New books

• Mitochondrial biology: new perspectives (coming soon)
• Vascular development (coming soon)
• Dietary supplements and health (coming soon)
• Tinkering: mechanisms of micro-evolution (new)
• Acetaldehyde-related pathology (new)
• Decoding the genomic control of immune reactions
• Sepsis: new insights, new therapies
• Innate immunity to pulmonary infection
• Empathy and Fairnes
• New treatment strategies for dengue and other flaviviral diseases
• Purinergic signalling in neuron–glia interactions
• Understanding nicotine and tobacco addiction
• Heart failure: molecules, mechanisms and therapeutic targets
• Epithelial anion transport in heath and disease: the role of the SLC26 transporter family
• Signalling pathways in acute oxygen sensing
• Mast cells and basophils: development, activation and roles in allergic/autoimmune disease
• Percept, decision, action: bridging the gaps
• Signalling networks in cell shape and motility
• Molecular mechanisms influencing aggressive behaviours
• The genetics of autoimmunity
• The hERG cardiac potassium channel: structure, function and long QT syndrome
• Stem cells: nuclear reprogramming and therapeutic applications
• Nuclear organization in development and disease
• Inflammatory bowel disease: crossroads of microbes, epithelium and immune systems
• Biology of IGF-1: its interaction with insulin in health and malignant states
• Pathological pain: from molecular to clinical aspects
• Osteoarthritic joint pain
• Reversible protein acetylation
• Mammalian TRP channels as molecular targets
• Anaphylaxis
• Cancer and inflammation

Novartis Foundation Symposium 287

Mitochondrial biology: new perspectives

Chair: David G Nicholls

Estimated publication date: September 2007 

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Novartis Foundation Symposium 283

Vascular development

Chair: Christer Betsholtz

Estimated publication date: July 2007 

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Novartis Foundation Symposium 282

Dietary supplements and health

Chair: Barry Halliwell

Estimated publication date: July 2007 

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Novartis Foundation Symposium 284

Tinkering: mechanisms of micro-evolution

Chair: Daniel E. Liebermann

Tinkering: The Microevolution of Development examines in detail the mechanisms by which evolution occurs, looks at the role of tinkering in speciation, and asks how we can gain information about microevolution from the fossil record.

This fascinating book is exciting reading for anyone working in the area of evolution, developmental biology, palaeontology, zoology or genetics.

Estimated publication date: June 2007 

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Novartis Foundation Symposium 285

Acetaldehyde related pathology

Chair: Peter Emery

Acetaldehyde-Related Pathology describes the toxic effects of acetaldehyde at the tissue and cellular levels, reviewing enzyme biochemistry, transgenic mouse models of alcohol dehydrogenase mutants, and the cell-signalling pathways implicated in alcohol-related pathology. It explores the mechanisms of acetaldehyde-induced damage to tissues, often a first step in carcinogenesis, including the oral cavity, the human airway, and the GI tract. The book considers pharmacological strategies and treatments for reducing oral and intestinal acetaldehyde. Acetaldehyde-Related Pathology features in-depth, round-table discussions by an international array of scientists from major laboratories worldwide involved in studies of acetaldehyde-related pathology.

This book is essential reading for anyone interested in the effects of this compound - pathologists, biochemists, toxicologists, cell and molecular biologists.

Published April 2007

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Novartis Foundation Symposium 281

Decoding the genomic control of immune reactions

Chair: Chris Goodnow

Contributors to this book explore existing strategies and examine possible new strategies for using the genome sequences of human, mouse, other vertebrates and human pathogens to solve outstanding problems in the treatment of immunological diseases and chronic infections. The assembled genome sequences now provide important opportunities for solving these problems, but the bottleneck is to identify key sequences and circuits controlling the relevant immune reactions. This requires innovative, interdisciplinary and collaborative strategies of a scale and complexity we are only now beginning to comprehend.

Some of the specific problems addressed are:

1. What kinds of information are we missing to understand how the genome sequence specifies the differentiation and response of immune system cells and system behaviour, such as immunological memory and tolerance?
2. Which genome sequences and cellular circuits cause or prevent pathological immune responses to foreign pathogens, allergens or self-tissues?
3. Which host and pathogen genome sequences and cellular circuits explain the failure of neutralizing immune responses to sophisticated human pathogens, such as the agents of tuberculosis, malaria, metazoan parasites and chronic viruses?

