by numerous illustrations and tables, and detailed reference lists.

Transfusion medicine provides an excellent bridge connecting the healthy community donors with the patient's needs at the bedside; the dominant philosophy has been on patient care and science, but it is now realised that blood banks manufacture increasing amounts of blood components to administer to patients -- a role analogous to manufacturing functions. The concept of Good Manufacturing Practice (GMP) is therefore relatively new. While quality has always been important, the impact of GMP, Total Quality Management (TQM) and Quality Assurance (QA) will be profound. As the regulatory agencies, like the FDA in the U.S.A. and the EEC Commission in Europe, increase their enforcement activities, doctors, technical experts and managers will have to face many issues of quality assurance including documentation, validation, audit system, regulatory laws, licensing, teaching and training of staff and their job descriptions, standards, processing facilities, procedure validations, automation, record keeping, internal and external quality control of products and their release.The expansion of this philosophy to include Good Clinical Practice (GCP) is an even greater challenge demanding consensus therapy protocols and quality management of transfusion through auditing by the hospital transfusion committees. Such comprehensive plans will profoundly affect the financial and organisational structure of blood transfusion in the future.

Due to the topology and structure of the lymph nodes, their role in the pathogenesis and development of diseases is a very special one. Each organ and even each organ-related region of the body has its own group of lymph nodes, specific topological reactions, such as in circumscribed inflammation or in the metastatic spread of malignant tumors. On the other hand, all the lymph nodes of an organism join in a uniform function effected by highly differentiated structures. Volume 84 of Current Topics in Pathology presents our current knowledge about the structure and reaction patterns of this "sec ondary" lymphoid organ. Despite our original intention to publish all the contributions in one book, it became necessary to divide them: Part 1 focuses on the involved nodal compartments, cell types, and functions, while Part 2 describes their reactions in inflammatory, neo plastic, and immune-deficient diseases. Even with the cooperation of more than 30 authors, the coverage cannot be exhaustive. The scope of both parts is limited to those reactions that can be described by direct and indirect morphological methods, including modern tech niques such as immune electron microscopy."

The idea to compile recent results on the ectoenzymes aminopeptidase N/CD13 and dipeptidylpeptidase IV/CD26 arose from the great interest given by readers world-wide to the two proceedings volumes edited by us in 1997 and 2000 (Ansorge and Langner, 1997; Langner and Ansorge, 2000). These volumes contained the presentations at two symposia held in Magdeburg (Germany) in 1996 and 1999 under the title "Cellular peptidases in immune functions and diseases", which was also the name of the Sonderforschungsbereich in Magdeburg, sponsored by the Deutsche Forschungsgemeinschaft between 1995 and 2001. Our groups in Magdeburg and Halle during the last two decades have provided results on these two enzymes in cells of the hematopoietic system that justify a review in an edited monograph like the present one (see the reviews by Kahne et at. , 1999; Lendeckel et at. ,1999; Riemann et at. , 1999). There are, however, many other groups in Europe, US and Japan which made important contributions to this field and particularly in topics improving the understanding of physiological and pathophysiological roles ofAPN/CD13 and DPIV/CD26. Therefore we decided to invite some of them to contribute reviews of their results to this book. Having worked for about 40 years in the field of proteolysis, for both of us to see the development of activities and knowledge from protein chemistry and enzymology to physiology and pathophysiology and even to therapy is very stimulating and fascinating. Of course, this development also reflects the dramatic improvement and refinement of methods.

I am honored to be invited to prepare a foreword for the proceedings of the Second International Lubeck Conference on Erythropoietin (Epo). I congratulate Wolfgang Jelkmann, Horst Pagel and Christoph Weiss for their organization of an excellent program for this conference which updated all of us on the advances made in erythropoietin research during the past few years since the first conference in June of 1988. I am sure that Professor Paul Carnot, had he been present at this conference, would be very pleased and proud of the advances made in the field of erythropoietin since his and Madame DeFlandre's seminal finding in 1906 (1) that rabbits produced a humoral substance following bleeding which controls red blood cell production. The reports by Hjort in 1936 (2) and by Erslev in 1953 (3) that large volumes of plasma or serum from rabbits following a bleeding stimulus, when injected into normal donor rabbits, produced a reticulocytosis, were very significant in confirming the existence of a humoral factor which controls erythropoiesis. Reissmann's parabiotic rat experiments in 1950 (4) reawakened interest in erythropoietin when he proved that hypoxia stimulated the production of a factor which regulates red cell produc tion. The studies of several investigators such as Jacobson et al. (5), Fisher and Birdwell (6), Kuratowska et al. (7) and Nathan et al."

