Although blood substitutes represent a goal that has been sought for more than a century, their development is now on the cutting edge of biotechnology: beyond biochemistry and molecular biology, these products are being integrated into the larger physiological picture of gas transport that is essential to every living organism. New products will find obvious clinical application, since they overcome many of the problems with blood transfusion, such as the need to crossmatch, storage limitations, and the risk of transmission of infectious disease. As work continues to bring this new class of products to market, discoveries have been made about very basic aspects of how red blood cells work with regard to the exchange of oxygen and carbon dioxide and interactions with molecules such as nitric oxide and carbon monoxide which may mediate contractility of smooth muscle. These new challenges are being met with impressive rapidity as products are readied for testing and introduction into clinical use. As more is understood about the general properties of artificial blood substitutes, attention is focusing on applications which will benefit the most from their availability. This volume is a collection of chapters by researchers currently working in the field of blood substitutes and closely related fields. Each of them focuses on current challenges from a different perspective, from the clinical question, "What is the target?", to detailed descriptions of the interactions with nitric oxide, endotoxin, and carbon dioxide. Included in the volume is a review of the peer-reviewed research published in 1995 and a general discussion of current products and potential clinical applications. Takentogether, these chapters provide an up-to-date picture of this rapidly evolving field.

In the summer of 1988, my developmental biology professor announced to the class that hematopoietic stem cells (HSCs) had finally been purified. Somehow, I never forgot the professor's words. When I started working in Dr. Irv Weissman's labo- tory at Stanford as a postdoctoral fellow, I realized that the findings mentioned by the professor were from Weissman's laboratory and had been published in a 1988 edition of the journal Science. It has been over 20 years since the publication of that seminal paper, and since then tremendous advances in understanding the biology and maturation of HSCs, namely the process of hematopoiesis, which includes lymphocyte development, have been made. These discoveries were made possible in part by advancements in technology. For example, recent availability of user friendly fluorescence activated cell sorting (FACS) machines and monoclonal an- bodies with a variety of fluorescent labels has allowed more scientists to sort and analyze rare populations in the bone marrow, such as HSCs. All classes of hematopoietic cells are derived from HSCs. Stem cell biology draws enormous attention not only from scientists, but also from ordinary people because of the tremendous potential for development of new therapeutic application to diseases that currently lack any type of effective therapy. Thus, this type of "regenerative medicine" is a relatively new and attractive field in both basic science and clinical medicine.

Hemoglobin and Hemoglobinologists This volume, Hemoglobin Disorders: Molecular Methods and Protocols, will be introduced with a review of the great milestones in the field, and the scientists responsible for those achievements. The history of hemoglobin can be divided into three periods: the Classical period, the Modern period, and the Post-Modern period. I am inclined to include as the four major members of the classical period Francis Roughton, Quentin Gibson, Jeffries Wyman, and Linus Pauling, not only because of their achievements, but also because of the superb scientists they trained and/or influenced. Francis John Worsely Roughton (1899-1972) (Fig. 1), in his laboratory at Trinity College in Cambridge, England, made the first measurements of the rapid reaction of oxygen with hemoglobin at the millisecond scale, at first by flow-mixing methods and later by flash photolysis. He not only opened an era of molecular research of hemoglobin, but also invented the methodology for fast reactions through the use of laser technology, which was later improved by others so that even faster reactions could be detected. Another contribution of Roughton was the education of Quentin H. Gibson (Fig. 2), his favorite s- dent, who, in his laboratory in Sheffield, continued to expand the horizon of ligand binding to hemoglobin, defining the oxygen binding constants for each of the hemes of hemoglobin. Though this did not, as expected, solve the und- lying mechanism of ligand cooperativity as discussed below, it was nonet- less an important milestone.