This book is an invaluable resource for researchers in both industry and academia performing either basic or clinical research in the disciplines of genomics and bioinformatics, immunology, microbiology and virology, cell and molecular biology, biotechnology, and genetics.

Published March 2007

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Novartis Foundation Symposium 280

Sepsis: new insights, new therapies

Chair: Mitchell P Fink

• Addresses the frequent, but under-recognised condition of sepsis and discusses new ways to prevent and treat it
• Describes numerous pharmacological approaches to therapy for early and late sepsis
• Includes detailed discussion of the various physiological systems implicated in sepsis
• Presents an international perspective, featuring contributions from experts from laboratories worldwide involved in the study of sepsis

Sepsis: new insights, new therapies is an invaluable resource for all critical care physicians and researchers. It is also an informative reading for immunologists, endocrinologists, neuroendocrinologists, physiologists, and pharmacologists.

Published January 2007

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Novartis Foundation Symposium 279

Innate immunity to pulmonary infection

Chair: Siamon Gordon

• Provides a comprehensive overview of pulmonary infectious diseases, including basic pathology, current and potential therapies and detailed consideration of the innate biological resistance mechanisms in the lung
• Thoroughly examines the major topic of innate immunity in immunology, which is now seen as key to the pathogenesis of and vaccination strategies for infectious diseases
• Describes the genetic and environmental factors which determine the outcome of infection, such as latency of Tuberculosis, blood stream invasion from local infection, and local target tissue damage
• Covers the roles of cells such as neutrophils, macrophages and dendritic cells and of molecular components such as Toll-like receptors
• Discusses the clinical applications of the new knowledge regarding innate immunity and how this can be used in both treatment and prevention (vaccination) strategies
• Includes contributions from an international and interdisciplinary group of experts

Innate immunity to pulmonary infection is an essential resource for researchers in both industry and academia. It is of interest for all those interested in the disciplines of immunology, virology, biology, biotechnology and genetics.

Published November 2006

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Novartis Foundation Symposium 278

Empathy and Fairness

Chair: Chris Frith

This book brings together work from a wide range of disciplines to explain processes underlying empathy and fairness. It approaches the topic of empathy and fairness from different viewpoints, namely those of social cognitive neuroscience, developmental psychology, evolutionary anthropology, economics and neuropathology.

Published November 2006

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Novartis Foundation Symposium 277

New treatment strategies for dengue and other flaviviral diseases

Dengue virus is a member of the Flaviviridae family, which includes viruses associated with human diseases such as yellow fever, Japanese encephalitis and hepatitis C.  Dengue fever is transmitted by mosquitoes, principally Aedes aegypti. There are four serotypes of dengue virus, of which DENV-2 has been the most prevalent in many recent epidemics. Following primary infection, lifelong immunity develops, preventing repeated assault by the same serotype. However, the non-neutralizing antibodies from a previous infection or maternally acquired antibodies are thought to form complexes with a different serotype during a subsequent infection and cause dengue haemorrhagic fever/dengue shock syndrome, which can be fatal. There is no treatment or vaccine available today that can combat this emerging and uncontrolled disease.

This book features contributions from the world’s leading researchers working on dengue and related flaviviruses who examine the current state of the art in the molecular biology of the dengue virus. Particular emphasis is placed on the structure and function of the virus and the targeting of virus proteins by potential antiviral agents. The pathogenesis of dengue and dengue haemorrhagic fever are discussed in detail, especially the target cells and the specific receptors on these cells, thereby developing a clear overview of host and viral factors that contribute to dengue haemorrhagic fever.  Finally, the book reviews the therapeutic options, paying particular attention to ways in which vector, host and environment can play a critical role in the spread of this disease.

With dengue fever and other emerging viral diseases becoming increasingly prevalent around the world, this book will provide valuable insight into the virus that causes this disease and potential ways to manage it.  It will be important reading for all those working in tropical diseases, public health and virology.

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Novartis Foundation Symposium 276

Purinergic signalling in neuron-glia interactions

Chair: R. Douglas Fields

Novartis Foundation Symposium 275

Understanding nicotine and tobacco addiction

Chair: William A. Corrigall

Cigarette smoking is estimated to lead to 4.9 million premature deaths per year worldwide. This is predicted to rise to 10 million by 2020. In western countries it kills half of all smokers who fail to stop.