The mammalian erythrocyte is a very suitable model for the study of aging at the cellular and molecular level. It is not only a matter of apparent simplicity in terms of biochemistry, biophysics and physiology but more likely this cell offers a great possibility for elucidating some basic problems in the process of aging. In fact, nowadays, it is possible to follow individual cells all along their life span in circulation, it is possible to obtain these cells when young, middle aged or old and it is possible to obtain cells from individuals of defined ages and transfuse them into compatible recipients to investigate the role of the environment where the cell lives, and finally it is possible to easily manipulate the red cell content in terms of enzymatic activities and/or metabolic properties to investigate the possible effect of these manipulations on cell survival. This book, Red Blood Cell Aging, is based on a symposium held in Urbino, Italy, at the end of 1990 and examines the impact of age on the membrane, metabolism, structural and enzymatic proteins of mammalian erythrocytes. The various contributions to this symposium not only described those processes of aging which affect the cell but also provided a nearly complete picture of the event{s} and mechanism{s} that every day permits to recognize among 25 trillion circulating red cells {in an average adult} that 1 percent that have reached the end of their 120 day life span in circulation.

The European Study Group for Cell Proliferation held its XVth Meet ing at Sundvolden, Norway, in September 1987. The program included a symposium on the cell kinetics of the in flammatory reaction, with invited speakers. This volume of Current Topics in Pathology contains the manuscripts submitted by the speak ers. Inflammation is a very broad area, and the cell kinetics of the inflammatory reaction comprises a large number of topics. A full cover age would fill more than one book. This volume therefore contains only a few of the important aspects of the cell kinetics of the inflammatory reaction. It is hoped that it will serve as inspiration for further research in this important area. Inflammatory diseases are even more important than cancer, and there is a great need for a more detailed information about inflammation. OLAV HILMAR IVERSEN Contents Chapter I The Cell Kinetics of the Inflammatory Reaction. Introduction and Overview."

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."

Siegmund J. Baum It has become a tradition to commence advocated by Leonard Cole) (3). important meetings of this society with At about the same time, Alpen and reminiscence and nostalgia. Bone marrow Baum (4), using a larger mammal, the dog, transplantation, which has a history of only demonstrated that injecting autologous marrow 30 to 40 years, permits this process, since post irradiation would protect lethally some of the early investigators are still with irradiated animals (see Table). Certainly, us. For example, over the past 15 years, we protection was obtained from the cellular have had three symposia in honor of Egon constituents of the bone marrow. Lorenz. As we all know, the team of Lorenz, We undertook to test on dogs the Uphoff and Congdon was involved in the first hypothesis of Gengozian and Makinodum (5) that successful transplantation of syngeneic and increasing the radiation dose will increase allogeneic bone marrow into irradiated immunologic tolerance for allogeneic implants.

vitro methodology for the cultivation of erythroid The purpose of In Vitro Aspects of Erythropoiesis is to broaden our understanding of the regulation of stem cells. The second series of papers treats cellular normal and neoplastic hematopoietic cells by means and soluble factors which affect erythroid stem cell of a synthesis of different techniques, divergent no- differentiation. Hormonal modulation of in vitro menclature as well as a closer standardization of re- erythropoiesis is the theme of the third session fol- agents and methods which had heretofore produced lowed by a series of papers in the fourth which fo- vagaries of results among different laboratories. cuses on erythropoiesis after transformation by ei- Hence the papers, discussions and appendices pre- ther Friend or Rauscher viruses. The fifth session deals with serum inhibitors to erythropoiesis and the sented in this volume will be of value and interest to investigators and clinicians as well as to students and role of the macrophage in red blood cell production. teachers of hematology. Finally, the sixth session concentrates on the biogen- In Vitro Aspects of Erythropoiesis is comprised of esis of erythropoietin in vivo and in vitro. thirty papers delivered by twenty invited contribu- Each of the six sections is followed by a discus- tors at a three day conference which was held in sion which was transcribed and initially edited at the Capri, Italy in October of 1977. The contributors meeting.

In the last six years, a remarkable series of stUdies have demonstrated an intimate relationship between red cell metabolism and the function of the cell as an organ of gas transport. First came the demonstration of binding of organic phosphocompounds of the red cell to hemoglobin; this was followed by studies that demonstrated modification of hemoglobin oxygen affinity by such binding. At present we are in an exhilirating phase of accrual of data showing that the levels of these phosphorylated inter mediates can be rapidly altered in the red cell to modulate hemo globin function. At one time it was said that the red cell was an inert bag full of hemoglobin. Now we know not only that the cell has an active metabolism crucial to its viability, but that this metabolism is just as crucial to the whole organism in the proper adjustment of oxygen transport. On October first, second and third, 1969, red cell biochemists, general biochemists, geneticists, cardio-pulmonary physiologists, exercise physiologists, experts in blood storage, and represen tatives from many other disciplines met in the Towsley Center for Continuing Medical Education at the University of Michigan, Ann Arbor, to present recent findings and discuss developments in this new interdisciplinary field. The meeting was dedicated to Dr. Alfred Chanutin, Professor Emeritus of the University of Virginia, to honor his retirement in 1967 and in recognition of his great contributions to the studies outlined in the first paragraph of this preface."

