As our knowledge of type 1 (insulin-dependent) diabetes increases, so does our appreciation for the pathogenic complexity of this disease and the challenges associated with its treatment. Many new concepts about the pathogenesis of this disorder have arisen. The role of genetics versus environment in disease formation has been questioned, and the basis on which type 1 diabetes is characterised and diagnosed is the subject of much debate. Additionally, the care and treatment of patients with type 1 diabetes has seen a rapid evolution; with genetically engineered insulins, glucose monitoring devices, and algorithms all contributing to a decrease in disease-related complications. We focus this seminar on these changing views, and offer a new perspective on our understanding of the pathogenesis of type 1 diabetes and on principles for therapeutic management of patients with this disorder.

Bacteria that adhere to implanted medical devices or damaged tissue can encase themselves in a hydrated matrix of polysaccharide and protein, and form a slimy layer known as a biofilm. Antibiotic resistance of bacteria in the biofilm mode of growth contributes to the chronicity of infections such as those associated with implanted medical devices. The mechanisms of resistance in biofilms are different from the now familiar plasmids, transposons, and mutations that confer innate resistance to individual bacterial cells. In biofilms, resistance seems to depend on multicellular strategies. We summarise the features of biofilm infections, review emerging mechanisms of resistance, and discuss potential therapies.

The identification of genes that place individuals at high risk of breast, ovarian, and colorectal cancer has greatly advanced our understanding of cancer predisposition over the past decade. This knowledge has received much attention from the media, and referrals to geneticists and surgeons, and requests for genetic testing, have risen. We review the published evidence for the management of people at increased risk of hereditary cancers, to draw attention to areas of uncertainty and to discuss implications for primary care. We focus on common inherited cancers, since they will have the greatest effect on clinical practice over the next decade. Cancer genetics offers a model of how information on the genetics of other common diseases could affect primary care in the future. Strategies to support the integration of genetic medicine in primary care are needed to enable primary-care practitioners to identify individuals at raised genetic risk and to reassure patients for whom genetic testing and increased surveillance offer little benefit.

Haematology represents a prime example of how rapidly immunology is moving towards the bedside. The diagnosis of blood disease has been modified by the "cluster of differentiation" (CD) nomenclature of leucocyte surface antigens, and the molecular genetics of the immune system has had a major effect on the diagnosis and treatment of blood malignancies. Lymphoid tumours represent a fertile area of interaction between immunology and haematology: B-cell malignancies are associated with dysregulation of the immune system, and antigen exposure might have an important role in the development of lymphoid malignant clones that interact with the microenvironment to avoid apoptosis and acquire better growing conditions. Understanding the pathophysiology of immune-mediated blood diseases has paved the way to the successful use of immunosuppressive agents, and the unravelling of the mechanisms of lymphocyte signal transduction and the relations between lymphocyte activation and apoptosis are allowing new therapeutic approaches. Paradoxically, lymphoid tumours are an excellent model to test the efficacy of manipulating the immune system for the purpose of tumour eradication.

The optimum duration of prophylaxis against venous thromboembolism after total hip or knee replacement is uncertain. Our primary objective was to establish the efficacy of extended-duration prophylaxis on symptomatic venous thromboembolic events.

Antigen delivers both immunogenic and tolerogenic signals to lymphocytes. The outcome of antigen exposure represents a complex integration of the timing of antigen binding with signals from many other immunogenic and tolerogenic costimulatory pathways. A road map of these signalling pathways is only beginning to be charted, revealing the mechansim of action and limitations of current immunotherapeutic agents and the points of attack for new agents. Ciclosporin and tacrolimus interfere with tolerogenic signals from antigen in addition to blocking immunogenic signals, thus preventing active establishment of tolerance. Corticosteroids inhibit a key immunogenic pathway, NFkappaB, and more specific inhibitors of this pathway may allow tolerance to be actively established while immune responses are blocked. New experimental therapies aim to mimic tolerogenic antigen signals by chronically stimulating antigen receptors with antigen or antibodies to the receptor, or aim to block costimulatory pathways involving CD40 ligand, B7, or interleukin 2. Obtaining the desired response with these strategies is unpredictable because many of these signals have both tolerogenic and immunogenic roles. The cause of autoimune diseases has been determined for several rare monogenic disorders, revealing inherited deficiencies in tolerogenic costimulatory pathways such as FAS. Common autoimmune disorders may have a biochemically related pathogenesis.