This issue of Hematology/Oncology Clinics, guest edited by Dr. Glenn J. Hanna, will focus on Head and Neck Cancer. This issue is one of six selected each year by our series consulting editors, Dr. George P. Canellos and Dr. Edward J. Benz. This issue addresses the evaluation and management of the complex head and neck cancer patient with articles focused on unique epidemiology and therapeutic principles by subsite of disease. Additional information relevant to rare head and neck malignancies is included. The issue further focuses on the evolving applications of minimally invasive surgery in oropharynx cancer and the role of immunotherapy in the management of advanced disease. Topics include: Radiologic Evaluation of the Head and Neck Cancer Patient, Robotic and Endoscopic Approaches to Head and Neck Surgery, Cancer of the Oral Cavity and Lip, Cancer of the Oropharynx and the Association with Human Papillomavirus, Cancer of the Larynx and Hypopharynx, Cancer of the Nasal Cavity and Paranasal Sinuses, Cancer of the Nasopharynx and the Association with Epstein-Barr Virus, Salivary Glands Cancers, Thyroid and Parathyroid Cancers, Cutaneous Malignancies of the Head and Neck, Managing Recurrent and Metastatic Head and Neck Cancer, and Immunotherapy for Head and Neck Cancer. Provides in-depth, clinical reviews on head and neck cancer, providing actionable insights for clinical practice. Presents the latest information on this timely, focused topic under the leadership of experienced editors in the field; Authors synthesize and distill the latest research and practice guidelines to create these timely topic-based reviews.

Heme oxygenase is rapidly taking its place as the centerpiece of multiple inter acting metabolic systems. Only 25 years ago heme oxygenase and its metabolic prod ucts appeared to be merely a simple metabolic system-one substrate, heme; one enzyme, heme oxygenase; and one set of products, iron to be recycled, and bilirubin and carbon monoxide to be disposed. From a group of about 25 people in 1974, as judged by attendance at various Gordon conferences, heme oxygenase has, in the year 2000, attracted working scientists-and clinicians I might add-by the hundreds and has produced referenced publications by the thousands. It is well-deserved attention. Heme oxygenase system is now similar to the metabolic networks surrounding glucose in those complex maps of glycolytic and non-glycolytic metabolic pathways, which we had to memorize as students. The relevance of heme oxygenase to regulatory biology was recognized many years ago, but the work conducted over the past five years has created a new wave of emphasis focusing on genetic manipulation to alter heme oxygenase gene expression, the regulatory actions of heme oxygenase products including carbon monoxide, and the significance of changes in the heme oxygenase system. The physiological and pathological relevance of heme oxygenase in the brain, heart, liver, bone marrow, organ transplant, lung and kidney, opens many areas of investigation in various dis ciplines. Advances in the pharmacology of bilirubin and its ability as an antioxidant have provided a new avenue in clinical research.

With this symposium the Red Cross Blood Bank Groningen-Drenthe affirms its well known reputation as an organizer of symposia of high standard and quality. Several important aspects of bloodbanking have been discussed in the past. The Blood Bank here is a specialist in its own field. Administrative processes in respect of the donor, information processes, the preparation of the blood and the laboratory process are automatized. New developments in these fields are undeway that you will certainly identify and investigate. I do hope that you will come to conclusions from which we can learn and get better results. As general manager of the Development and Investments Company for the Northern Netherlands - NOM - for several reasons I am very much interested in the outcome of this symposium. In the first place I am proud that the Red Cross Blood Bank Groningen Drenthe is doing its utmost to be excellent in regard of research, education and bloodprocessing. In being so, the Blood Bank can produce spinn-offs for healthservices and the related industry."

The haemostatic system is one the most important physiological systems for maintaining health and well being, and thus the investigation of the haemostatic system remains a research priority. Disturbances of the haemostatic system in the broader sense, such as heart disease and strokes, arguably constitute the single greatest contribution to non-infectious mortality in the world today. Therefore, understanding the laboratory methods to assess the haemostatic system is vital for the practice of complex clinical medicine. In Haemostasis: Methods and Protocols, experts in the field address the major components of the haemostatic system, general principles of haemostatic testing, and techniques used to assess various aspects of the haemostatic system, grouped according to their functional indications. Written in the successful Methods in Molecular Biology (TM) series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible protocols, and notes on troubleshooting and avoiding known pitfalls. Authoritative and easily accessible, Haemostasis: Methods and Protocols provides an ideal guide to scientists of all backgrounds and serves an urgent need for further research to develop superior methods of assessing the haemostatic system in humans.