Hemoglobin and the red cell have continued to set a dizzying pace as the objects of research in the two and one-half year interval since the First International Conference on Red Cell Metabolism and Function. Most exciting perhaps, is a beginning molecular attack on sickle cell disease. The story of the inter action of red cell metabolism and oxygen transport has continued to unfold, and we can now infer that patients with hypoxia usually utilize red cell metabolic adjustments to improve oxygenation. This puts the red cell squarely in the center of medical practice, since much of medicine-heart, pulmonary, and blood disease- deals with inadequate oxygenation. On April 27th through the 29th, 1972, crystallographers, chemists, biochemists, physiologists, geneticists, and physi cians from many medical disciplines met in the Towsley Center for Continuing Medical Education at the University of Michigan, Ann Arbor to present new data, to review recent developments, and to try to piece together additional features of the red cell puzzle. The meeting was dedicated to Dr. Francis John Worsley Roughton, Professor Emeritus of Colloid Science, University of Cambridge, England, in recognition of his numerous excellent contributions to the understanding of hemoglobin and red cell function. The program got off to a good start with a paper from M. F. Perutz, Nobel Laureate, on the structure of hemoglobin. Dr."

This book is not a "proceedings" volume. Rather the chapters are essays by experts in the field of blood substitutes, invited by the editors to con tribute to the 1996 "Current Issues in Blood Substitutes Research and Development" course given in San Diego, March 18-21. The contributors were selected because of their expertise in areas deemed by the editors to be critical to the advancement of the field. The course, as in past years, is heavily influenced by feedback from par ticipants, and by research in this and related fields. In addition to the didactic lectures (for which these chapters are the foundation), the course also offers the opportunity for presentation of research reports, progress reports from the various companies currently commercializing products, and round table discussions of selected subjects. Thus, we are grateful to past participants for their helpful comments. Production of a book, especially on a short timeline, is not an easy feat."

Sixty years ago, G. Fanconi published a paper entitled: "Familiiire infantile pemiziosaartige Aniimie (pemizioses Blutbild und Konstitu- tion)", in which he reported that this type of severe aplastic anemia represents a hereditary disease distinct from other pancytopenias of childhood (Fanconi 1927). Later this syndrome was named Fan- coni anemia (FA; van Leeuwen 1933). A more recent study of the genetics of FA confirmed that the syndrome is inherited in an au- tosomal recessive manner (Schroeder et al. 1976). Prenatal diagno- sis in FA families showed that about 25% of fetuses are affected (Auerbach et al. 1985, 1986). In 1964, Schroeder et al. discovered high frequencies of chro- mosomal aberrations in cultured peripheral blood lymphocytes from patients with FA. Schuler et al. (1969) reported that cells from FA patients are particularly sensitive to the chromosome-breaking activity or clastogenic effect of a polyfunctional alkylating agent. Since that time, studies of baseline and induced frequencies of chromosomal aberrations have been used for the identification of patients with FA. There is now a large body of data concerning the possible mechanism(s) underlying the hypersensitivity of FA cells to DNA cross-linking agents, the biochemical basis for which is still unknown. Complementation analysis, using cells from different FA pa- tients, has demonstrated genetic heterogeneity in the syndrome.

The 6th volume of the book series Acute Leukemias presents both therapeutic and prognostic updates of the most recent results of major multicenter clinical trials. Additional chapters report on new trends in leucemia cell biology, the monitoring of minimal residual disease and secondary leucemias as well as new antileucemic drugs, antimicrobial strategies and the use of cytocines. Acute Leukemias VI provides a new update on the rapid progress being made internationally concerning leucemic diseases.

The 11 th meeting in "Modern Trends in Human Leukemia" took place from June 19 to 21, 1994 in Wilsede in the middle of the Liineburger Heide, South of Hamburg. Interwoven with the Leukemia program was the Nato-sponsored Symposium of the ASI-Series "Gene Technology in Analysis of Malignant and Inherited Human Diseases Related to Development" . The Wilsede meeting was continued on a ship of the Neva leading through lake Ladoga and lake Onega. The topics of both meetings included discussion on recent progress isolation and development of hematopoietic stem cells, genes crucial for development and diseases, methods of gene transfer, application of gene transfer; oncogenes and anti-oncogenes as targets for gene therapy; receptors and their ligands in normal development and diseases, immunology and immunotherapy, radiation biology, clinical leukemias and bone marrow transplantation. The Nato workshop concentrated not only on analysis of cell systems useful for somatic gene therapy, but also on actual themes directly related to correction of human diseases. The latter aspects emphasized themes related to biotechnology, the first part was by nature more general. We also included a few contributions that discussed perspectives for the future of gene therapy and possible relationships to evolution.

51 worldwide leading experts in the field of erythrocyte research contributed to this first book on transport processes in red blood cells. It explains the latest findings on the basis of well-established principles, in an accessibly structured and carefully organized compilation.