The prevailing model for tobacco addiction is that nicotine from cigarettes rewards smoking and punishes abstinence, tapping into a motivational system of operant conditioning that requires no conscious awareness. However, there are also accounts which involve cognitive biases and the effect of nicotine on impulse control. The brain pathways involved have been studied extensively, but the role of different nicotine receptor subtypes and other neurotransmitter systems is still subject to debate. 

In western countries, cigarette smoking as an adult has a heritability of 30–50% and candidate genes have been identified that may contribute in part to addiction susceptibility. Many socio-cultural correlates of cigarette smoking have been established, but a comprehensive model that accounts for these and links them with the psychobiological aspects of nicotine addiction has not been forthcoming. Structured behavioural support programmes aid cessation attempts, as do a number of pharmacotherapies, most notably nicotine replacement treatments and bupropion, but the underlying mechanisms are unclear. 

This book deals with the problems involved in understanding and treating nicotine and tobacco addiction. Topics covered include the nature of the worldwide health problem posed by cigarette smoking, the psychodynamics of cigarette addiction, and the basic pharmacology and biochemistry of nicotine and its effect on the brain. Further chapters analyse the genetic basis of susceptibility to nicotine addiction. Finally, the contributors address approaches to therapy. A continuing theme in the discussions throughout the book is how best to treat nicotine addiction, given that many smokers would like to stop smoking but are unable to do so because of their addiction. 

This book will be of great value to all psychologists and psychiatrists working on addiction, specifically to nicotine but also to other compounds and behaviours.  It will also be of interest to neuroscientists and pharmacologists working on nicotine receptors and the brain pathways involved in dependence, as well as to biochemists, molecular biologist and to public health officials.

Published April 2006 

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Novartis Foundation Symposium 274

Heart failure: molecules, mechanisms and therapeutic targets

Chair: Eric N. Olson

This book describes the work of leading investigators studying the basic mechanisms of cardiac growth, function and dysfunction. There are also exciting contributions from researchers developing novel therapeutic strategies for cardiac disease. The unique feature is the discussions amongst the contributors, which always return to the same basic problem: how can new data from biological studies be used to design novel therapies for the treatment of cardiac dysfunction following myocardial infarction, hypertension and other disorders?

With its strong emphasis on translational research, this book will appeal to both scientists and clinicians interested in diminishing the impact of the current epidemic of cardiac disease.

Published July 2006

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Novartis Foundation Symposium 273

Epithelial anion transport in heath and disease: the role of the SLC26 transporter family

Chair: Michael Welsh

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 with other 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.

Published June 2006 

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Novartis Foundation Symposium 272
Signalling pathways in acute oxygen sensing

Chair: Michael Duchen

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.

Various mechanisms have been proposed as oxygen sensors, including the mitochondria, NAD(P)H oxidases, cytochrome p450 enzymes, and direct effects on enzymes and ion channels.  Recently, there has been a resurgence of interest in the role of mitochondria based partly on the ability of mitochondrial inhibitors to mimic hypoxia, although this is questioned in some quarters. There is however little consensus concerning mechanisms. Whilst 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. Yet others do not support a role for ROS at all, and a recent report has cast doubts on any role for the ETC in oxygen sensing in the carotid body. Moreover, in tissues such as neuroepithelial cells, an NAD(P)H oxidase may act as the oxygen sensor.  There are also key conceptual problems concerning the ability of mitochondria to respond to physiological hypoxia, as some reports suggest that mitochondrial respiration is only inhibited when hypoxia is very severe.

There is also diversity concerning the endpoint effector(s).  There is considerable support for a key role for potassium channel inhibition, followed by depolarisation and calcium entry via L-type channels.  However, the molecular identity of the channels involved is contentious.  An essential role for potassium channel inhibition has however been questioned, particularly in the hypoxic pulmonary vasoconstriction (HPV), where it has been suggested that release of Ca²⁺ from intracellular stores, or capacitative Ca²⁺ entry and other voltage-independent pathways may be more important.  Moreover, there is also good evidence for an endothelium dependent Ca²⁺ sensitizing pathway involving Rho and possibly other kinases.