This issue of Hematology/Oncology Clinics, guest edited by Dr. Jennifer R. Brown, will focus on Chronic Lymphocytic Leukemia. This issue is one of six selected each year by our series consulting editors, Dr. George P. Canellos and Dr. Edward J. Benz. Topics discussed in this issue will include: Chronic Lymphocytic Leukemia: Do We Know the Cell of Origin Yet?; Significance of BCR Stereotypy; Prognostic and Predictive Implications of Cytogenetics and Genomics; Role of Epigenetics in Chronic Lymphocytic Leukemia; Genomics of Resistance to Targeted Therapies; First Line Therapy for Chronic Lymphocytic Leukemia; The Ongoing Unmet Needs in Chronic Lymphocytic Leukemia Therapy; BTK Inhibitors; Minimal Residual Disease; Should Undetectable MRD Be the Goal of Chronic Lymphocytic Leukemia Therapy?; Management of Chronic Lymphocytic Leukemia after Progression on BTK Inhibitors; Role of PI3K Inhibitors in Chronic Lymphocytic Leukemia; Can We Restore the Immunodeficiency of Chronic Lymphocytic Leukemia?; and Immune Therapy for Chronic Lymphocytic Leukemia

It has been generally accepted that angiogenesis is involved in the pathogenesis of hematological malignancies, like acute and chronic leukemia, lymphoma, myelodysplastic syndromes, myeloproliferative neoplasms and multiple myeloma. The extent of angiogenesis in the bone marrow has been correlated with disease burden, prognosis and treatment outcome. Reciprocal positive and negative interactions between tumor cells and bone marrow stromal cells, namely hematopoietic stem cells, fibroblasts, osteoblasts/osteoclasts, endothelial cells, endothelial progenitor cells, T cells, macrophages and mast cells, mediated by an array of cytokines, receptors and adhesion molecules, modulate the angiogenic response in hematological tumors. More recently, it has been emphasized the pro-angiogenic role of the so called "vascular niche," indicating a site rich in blood vessels where endothelial cells and mural cells such as pericytes and smooth muscle cells create a microenvironment that affects the behavior of several stem and progenitor cells, in hematological malignancies.

This volume provides a comprehensive overview of critical care of the pediatric immunocompromised hematology-oncology patient. The text focuses on unique aspects of the pediatric immunocompromised patient that predisposes the child to significant illness, and presents critical care management strategies specific to the patient population. In addition to chapters on oncology, primary immune deficiency, immunocompromised hematology, and hematopoietic cell transplant patients, the book covers the changing landscape of ICU care, pharmacologic considerations, and psychological and social aspects of the critical care of hematology-oncology patients. Written by experts from a range of disciplines, Critical Care of the Pediatric Immunocompromised Hematology/Oncology Patient: An Evidence-Based Guide is a valuable resource for clinicians and practitioners who treat this patient population.

Ayalew Tefferi, MD, and a team of authoritative practicing physicians concisely detail their most effective approaches to the diagnosis and treatment of a wide variety of hematological disorders, including anemia and other cytopenias, primary and secondary myeloproliferative disorders, lymphoid and plasma cell disorders, and thrombotic and bleeding disorders. For each illness these expert clinicians provide a brief review of basic concepts and a discussion of its symptomology and classification, its diagnostic tests, and strategies for its management, along with suggested readings for more detailed information. Numerous decision trees clarify diagnosis, and summary boxes highlight key points and dosage parameters. Concise, practical, and up-to-date, Primary Hematology offers busy primary care physicians, internists, hematologists, and oncologists a much-needed action-oriented summary of proven approaches to the optimal diagnosis and treatment of hematologic disorders today.

