Dietary supplements can contain a wide variety of ingredients, either singly or in combination, including nutrients, botanicals and 'bioactive components' commonly found in foods. They are marketed and used by consumers for a range of reasons: to enhance "well-being," as traditional medicines, for health promotion or disease risk reduction, and as alternatives or complements to conventional drug therapies.

On a global basis, the dietary supplement industry has enjoyed rapid growth, becoming a multi-billion dollar enterprise over the last 10 years. This growth has been associated with significant changes in both the types of products available and the reasons for using these products.

In many cases, these changes have occurred without the benefit of a sound scientific basis for evaluating the safety and efficacy of these products under the new conditions of use and frequently the same limited scientific evidence is used, even though current product composition, user populations, purported beneficial effects, and conditions of use may differ significantly from the available evidence or historical usage.

This book presents systematic examinations of the scientific data that are available and/or needed to substantiate and evaluate the safety and efficacy of dietary supplements. A series of case studies that are illustrative of the types of scientific challenges that have been encountered in substantiating safety and efficacy for various product types are employed to point out some of the successes but also frustrations that have occurred in recent years. Discussions among presenters and participants identify the lessons learned from these experiences and formulate ideas forimproved approaches to identifying research needs and for enhancing the quality and relevance of the scientific evidence available for policy decisions.

"Dietary Supplements and Health" constitutes a useful resource for nutritionists, biochemists, public health researchers and anyone interested in herbal, alternative medicines.

ATP, the intracellular energy source, is also an extremely important cell-cell signalling molecule for a wide variety of cells across evolutionarily diverse organisms. The extracellular biochemistry of ATP and its derivatives is complex, and the multiple membrane receptors that it activates are linked to many intracellular signalling systems.

Purinergic signalling affects a diverse range of cellular phenomena, including ion channel function, cytoskeletal dynamics, gene expression, secretion, cell proliferation, differentiation and cell death. Recently, this class of signalling molecules and receptors has been found to mediate communication between neurons and non-neuronal cells (glia) in the central and peripheral nervous systems. Glia are critical for normal brain function, development and response to injury. Neural impulse activity is detected by glia and purinergic signalling is emerging as a major means of integrating functional activity between neurons, glia and vascular cells in the nervous system. These interactions mediate effects of neural activity on the development of the nervous system and in association with injury, neurodegeneration, myelination and cancer.

Bringing together contributions from experts in diverse fields, including glial biologists, neurobiologists and specialists in purinergic receptor structure and pharmacology, this book considers how extracellular ATP acts to integrate communication between different types of glia, and between neurons and glia. Beginning with an overview of glia and purinergic signalling, it contains detailed coverage of purine release, receptors and reagents, purinergic signalling in the neural control of glial development, glial involvement in information processing, and discussion of the interactions between neurons and microglia.

Stem cells are specialized cells with unique potential for self-renewal and specific cell-type commitment. They remain uncommitted until a particular physiological signal prompts them to differentiate and become lineage-specific cells with particular physiological functions.

In 1998 investigators isolated embryonic stem cells from human embryos for the first time and were able to culture these "in vitro," Since then, stem cell-based technologies have received enormous scientific attention because of their potential for developing novel therapeutic applications. Potential clinical applications covered in the book include the production of cardiomyocytes to replace damaged heart tissue, the production of insulin-producing cells for patients with diabetes, and the generation of neurons for the treatment of patients with Parkinson's disease or spinal cord injury.

Particular attention is paid to the factors that maintain stem cells in a pluripotent state or which drive them to create differentiated and lineage-committed cells "in vitro" and "in vivo," Understanding stem cells at the molecular level is essential to understanding their behaviour in a physiological context. Nuclear reprogramming, the process by which a nucleus acquires developmental potential, is currently a focus of great interest in the scientific community and is covered here. It is relevant to stem cell research generally, and also to research on the cloning of animals by nuclear transfer.