Whilst some of these differences can be attributed to variation between tissues, many must be related to differences in interpretation or methodology.  The aim of this symposium volume, therefore, is to bring together contributions from experts in the field of acute oxygen sensing working in different tissues, to address these controversies and their possible origins and to develop approaches whereby these controversies might be resolved.

Published January 06

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Novartis Foundation Symposium 271

Mast cells and basophils: development, activation and roles in allergic/autoimmune disease

Chair: Santa J Ono

The focus of this symposium volume is on the latest basic (primarily molecular) research on the mast cell and basophil and its significance in relation to allergic and autoimmune diseases.

Presented in the book are recent advances relating to the factors and mechanisms that regulate the growth, differentiation and function of mast cells and basophils; discussion of new technological advances that directly impact on studies on these cells; and integration of the basic scientific findings in the context of therapeutic possibilities for the treatment of diseases such as allergic inflammation and autoimmune disease which are mediated, in part, by these granulocytes.

Topics include: (1) the development of mast cells and basophils, (2) early and late events in IgE/antigen activation of mast cells and basophils, (3) mechanisms of exocytosis, (4) non-IgE mediated activation of mast cells and basophils, as well as on those surface receptors that dampen activation responses, (5) protease, proteoglycan, lipid and cytokine mediators released from activated mast cells and basophils, and (6) bilateral interactions of mast cells with other cell types.

It is hoped that, by bringing together an international and interdisciplinary group of experts whose work is focused on many different aspects of these granulocytes, the meeting will reveal much new and exciting work in this area, help to identify and stimulate promising new research directions and encourage continuing and new collaborations between investigators.

Published October 05 

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Novartis Foundation Symposium 270

Percept, decision, action: bridging the gaps

Chair: Ranulfo Romo

For those who wish to understand their underlying brain basis, behaviours that at first glance seem terribly simple turn out, on reflection, to be discouragingly complex.  For many years, cognitive operations such as sensation, perception, comparing percepts to stored models (short-term and long-term memory), decision-making, and planning of actions were treated by most neuroscientists as separate areas of research. This was so probably not because the neuroscience community believed these operations to act independently: indeed, it is intuitive that any common cognitive process seamlessly interweaves these operations. The more likely explanation is twofold.  First, because too little was known about the individual processes comprising the full behaviour (and it is difficult to form bridges between processes that are not, separately, understood) and, second, because experimental paradigms and data collection methods were not sufficiently well developed to put the processes in sequence in any controlled manner.  These limitations are now being overcome in the leading cognitive neuroscience laboratories, and this book is a timely summary of the current state of the art.

The underlying theme is to address how the brain uses sensory information to develop and decide upon the appropriate action and how the brain determines the appropriate action to optimize the collection of new sensory information.  Key questions include: how are percepts built up in cortex, how are judgments of the percept made?  In what way does information flow within and between cortical regions, and what is accomplished by successive (and reverberating) stages of processing?  How are decisions made about the percept subsequently acted upon, through their conversion to a response according to the learned criterion for action?  How does the predicted or expected sensation interact with the actual incoming flow of sensory signals?  In confronting these questions it is necessary to understand sensory-motor loops – that is, the fact that our perception of the world drives new actions, and the actions undertaken at any moment lead to a new “view” of the world.

The aim of this book is to present new ideas, and discard unsupported ideas, about how humans and animals move through the world, actively interdigitating percepts with actions and to encourage the search for principles that extend beyond a single sensory modality or species.  To accomplish this, research on somatosensory-motor and visual-motor areas and concentrated in three experimental models (rats, non-human primates, and humans) is presented.

Published January 06

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Novartis Foundation Symposium 269

Signalling networks in cell shape and motility

Chair: Gary Borisy

Cells change their shape by altering the internal cytoskeleton.  The dynamics of cytoskeletal structures underlies the changes in changes in shape and signals that drive such changes must be interpreted by cellular machinery in order to carry out the required remodelling.  Until recently it has been very difficult to obtain detailed mechanistic information about these signalling processes.  It is clear that signalling pathways exist to orchestrate dynamic aspects of the cytoskeletons, especially actin-mediated events, and also events in the intermediate filament and microtubule networks.  These components are common to all cells although they can be arranged in quite different ways. Understanding the processes that regulate cell morphology is critical to understanding complex biological questions such as cell migration during embryonic development, axonal guidance, or the basis for metastasis of cancer cells.