Myelodysplastic syndromes (MDS) are the most common hematological malignancies involving mostly the elderly population. The major morbidity relates to patients' symptomatic cytopenias.MDS was previously named as "preleukemia " or " smoldering leukemia" as the lack of terminal cells in MDS and because about 25% of all cases progresses into acute myeloid leukemia. According to various reports the annual incidence of MDS ranges widely from 2-12 per 100.000, increasing to 30-50 cases per 100.000 among persons aged 70 or older. It is believed that the true incidence of MDS have been underestimated however it seems to be comparable to that for multiple myeloma and chronic lymphocytic leukemia. In the past decade much progress had been made; we know more on the disease pathology, there is more emphasis on the care and more targeted therapy had been invested. Athors provide updated knowledge in this book on all clinically important aspects of the disease. Hot topics of our days are discussed in chapters by outstanding and well known scientists from all over the world. We would offer this product both for medical students and postgraduates as well as for all who are interested in this very exciting and fast progressing field of hematology. With this work authors should call attention on the disease for decision makers in healt care systems as well.

Haemoglobin is one of the most important molecules in the animal kingdom. Its function is to carry oxygen to tissues. In lower invertebrates the blood pigment is present in the haemolymph and is not bound in cells. Later in the course of phylo genesis haemoglobin remains associated with cells which produce it and in this form it reaches the peripheral circulation. In higher organisms the haemoglobin production is thus determined by two main factors: haemoglobin synthesis in erythroid cells and the formation of these erythroid cells which depends on cell proliferation in haematopoietic organs. Human haemoglobin is made up of two chains which combine from four different polypeptide chains formed in varying ratios in different periods of the life cycle. During the life span of humans the following haemoglobins are formed: embryonic haemoglobins Gower 1 and 2, foetal haemoglobin F and two adult haemoglobins A and A . E-and IX-chains are part of the embryonic haemoglobins Gower 1 (E4) and 2 Gower 2 (1X2E2). These haemoglobins predominate in embryos during the second month of pregnancy and at the end of the first trimester they are completely re placed by foetal haemoglobin F ( Y2). Adult haemoglobin A consists of two IX and two -chains and is the main component of red cells in adults. A relatively small component of red cells accounting for less than 2 % of the total haemo globin, is haemoglobin A2 (1X0)."

WEGENER'S GRANULOMATOSIS & ANCA-ASSOCIATED DISEASES: THE STORY CONTINUES The disease now designated as Wegener's granulomatosis (WG) was first described in 1931 by Heinz Klinger, who considered it to be a special form of polyarteritis nodosa. Klinger's friend, Friedrich Wegener, expanded on the first observations and interpreted the pathological and clinical fmdings to represent a distinct disease entity (Wegener, 1939). He described this entity as a "peculiar rhinogenous granulomatosis with a unique participation of the arterial system and the kidneys". Later, Godman and Churg (1954) established the classical diagnostic criteria (the "WG triad"): granuloma, vasculitis, and glomerulonephritis. In 1958 Walton pointed out the poor prognosis of WG based on a small number of published cases (mean survival time: 5 months). In 1966 Carrington and Liebow reported "limited forms" of WG with a defmitely more favorable prognosis. Since then positive results have been reported with cyclophosphamide therapy. In addition, a retrospective study of combined low-dose cyclophosphamide and prednisolone in 85 WG patients over a period of 21 years found a similarly encouraging outcome. The*latter experience led to the current "standard" treatment protocol (FAUCI et al. , 1973 and 1983). More recently, strong evidence has emerged that some of the morbidity and mortality ofWG - and other types of systemic vasculitis - may be a consequence of this treatment (Hoffman et al. , 1992).