The book features animated discussion from the world's experts in this topic on the important ethical issues that are raised by research on stem cells. They review the various regulatory regimes which apply in differentcountries―a key factor in determining where future stem cell research is carried out. This book is an essential purchase for all those engaged in stem cell research, whether in the laboratory, the clinic or the regulatory authorities.

The astounding diversity of the immune system and the complexity of its regulatory pathways makes immunology a combinatorial science. Computational analysis has therefore become an essential element of immunology research and this has led to the creation of the emerging field of immunoinformatics. This book is the first to feature thorough coverage of this new field.

Immunoinformatics facilitates the understanding of immune function by modelling the interactions among immunological components. Biological research provides ever deeper insights into the complexity of living organisms while computer science provides an effective means to store and analyse large volumes of complex data. Combining the two fields increases the efficiency of biological research and offers the potential for major advances in the study of biological systems.

This book encompasses key developments in immunoinformatics, including immunological databases, sequence analysis, structure modelling, mathematical modelling of the immune system, simulation of laboratory experiments, statistical support for immunological experimentation and immunogenomics.

The difficulties in effective application of bioinformatic tools in immunology arise at both ends of the spectrum: most immunologists have only a limited comprehension of sophisticated data analysis and applicability and limitations, while the average computer scientist lacks knowledge of the depth and complexity of biological data. The purpose of this book, therefore, is to present contributions from a multidisciplinary team of biologists and computer scientists to explore the issues related to better understanding of immune function and, in particular, to help apply new computer science methods to immunological research.

Related Novartis Foundation symposia:

247 In Silico Simulation of Biological Processes

Chair: Denis Noble

252 Generation and effector functions of regulatory lymphocytes

Chair: Jean-François Bach

Recent technological advances have led to a rapid acceleration in our ability to gather genetic data. The complete genetic sequences are now known to several organisms and accelerated programmes are in place for sequencing many other genomes, including human. The speed with which complete sequencing can be accomplished will continue to increase as new technologies come online. In principle, the scope for developing new diagnostic techniques and drugs is now greater than at any time in human history, but the pathway from genetic information to usable drug is a long and complex one.

This exciting book brings together a high-calibre group of experts to discuss the practical application of genomic information to the development of drugs. The subjects covered include the current state of the art in sequencing technology, the applications of these new technologies to sequencing the genomes of various organisms, and the challenge of proteomics. Additional contributions deal with legal and ethical implications of the new uses of genetic data, and functional genomes from the point of view of the pharmaceutical industry.

This book examines the sophisticated mechanisms that plants use to defend themselves against attack by insects and pathogens, focusing on the networks of plant signalling pathways that underlie these defences. In response to herbivory, plants release a complex blend of as many as 100 volatile chemicals, known as semiochemicals (‘sign chemicals’). These act as an airborne SOS signal, revealing the presence of the herbivore to the predators and parasitoids that are its natural enemies. Plants also have endogenous defence mechanisms that can be induced in response to pathogens, and separate chapters deal with systemic acquired resistance, phytoalexins, and the interacting pathways in pathogen and pest resistance. The book discusses underlying biochemical mechanisms by which plant stress leads to the biosynthesis of chemical signals from pools of secondary metabolite precursors, or even from the primary metabolism source. Finally, consideration is given to the possibilities for exploiting these signalling pathways by plant molecular genetics. The use of plant signals and their analogues to switch on defence pathways in crop plants is covered in depth. Bringing together contributions from entomologists, chemical ecologists, molecular biologists and plant physiologists this book is truly interdisciplinary, and will be essential reading for anyone with an interest in agricultural pest control.