This book is the outcome of a meeting which brought together relevant experts from the fields of cell biology, genetics, neurobiology, immunology and structural biology.  The unifying element is that all of the participants study processes of cell shape change and motility.  The group considered a number of key questions in this field of research: What are the organising principles behind cell shape change? Are there ‘master switches’ present in every cell type? How are extra-cellular signals interpreted by the cell in order to activate intra-cellular mechanisms? What is the influence of the extra cellular matrix on cell movement and internal signalling pathways? How do pathogens subvert cellular systems in order to stimulate or block their uptake?

The book contains data and discussions relevant to all of these important questions.  Data are presented on the key proteins that regulate cell shape: the GTP binding proteins of the Rho family. There are also extensive discussions in the book of the potential applications of the data to clinical problems, particularly the problems of cell motility in cancer.

Published September 05

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Novartis Foundation Symposium 268

Molecular mechanisms influencing aggressive behaviours

Chair: Donald Pfaff

The experimental analysis of aggression has been of interest to scientists for a very long time.  This has included study of the ethological forms of aggression, its neuroanatomy and its neuropharmacology.  There have been many interdisciplinary studies of aggression in both animals and humans.  However, during the past five years or so, the application of new molecular genetic techniques has enabled us to explore mechanisms of aggression in ways that were not previously possible, yielding new information and insights.

This book represents the outcome of a meeting where scientists from a broad spectrum of disciplines discussed recent data on aggression in laboratory animals and examined the data with particular reference to possible implications for understanding human aggression.  Chapters in this book focus on the major current experimental issues in the study of aggression in humans and animals: sex differences in aggression and related hormonal effects; specific genes for neurotransmitters, neuropeptides, and nitric oxide; and finally aggression in primates both human and animal.  The discussions printed in the book deal with some of the specific problems of interpretation at the molecular level, but general issues relating to our understanding of human and animal aggression are considered in some detail.  This book will provide a comprehensive account of the state-of-the-art in our understanding of the underlying biology of aggression in humans and animals.

Published July 05 

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Novartis Foundation Symposium 267

The genetics of autoimmunity

Chair: Abul Abbas

Novartis Foundation Symposium 266

The hERG cardiac potassium channel: structure, function and long QT syndrome

Chair: Michael Sanguinetti

Since being identified in 1995 as a major culprit for congenital and acquired forms of long QT syndrome, the fundamental importance of hERG (the human ether-à-go-go-related gene) has been recognized by academic scientists, regulatory authorities dealing with new drug registration and pharmaceutical companies alike. This has coincided with an explosion in the molecular, structural and detection techniques available to researchers studying ion channel structure and function.

(hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier potassium current in cardiac mycoytes, I_Kr. Physiologically, it is one of several ion channels involved in the normal action potential repolarization in cardiac myocytes. Pharmacologically, it is the target for class III antiarrhythmic agents e.g. quinidine, amiodarone and dofetilide. Toxicologically, it is considered to demonstrate promiscuous binding to a wide-range of structurally diverse compounds leading to prolongation of the QT interval. This drug-induced QT interval prolongation, leading to risk of ventricular tachyarrhythmia, Torsade de Pointes and mortality has precipitated the withdrawal of medicines from the marketplace, particularly amongst certain therapeutic classes including antihistamines, gastrointestinal prokinetics, antipsychotics and antibiotics.

This book draws together contributions from basic, pharmaceutical and clinical sciences and regulatory authority perspectives aimed at a better understanding of the structure and function of hERG, the molecular basis for compound binding and preferred preclinical test systems. Topics include hERG channel gating, regulation of functional expression, pharmacological properties of hERG/I_Kr channels, drug-induced long QT syndrome and preclinical evaluation and regulatory recommendations for assessing QT prolongation risks. It is hoped that a better understanding of the role of the hERG channel in drug-induced cardiac arrhythmias will ultimately lead to the development of important, new and safer medicines.