Since the first concepts of gene therapy were formulated, the hemopoietic system has been considered the most natural first target tissue for genetic manipulation. The reasons for this include the fact that a very large number of inherited disorders (including some of the most common disorders, such as the hemoglobinopathies) are disorders of the hemopoietic system, and the large amount of experience in hematopoietic transplantation biology. The consequence of this resulted in the first clinical trial of gene therapy in 1989, where two children suffering from severe combined immune deficiency (ADA-SCID) were transplanted with T-cells express ing adenosine deaminase (the defective enzyme in patients with this disorder). The partial success of this treatment was perhaps responsible for undue optimism among those proposing other gene therapy treatments within the hematopoietic system, and it has since become clear that there are a number of technical and biological difficulties to overcome before hematopoietic gene therapy becomes a mainstream therapeutic strategy. The chapters in this book evaluate the need for gene therapy in the hematopoietic system, discuss how efficient gene transfer and expression can be achieved in the target cells, highlight areas of difficulty to be addressed, and examine a number of potential applications of the gene therapy approach. The book begins with a chapter by Testa and colleagues, discussing the various sources of hematopoietic cells for both transplantation and gene therapy."

This series presents reviews covering all aspects of haemodynamics and haemorheology. Topics covered include the complexities of microcirculation, the rheology of blood and blood vessels, and the mechanics of blood flow in arteries and veins. The contributions aim to reflect the advances being made in experimental techniques and instrumentation for laboratory and clinical measurements and in numerical and mathematical modelling. Emphasis is placed on the scientific and engineering principles involved, but particular attention is also given to the clinical significance of this area of research. Topics covered by this volume include viscoelastic properties of blood and blood analogues; blood flow through narrow tubes; and numerical modelling of blood flow.

Transferring hematopoietic stem cells and immune cells has continued to be a promising therapeutic alternative and a fascinating area of cell biology as well as a field of persistent procedural problems. This explains why substantial parts of basic research on cell growth and differentiation, immune tolerance and antitumor effects, gene transfer, minimal residual disease and supportive care have settled around clinical transplantation in hematology and oncology. This second volume updates the current role of allogeneic and autologous transplantation in leukemias, lymphomas and solid cancers, including controversial strategies and novel experimental approaches. Outstanding representatives of leading groups guarantee first-hand information and indicate how we can work and cooperate more effectively to the benefit of our patients.

In September 1998 experts from 19 countries came together for an interdisciplinary discussion of the function of animal peroxidases, a family of enzymes embracing myeloperoxidase, eosinophil peroxidase, thyroid peroxidase and lactoperoxidase. Their papers have been updated for publication, yielding a wide-ranging overview of the state of the art. The chapters cover a wide range of topics, including three-dimensional structure of representative family members, their biosynthesis and intracellular transport, mechanism of action as well as applications to clinical medicine. They are of clinical relevance in, for example, arteriosclerosis, multiple sclerosis, infections, tumorigenesis, rheumatic diseases and hypothyroidism. This book forms an excellent introduction for anyone interested in the peroxidase family of enzymes.

A cutting-edge review of the latest findings on the complexities of platelet function and the various means of inhibiting platelet clot formation. The authors delineate an up-to-date picture of platelet biology and describe methods for assessing platelet function, including the commonly used platelet aggregation, thromboxane production, procoagulant function, platelet function under flow, and the expression of platelet activation markers. The focus is both on the technology and the outcome of research on platelets, including the fast developing fields of proteomics and genomics and their application to platelet research. The clinical applications of the various methods for the assessment of platelet function in vivo, as well as antiplatelet therapy, are fully discussed.

Are you constantly exhausted? Does sleep not refresh you? Is your balance not what it was? Do you have tingling or even burning in your fingers and toes? Then your problem may be vitamin B12 deficiency. Your doctor may test you for this but your blood levels look OK so what should you do then? Or you may receive treatment but not feel any better? This book is a guide to the complexities of this deceptively simple problem - how it can be diagnosed, how it can be treated, and how those who have it can cope with the lifelong repercussions. Incorporating the latest research, and the input of the thousands of members of the Pernicious Anaemia Society, this book is both practical and engaging, illustrated with many personal stories that will resonate with sufferers and their friends and families.