Chronic obstructive pulmonary disease (COPD) is the most common respiratory disorder of adults in the developed world and is the fourth main cause of death in the USA. It is also associated with high morbidity, and poses an enormous burden of suffering and expense. Despite this, the disease has received little attention compared with other respiratory conditions such as asthma and lung cancer.
Current treatment can offer some marginal symptomatic relief but does not address the underlying disease process. Indeed, smoking cessation is the only intervention known to alter the rate of disease progression. There is clearly great need, and potential, for the development of superior therapies for symptomatic relief and disease modification. This book brings together leading researchers and physicians to discuss the most recent advances in our understanding of COPD, and draws together basic and clinical aspects relevant to the topic. Coverage includes the basic pathology, current and potential therapies, and detailed consideration of the major theories for the pathogenesis of COPD.

This exciting book is based on a symposium that brought together leading scientists working at the interface between the cell cycle, cell growth and development in a variety of model systems. This research interface is just starting to emerge, and this symposium is the first to discuss these issues in depth - discussions that are included here along with the written papers.
The book begins with a thorough investigation into the relationship between the cell cycle and cell growth, and then continues with a discussion of cell size control, asymmetric cell division, the specification of cell fate decisions and cell death. The focus throughout is on understanding how such diverse developmental inputs can modulate cell cycle regulation and, reciprocally, how a common way of regulating cell cycle progression can participate in different developmental strategies. This provides an opportunity to identify the evolutionary conserved threads that have been utilized to coordinate cell cycle and developmental decisions.

The field of neural transplantation is at a crucial stage, with important clinical trials on transplantation in patients with Parkinson's disease nearing completion and novel, alternative approaches to fetal transplantation being developed.

This timely book brings together leading neuroscientists, clinicians, and cell and developmental biologists to discuss the use of neural transplants in neurodegenerative disorders, such as Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis and spinal cord injury. There is also extensive coverage of the potential alternatives to freshly derived fetal tissue as the source of transplants, for example xenografts, encapsulated cells and immortalized stem cells. With authoritative contributions and lively discussion sections, this book presents much new and exciting work in this field and identifies promising new research directions.

Although normally thought of as a sex hormone, recent research has highlighted the numerous and significant effects that oestrogen has on the CNS, extending far beyond its important reproductive role. It has been shown that oestrogen acts as a neural growth factor with important influences on the survival, plasticity, regeneration and ageing of the mammalian brain.
This exciting book brings together leading clinicians and researchers to discuss oestrogen's basic mechanisms of action, the extrahypothalmic brain regions it affects, and its influence on cognitive functions in animals and humans. Finally, recent research on the role of oestrogens in ageing and dementia, including the significance of oestrogen action in Alzheimer's disease, is discussed. The 15 papers contained in this book, together with the extensive discussion sessions that follow them, reveal much new and exciting work in this area, and identify promising new research directions.

Although nature employs a wide variety of sex-determining mechanisms, it is only comparatively recently that the tools have become available for these to be explored at the molecular and cellular levels. A major landmark was the discovery in 1990 of the Sry gene and the subsequent demonstration of its key role in triggering male sex determination in transgenic mice. Since that time, while other key genes in the sex-determining pathway have been uncovered, the story remains far from complete.

This ground-breaking book draws together leading researchers to review and discuss the most recent advances in the understanding of the molecular genetic pathways of sex determination. Coverage includes the genetics and biochemistry of mammalian sex determination, comparisons with other modes of sex determination, and consideration of the biology of sexual development and of the evolution of sex-determining mechanisms. A major theme running through several chapters is the value of comparative studies of sex-determining mechanisms in different species. In addition, clinical aspects and the genetic analysis of anomalies of human sexual development are also addressed. This exciting book reviews much new and exciting work in this area and identifies promising new research directions.

This book brings together a cross-fertilization of ideas between human molecular genetics, developmental biology, tissue biology and the biochemistry of cell signalling pathways, in order to create new insights into the mechanisms of normal and abnormal skeletogenesis. This broad perspective is essential in order to understand the aetiology of genetic diseases affecting skeletal development at all levels from genotype to phenotype, i.e. from mutation to syndrome.
The book encompasses normal and abnormal skeletogenesis process by process, beginning with the signalling pathways that control early patterning events, then the molecular control of osteoblast, chondrocyte and osteoclast differentiation, joint formation and finally osteoclast activity. Each step takes into consideration the results of mouse gene cloning and knockout studies, human molecular genetics, and new mouse studies stimulated by the human information. Such an integrated approach is essential if this new understanding is to be applied for future therapeutic strategies.