Published February 05  

Read a report on Long QT and hERG

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Novartis Foundation Symposium 265

Stem cells: nuclear reprogramming and therapeutic applications 

Chair: John Gearhart

The nuclear envelope is the boundary between a cell’s nucleus and the surrounding cytoplasm, and consists of inner and outer membranes traversed by the nuclear pores. Stem cells are specialized cells with unique potential for self-renewal and specific cell-type commitment. These cells are uncommitted cells until a particular physiological signal turns them into differentiating and lineage-committed cells with particular physiological functions.

In 1998 investigators isolated embryonic stem cells from human embryos for the first time and were able to grow these in in vitro culture systems. Since then, stem cell-based technologies have received an enormous amount of scientific attention because of their potential for developing novel therapeutic applications. Potential clinical applications range from 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 in general, and also to research on the cloning of animals by nuclear transfer. 

This book also covers the important ethical issues that are raised by research on stem cells, as well as are the various regulatory regimes which apply in different countries: these are likely to be influential in determining where future stem cell research is carried out.

Published March 05  

Read a recent bulletin report on cardiac stem cells

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Novartis Foundation Symposium 264

Nuclear organization in development and disease

Chair: Robert Goldman

Underlying the inner nuclear membrane is a thin proteinaceous layer, the nuclear lamina, which is made up principally of the nuclear lamins. These are intermediate filament-type proteins. This envelope has an important role: it regulates the traffic of molecules between the nucleus and the cytoplasm, nuclear morphology during the cell cycle, DNA synthesis and chromatin organization.

Nine human diseases are linked to mutations in components of the nuclear envelope, most of which are linked to mutations in the lamin A gene (LMNA). These diseases include the cardiac and skeletal myopathies (Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and limb girdle muscular dystrophy 1B); Dunnigan’s partial lipodystrophy and mandibuloacral dysplasia (MAD), which involve the loss of white fat as well as skeletal abnormalities in MAD; a peripheral neuropathy, Charcot-Marie-Tooth disorder type 2, affecting the myelin sheath; and, most recently, the premature ageing condition Hutchinson-Gilford progeria. Another disease, Pelger-Huet anomaly, that affects nuclear morphology and skeletal development, is linked to the envelope-associated protein, the lamin B receptor. Furthermore, a recent study suggested that other diseases may be linked to many newly identified nuclear envelope-associated proteins.

This important new book draws together contributions from cell and developmental biologists, structural biologists, geneticists and clinical scientists, whose discussions were aimed at furthering our understanding of the cellular and molecular basis of these diseases. Topics include how nuclear structure and location within a nucleus affect gene expression, chromatin organization and cell differentiation; the nature of the interactions between the nuclear envelope and the cytoskeleton; and the extent to which the cytoskeleton mediates communication between the cell membrane and nucleus in regulating gene expression, and whether disruption of such communication might underlie the disease processes. 

Published January 05  

Read a recent bulletin report on lamins and lamin-associated diseases

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Novartis Foundation Symposium 262
Biology of IGF-1: its interaction with insulin in health and malignant states

Chair: Derek LeRoith

Insulin-like growth factor (IGF-1) is the anabolic effector hormone of growth hormone. In addition to its effect on normal growth it has been linked in recent years with several types of malignancy. These include prostate cancer, ovarian cancer, and colon cancer. However, the nature of this relationship with cancer is uncertain and the linkage itself is controversial.

The IGF-1 receptors and post-signalling pathways are similar to those of insulin in spite of differences in the biological actions of these hormones. Given the similarities, IGF-1 and insulin are often considered together when the link between IGF-1 and cancer is discussed.

The clinical use of long-term growth hormone treatment is increasing, and such treatment leads to raised IGF-1 levels. Increased insulin levels are also more common as the prevalence of obesity and type 2 diabetes increase in the population. Therefore, a careful discussion of the role of IGF-1 and insulin in various cancers is urgently needed. This book arises from a meeting where these issues were examined in detail. Containing contributions from the leading scientists and clinicians in the field, this book should prove essential reading for anyone with a clinical interest in the insulin and the IGFs. 

Published September 04 

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Novartis Foundation Symposium 261, in collaboration with the Novartis Foundation, Japan
Pathological pain: from molecular to clinical aspects

Chair: Takao Kumazawa

Recent decades have seen an explosion of research into the mechanisms of pain in both normal and pathological states. Neurobiological studies have revealed the detailed characteristics of nociceptive systems and endogenous analgesic systems. Such studies are, however, of only limited use in explaining the mechanisms implicated in pathological pain. Plastic changes in pain systems occur in chronic neuropathic pain, even resulting in structural changes within the CNS and neuronal plasticity seems to be the key to a better understanding of pathological pain, perhaps reflecting the primitive and poorly differentiated nature of the pain system.