Gastroenteritis viruses are a major cause of morbidity and mortality in humans. Many hundreds of thousands of children die annually from rotavirus diarrhoea in the developing world, and although in industrialized countries rotavieus infection is rarely fatal, the economic burden of the disease is substantial. Human caliciviruses have emerged as a significant cause of viral gastroenteritis globally. This book contains presentations and discussions by internationally recognized experts on virus structure, replication, pathogenesis, immune response and correlates of protection, molecular-epidemiological surveillance, advances in treatment, and efforts to develop vaccines, particularly against rotavirus disease. The spectrum of viruses covered comprises rotaviruses, human caliciviruses, astroviruses, coronaviruses and viruses causing gut disease in the immunocompromized host. The book not only conveys facts but also gives ample room to lively discussions on many issues at the forefront of research and development.

With the recent renaissance in mitochondrial biology and increasing recognition of their role in many diseases, this book provides a timely summary of the current state-of-the-art in mitochondrial research. The book opens with the regulation of mitochondrial replication and biogenesis and reviews the mechanisms and functional consequences of mitochondrial fission and fusion. Further chapters address mitochondria and oxidative stress and their roles in cell signalling and cell death. The book includes extensive, fascinating discussion of the biochemistry of mitochondrial cell signalling (especially involving calcium) and of oxidative stress. The nature of the proteins engaged in these processes, many only recently discovered, is covered in detail.

Mitochondria have been strongly implicated in neurodegenerative diseases such as Parkinson's, Huntington's and amyotrophic lateral sclerosis. They are also affected in cancer, ageing and cardiovascular disease. The final section of the book reviews mitochondrial mutations and their consequences in ageing and other phenotypic manifestations. The authors discuss how mitochondrial proteins might constitute important therapeutic targets and describe initial attempts to develop compounds that can regulate their function.

Retinal dystrophies are the major causes of incurable blindness in the Western world. Our insight into their aetiology has improved remarkably over the past decade and a number of key genes have been identified. Together with a more detailed understanding of disease processes, this knowledge is stimulating new approaches to therapeutic strategies involving gene therapy, growth factors and retinal cell transplantation.

Molecular genetic studies have provided detailed information on the pathogenesis of retinal dystrophies. An important proof of principle that gene therapy holds great promise for the treatment of these conditions was demonstrated in the "rds" mouse: introduction of a functional copy of the "peripherin" gene subretinally resulted in complete rescue of rod outer segment structure. Novel approaches are being developed based on the manipulation of biochemical pathways that previously were not considered relevant to these diseases. For example, renewed interest in retinal dystrophy pathogenesis led to the successful use of high dose vitamin A treatment in Sorsby fundus dystrophy.

This important new book covers all aspects of retinal dystrophies from the molecular and developmental biology of these disorders to possible therapeutic approaches, with special reference to gene therapy. Specific chapters deal with the molecular genetics of gene therapies, clinical genetic studies, molecular and cellular mechanisms of the development of the disease, functional genomics of retinal diseases, animal models of retinal dystrophies, and finally with studies on gene therapeutic approaches to correcting the disorder. With contributions by many of the leading researchers worldwide, this book is likely to be an important milestone in this rapidly developing field.

This groundbreaking book brings together contributions by leading scientists from different fields to provide a balanced view of the spectrum of current studies on autism. Four main areas of research are covered.

• Twin and family data indicate that the heritability of the underlying liability to autism exceeds 90%. This probably involves interactions among a relatively small number of susceptibility genes, an hypothesis that is examined in detail.

• New techniques are now available for examining the neurobiology of autism. The book contains results from imaging studies showing the contributions of different brain regions to this disorder and addresses the neuropathology of autism.

• There has been considerable discussion in the literature on the fundamental nature of the psychological deficit in children with autism. The book discusses the evidence that so-called ‘Theory of mind’ deficits are associated with autism.

• The most important practical question facing medical practitioners is how to help children with autism. Possible psychological or psychiatric interventions for rehabilitation of children with autism are examined in detail. Drug treatments have been disappointing in this field and one chapter addresses this problem.

Other topics covered include the epidemiology of autism, immunological aspects—including the possible role of infectious agents in the pathogenesis of neurodevelopmental disorders—and language impairments.

This broad-ranging, authoritative book is essential reading for anyone with an interest in autism and its treatment.

Novartis Foundation Symposium 291

The Biology of Extracellular Molecular Chaperones
Chair: Peter Csermely

The heat shock, or cell stress, response was first identified in the polytene chromosomes of "Drosophila," This was later related to the appearance of novel proteins within stressed cells, and the key signal stimulating this appearance was identified as the presence of unfolded proteins within the cell. It is now known that this is a key mechanism enabling cells to survive a multitude of physical, chemical and biological stresses.

Since the promulgation of the 'molecular chaperone' concept as a general cellular function to control the process of correct protein folding, a large number of molecular chaperones and protein folding catalysts have been identified, and it has been recognized that not all molecular chaperones are stress proteins and vice versa. The discovery of molecular chaperones as folding proteins went hand-in-hand with their recognition as potent immunogens in microbial infection. It was subsequently shown that administration of molecular chaperones such as Hsp60, Hsp70 or Hsp90 could inhibit experimental autoimmune diseases and cancer.

More recently evidence has accumulated to show that certain molecular chaperones are also present on the surface of cells or in extracellular fluids. A new paradigm is emerging: at least some molecular chaperones are secreted proteins with pro- or anti-inflammatory actions, regulating the immune response in human diseases such as coronary heart disease, diabetes and rheumatoid arthritis. In addition to having direct effects on cells, molecular chaperones can bind peptides and present them to T cells to modulateimmune responses. This may be significant in the treatment of cancer.

This book brings researchers together to review and discuss: our current knowledge of cell stress response and molecular chaperones the changing paradigms of protein trafficking and function cell stress proteins as immunomodulators and pro- and anti-inflammatory signalling molecules the role of these proteins in various chronic diseases and their potential as preventative or therapeutic agents.

"The Biology of Extracellular Molecular Chaperones" will be of particular interest to immunologists, cell and molecular biologists, microbiologists and virologists, as well as clinical researchers working in cardiology, diabetes, rheumatoid arthritis and other inflammatory diseases.

To understand the brain and its devastating diseases, we need to reveal the mechanisms that produce it and the ways in which it can constantly change throughout a lifetime. This book features a timely and insightful discussion between developmental neurobiologists and clinicians who deal with disorders of the nervous system.

Chapters in this book deal specifically with cell fate determination, cell migration and disorders of cell migration; current concepts and new ideas about cortical arealisation, and disorders which can arise from incorrect arealisation; genes implicated in the development of cortical connectivity and related pathologies such as schizophrenia and synaesthesia; and susceptibility genes for cognitive disorders such as schizophrenia, autism, dyslexia, and attention deficit disorder.

Novartis Foundation Symposium 289

"Growth factors and psychiatric disorders"

Chair: Moses V. Chao

Psychiatric disorders such as depression, bipolar disease and schizophrenia are debilitating illnesses that are influenced by many genetic and environmental factors. While little is known about the neural circuits that underlie such disorders, the convergence of psychiatric, genetic and basic neuroscience research is providing new and exciting insights.

In recent years genetic studies have identified several growth factors as susceptibility genes for depression, schizophrenia, and learning and memory. This suggests that psychiatric disorders may be influenced by a small number of genes with multiple actions. These genes will provide clues to the biochemical mechanisms and pathways that underlie these complex disorders.