In evolutionary terms, the pain system emerged at a very early stage of neuronal development. These early origins are reflected by its plasticity, its intimate relationship with instinctive and other fundamental bodily functions such as the autonomic nervous system, and the involvement of humoral signalling messengers.

Recent progress in pain research has shed light on some of the molecules involved in humoral messenger systems, including cytokines, neurotrophins, neuropeptides, inflammatory mediators and ion channels. Precise electrophysiological investigations combined with a detailed molecular understanding are providing important clues about the mechanisms involved in pathological pain. This work is aided by studies of the cellular mechanisms involved in the development of opioid tolerance. In addition, non-invasive, brain imaging technologies continue to shed light on pain mechanisms at a cognitive level.

This book brings together contributions from key investigators in the area of pathological pain. It includes coverage of the receptors and channels involved in nociception, the possible messages that cause neuropathic plasticity, spinal plasticity in neuropathy, plastic changes in opioid systems in neuropathy and opioid tolerance, and plastic changes related to pathological pain. It should prove to be essential reading for pain researchers and clinicians involved in the treatment of chronic or pathological pain. 

Published July 04 

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Novartis Foundation Symposium 260
Osteoarthritic joint pain

Chair: David T. Felson

Osteoarthritis (OA) is a chronic degenerative disease associated with joint pain and loss of joint function. It has an estimated incidence of 4 out of every 100 people and significantly reduces the quality of life in affected individuals. The major symptoms are chronic joint pain, swelling and stiffness, and severe pain is often the central factor causing patients to seek medical attention. Within the affected joint there is focal degradation and remodelling of articular cartilage, new bone formation and mild synovitis.

Several mechanisms are thought to contribute to OA joint pain. These include mild synovial inflammation, bone oedema, ligament stretching, osteophyte formation and cartilage-derived mediators. Changes in joint biomechanics and muscle strength are also candidate factors in the severity and duration of joint pain in OA. From a nervous system perspective, the relative contributions of peripheral afferent nociceptive fibres and central mechanisms remain to be defined. Importantly, there is a clear disconnect between clinical severity, as measured by radiographic changes, and the presence and severity of joint pain. Treatments for OA joint pain include non-steroidal anti-inflammatory compounds, exercise and surgical intervention. To date, there remains a critical need for improved control of joint pain in OA.

This book brings together contributions from key investigators in the area of OA joint pain. Coverage includes the clinical presentation of joint pain, the pathways involved in joint pain, OA disease processes and pain, experimental models and pain control. The discussions provide insights into the nature of OA joint pain, identify key studies needed to advance understanding, highlight possible intervention points and serve to delineate future directions towards a better treatment of OA joint pain. 

Published May 04

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Novartis Foundation Symposium 259
Reversible protein acetylation

Chair: Eric Verdin

The reversible acetylation of histone on lysine residues 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 specific 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 HATs and HDACs are represented by rapidly growing protein families. For example, more than 18 distinct HDACs have been identified in humans so far. These proteins play critical roles in a wide variety of biological functions, including transcriptional regulation, cell cycle and differentiation. The identification and characterization of HATs and HDACs has led to the realization that 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-κB) and coactivator recruitment (HIV Tat protein). 

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 arises from the interactions of a multidisciplinary group of scientists involved in the study of acetylation. Work over the past five years is discussed in detail with an emphasis on major unanswered questions. This novel research opens up new and exciting possibilities for drug design. 

Published April 04

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Novartis Foundation Symposium 258
Mammalian TRP channels as molecular targets

Chair: James W. Putney Jr

Transient receptor potential (TRP) genes were originally identified as critical components of phototransduction in Drosophila. Since the discovery of the first mammalian transient receptor potential channel (TRPC), more than 20 mammalian homologues have been reported. These ion channel proteins are widely distributed in tissues and appear to play a fundamental role in cell signalling, growth and death, though their specific physiological functions are largely unknown. 