This is the first book to undertake a comprehensive investigation of this research. International leading experts are brought together to discuss the latest findings and look at future directions.

Topics addressed include Neuroplasticity and neurotrophic factors. Mechanisms of intracellular trafficking of growth factors. BDNF gene variants in affective disorders. Trophic factors and cognitive functions. Neurotrophins and depression. Schizophrenia genes and neuropathology. Pharmacological treatments of schizophrenia.

"Growth factors and psychiatric disorders" will be of particular interest to psychiatrists, neurologists and geneticists, as well as cell and molecular biologists, and neuroscientists.

The reversible acetylation of lysine residues on histone proteins has emerged as a major factor in the regulation of transcription in eukaryotes. All core histone proteins are acetylated and unique functional chromosomal domains are characterized by specific patterns of acetylation within their histone proteins. Functional correlations have been established between the level of acetylation of individual genes and their transcriptional activity. These complex signals are currently being elucidated in the context of the 'histone code hypothesis'. This model posits that distinct acetylation patterns in histones, along with other post-translational modifications, serve as specific signals recognized by the nuclear transcriptional machinery.

Histone acetylation is under the control of competing histone acetyltransferases (HATs) and histone deacetylases (HDACs). Both enzyme families contain many members: at least 18 distinct human HDACs have been identified. As well as regulating transcription, these proteins play critical roles in cell cycle control and differentiation. Acetylation is not restricted to histone proteins; a growing number of important biological functions appear to be regulated via acetylation. These include DNA binding (p53), nuclear-cytoplasmic shuttling (NF-kB) and coactivator recruitment (HIV Tat protein).

This novel research opens up new and exciting possibilities for drug design. Inhibitors have been developed that specifically target either HDACs or HATs. HDAC inhibitors exhibit selective toxicity towards tumour cells and are being developed as potential anticancer drugs. This book describes current knowledge of acetylation and features extensive discussionsamongst the world's experts in this field, with an emphasis on major unanswered questions.

Much recent research in evolutionary developmental biology has focused on the origin of new body plans. However, most evolutionary change at the population and species level consists of tinkering: small-scale alterations in developmental pathways within a single body plan. Such microevolutionary events have been well studied on a population genetic level and from the perspective of adaptive phenotypic evolution, but their developmental mechanisms remain poorly studied.

This book explores both theoretical and practical issues of tinkering. It features a wide range of perspectives to address several fundamental questions. How does tinkering occur developmentally, and how is it manifested phenotypically? Are the developmental mechanisms by which tinkering occur different from those that underlie larger evolutionary changes? What are the developmental constraints on tinkering? And how do we test hypotheses about microevolutionary shifts in development from the fossil record?

With contributions from experts in a range of fields, this fascinating book will make exciting reading for anyone studying evolution, developmental biology or genetics.

The past decade has seen mounting global concern regarding viral outbreaks such as SARS, avian influenza and West Nile virus. In 2004 and 2005, reports of bird-to-human, and possible human-to-human, transmissions of the H5N1 influenza viruses raised fears that these viruses could cause a pandemic on the scale of the Spanish flu pandemic of 1918. Previous to this, a novel coronavirus had been identified as the aetiological agent of the severe acute respiratory syndrome (SARS), a new respiratory viral disease that emerged at the end of 2002 and caused profound disturbances in over 30 countries worldwide in 2003. It is not known whether the SARS coronavirus will re-emerge, especially since its origins and potential reservoir(s) are unresolved. However, these outbreaks have shown that these viruses can emerge in any part of the world at any time.

This book critically evaluates the latest scientific evidence on novel or re-emerging viral diseases and brings together contributions from world experts on this topic, explaining best practice in their area, and discussing lessons learned and how best to collaborate to prevent and control future outbreaks.

Topics covered include: the latest advances in virology, particularly in the area of epidemiology diagnostics animal models for viral infection, and antiviral and vaccine development.