There are two major subfamilies of TRP channels. The TRPV channels include the VR1 vanilloid receptor, epithelial Ca²⁺ channels, and OTRPC4, a channel that appears to be regulated by changes in osmolarity. Thus, the TRPVs may have a variety of functions ranging from sensory transduction in nerves to Ca²⁺ transport in vitamin D-responsive epithelial cells of the gastrointestinal tract and renal tubule. The TRPM channels, which are the largest proteins in the TRP family, include the founding member, melastatin, and a novel bifunctional channel enzyme, TRP-PLIK. The physiological role of the TRPM channels remains largely unknown. 

Little is currently known about the actual subunit composition of native mammalian TRP channels. On the basis of the structure of other channel types, it is assumed that TRP channels are composed of four subunits and there is evidence supporting heteromultimeric channel assembly, but the channel composition and the rules governing subunit assembly remain to be determined. Likewise, how these tetrameric channels are localized in the plasmalemma to specific signalling microdomains is unknown.

This book brings together contributions from key investigators in the area of TRP channel structure and function. The book includes coverage of the structure, function and regulation of mammalian TRP channels and of mechanisms of signal transduction. The discussions serve to delineate future directions towards a better understanding of the role of TRP channels in normal cellular physiology, the involvement of TRP channels in disease states, and their potential use as molecular targets for novel therapeutic agents.

Published March 04

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Novartis Foundation Symposium 257
Anaphylaxis

Chair: Stephen Galli

Anaphylaxis is an immediate-type allergic reaction involving the whole organism. It is the most life-threatening allergic condition. Although there are few exact epidemiological data regarding prevalence, estimates regarding insect sting anaphylaxis range between 1–3% in the general population, but much higher values are reported by some authors for food and drug-induced anaphylaxis. Anaphylaxis is the main acute killer of allergic individuals.

Although anaphylaxis was discovered at the beginning of the 20th century there are still many unsolved problems. These include non-IgE-mediated anaphylactoid reactions, non-immunologically mediated anaphylactoid (pseudo-allergic) reactions, pathophysiological events at the microcirculatory level, appropriate therapy for the acute reaction, strategies for prevention, public education about the problem and new approaches to prevention and therapy at the IgE level. All these subjects are discussed in this book.

Since anaphylaxis occurs acutely and is unforeseen, it is very difficult to organize controlled studies regarding therapy and prevention. Since the spectrum of symptomatology covers interdisciplinary areas (skin, respiratory, cardiovascular and gastrointestinal system), inter-disciplinary approaches are necessary for progress in the field. There is widespread uncertainty among physicians about therapy, especially regarding the problem of self-administered treatment.

In this important book, an interdisciplinary group of experts explore the pathophysiology of different types of anaphylactic and anaphylactoid reactions. Data are presented on the epidemiology of these conditions and problems concerning diagnosis, therapy and prevention are explored in detail. This thorough and up-to-date coverage of the subject will be of great interest to all clinical immunologists, researchers and physicians who deal with this important life-threatening condition. 

Published January 04

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Novartis Foundation Symposium 256
Cancer and inflammation

Chair: Siamon Gordon

Chronic inflammation predisposes to some forms of cancer, and the host response to malignant disease has several parallels with inflammation and wound healing. The cells involved in inflammation are detected in a range of common cancers, along with the inflammatory cytokines and chemokine ligand/receptor systems. Neutralization or deletion of the gene for some inflammatory cytokines confers resistance to tumour induction and experimental metastasis. Over-expression of such cytokines in tumour cells may enhance malignant potential. Certain chemokines are likely to subvert antitumour immunity by favouring development of ineffective Type 2 responses. Tumour cells may even utilize chemokine receptors in homing to lymph nodes and other organs. Thus the cells, cytokines and chemokines found in tumours are more likely to contribute to tumour growth, progression and immunosuppression, than they are to mount an effective host antitumour response. 

This book draws together contributions from an international group of scientists and clinicians from diverse disciplines, ranging from epidemiology to immunology, cell biology, molecular oncology, molecular medicine and pharmacology to debate these and related issues. Topic coverage includes the epidemiological links between cancer and inflammation, the parallels between inflammation and cancer, the role of inflammation in cancer, inflammatory genes as cancer risk and progression factors, inflammation and cancer angiogenesis, and preventative and therapeutic strategies.

Published January 04

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