"Novel and Re-emerging Respiratory Viral Diseases" offers a comprehensive and interdisciplinary account of all aspects of the topic, from basic molecular biology to public health issues, and is therefore essential reading for virologists, infectious disease specialists, public health managers, researchers and epidemiologists, as well as those working invaccine development, pharmaceutical medicine and drug discovery

Cl- absorption and HCO3- secretion are intimately associated processes vital to epithelial function, itself a key physiological activity. Until recently the transporters responsible remained obscure, but a breakthrough occurred with the discovery of the SLC26 transporters family. It is now clear that the SLC26 transporters have broad physiological functions since mutations in several members are linked to a variety of diseases. This book describes the properties of this family in detail, with contributions from the leading global researchers in the field. Complementary views from experts on other ion channels are offered in the discussions, which make fascinating reading.

This family consists of at least 10 genes, each of which has several splice variants. Most members of the family are expressed in the luminal membrane of epithelial cells. Characterization of anion transport by three members has revealed that all function as Cl-/HCO3- exchangers, suggesting that SLC26 transporters are responsible for the luminal Cl-/HCO3- exchange activity. The SLC26 transporters are activated by the CF transmembrane conductance regulator and activate it in turn, leading to a model in which these molecules act together to mediate epithelial Cl- absorption and HCO3- secretion.

The book includes chapters on the transport of other molecules by the SLC26 family, including oxalate in the kidney and sugars in cochlear hair cells amongst others. It also describes recent discoveries that most SLC26 transporters bind to scaffold proteins and that they all contain a conserved domain predicted to participate in protein-protein interactions. These suggest the SLC26 transporters exist in complexes withother Cl- and HCO3- transporters, and possibly other regulatory proteins. This book explores the functional role of these interactions, leading to better understanding of transepithelial fluid and electrolyte secretion and the diseases associated with it.

Oxygen sensing is a key physiological function of many tissues, but the identity of the sensor, the signalling pathways linking the sensor to the effector, and the endpoint effector mechanisms are all subjects of controversy. This book evaluates the various mediators that have been proposed, including the mitochondria, NAD(P)H oxidases, cytochrome p450 enzymes, and direct effects on enzymes and ion channels. There has been a resurgence of interest in the role of mitochondria, based partly on the ability of mitochondrial inhibitors to mimic hypoxia, but there is little consensus concerning mechanisms. Some favour the view that the primary signalling event is a reduction in cell redox state and reactive oxygen species (ROS) due to general inhibition of the electron transport chain (ETC); others support a key role for complex III of the ETC and an increase in ROS generation, while others doubt either of these components is the key intermediary. All these hypotheses are discussed in the book, together with conceptual problems concerning the ability of mitochondria to respond to physiological hypoxia.
The other area of controversy covered in the book is the identity of the endpoint effector(s). Some authors favour K+ channel inhibition, followed by depolarization and Ca2+ entry via L-type channels, while others propose that release of Ca2+ from intracellular stores, or capacitative Ca2+ entry and other voltage-independent pathways may be more important. The book also describes evidence for an endothelium-dependent Ca2+-sensitizing pathway involving Rho and possibly other kinases.
While some of these differences can be attributed to variation between tissues, many must be related to differences in interpretation or methodology. In this book, experts in the field of acute oxygen sensing working in different tissues address these controversies and their possible origins, and discuss possible approaches whereby these controversies might be resolved.
The book will be of great interest to all those working in fields where oxygen sensing is important, particularly cancer and wound healing, as well as researchers in drug discovery and biotechnology.

* This book is a comprehensive and up-to-date account of where we stand in immunological strategies for preventing or treating type 1 diabetes (T1D).* Brings together contributions from the leaders in the arena of clinical immunotherapy, not limited to the diabetes field exclusively, in order to delineate a road-map that would lead to future clinical trials.* The book integrates information from human and animal studies.* The book considers T1D within the broader context of autoimmune disease.* The format contains several discussions, which address specific questions and provides guidelines for future strategies and solutions for discovering a cure.