Raynaud's phenomenon is characterised by episodic vasospasm of the fingers and toes typically precipitated by exposure to cold. Mild Raynaud's is common and is not usually a harbinger of clinically important disability; its onset, however, can be startling and uncomfortable for patients, and the well recognised association in some cases with systemic rheumatic conditions often precipitates aggressive assessments for underlying diseases. Advances in vascular physiology have shed light on the role of the endothelium as well as endothelium-independent mechanisms in the altered vasoregulation of Raynaud's. We review clinical aspects of the disorder and new insights with respect to pathophysiology, and we discuss potential new therapeutics based on the disease mechanism, such as prostacyclin analogues, serotonin antagonists, and calcitonin gene-related peptides.

Immunogenetic analysis of disease susceptibility has been encouraged by the identification of strong HLA associations with several diseases of uncertain cause. Weaker HLA associations exist with a large number of infectious and non-infectious diseases and the mechanisms of these effects are beginning to be uncovered. Extensive analyses of non-HLA immunogenetic variants have also been undertaken and associations with a variety of genes identified. Genetic linkage analysis of multicase families has recently identified new major susceptibility loci for a few immunologically determined common diseases. However, the greatest potential for the future lies in genome-wide searches for susceptibility genes that individually might have quite modest effects but cumulatively have a large impact on individual risk. This new era of immunogenomics promises to provide key insights into disease pathogenesis and identify multiple molecular targets for intervention strategies.

Detrusor-external sphincter dyssynergia (DSD) is a common cause of bladder outlet obstruction in men with spinal cord injuries, which if left untreated leads ultimately to renal failure. External sphincterotomy is currently the main treatment for DSD. However, obstruction persists in a substantial proportion of cases after this procedure. There is no effective drug treatment for DSD. Nitric oxide is an inhibitory neurotransmitter synthesised by nitric oxide synthase. Both animal and human studies suggest that nitric oxide mediates urethral sphincter relaxation. Nitric-oxide-synthase staining neurons have been identified in very high density in the urethral sphincters of a variety of animals and in human beings. Relaxation of the urethral sphincter is abolished by inhibitors of nitric oxide synthase and enhanced by nitric oxide donors. Mice with targeted deletion of the gene, for neuronal nitric oxide have urethral sphincters that do not relax in response to electrical stimulation. We hypothesise that augmentation of external sphincter nitric oxide could be an effective pharmacological treatment for DSD. Currently available nitric oxide donors such as glyceryl trinitrate or isosorbide mononitrate could be used to deliver nitric oxide to the urethral sphincter. The variable pharmacokinetics of these drugs combined with different modes of delivery (sublingual, buccal, or oral) could be used to achieve both short-term and long-term increases in concentrations of sphincter nitric oxide, thereby resulting in either acute or chronic lowering of urethral pressure. The safety and efficacy of this potential treatment for DSD needs to be established in clinical trials of men with spinal cord injures with DSD.

Immunosuppressive drugs developed in the past two decades have improved the short-term survival of organ allografts, but tolerance has not been achieved and almost all transplant recipients continue to require drugs throughout life. Graft rejection arises from the cognate interaction of T cells with antigen-presenting cells, the recognition of alloantigen through the T-cell receptor, and the delivery of accessory stimulation signals. Once activated by the specific antigen, replicating T cells die if they are re-exposed to the same antigen. Since depletion of antigen-activated T cells is one critical mechanism of transplantation tolerance, drugs such as ciclosporin that interfere with activation-induced T-cell death could inhibit tolerance, whereas drugs such as mycophenolate mofetil, that induce the death of activated T cells, could facilitate tolerance. Other tolerance mechanisms depend on inactivation rather than elimination of allograft reactive T cells. When antigen recognition occurs without costimulation through the CD28 and CD154 accessory receptors, or in absence of cell division, T cells become unresponsive. Thus, inhibitors of CD28 and CD154, and inhibition of T-cell division by rapamycin promotes transplantation tolerance.

Pacing for patients with severe heart failure without bradyarrhythmia has been proposed as an addition to medical therapy over the past decade. Alteration of the normal electrical activation sequence of the heart modifies its mechanical action, especially when ventricular function is poor. Both the site of ventricular-lead placement and timing with the atria have been manipulated in attempts to alleviate the symptoms of heart failure. Most recently, in addition to the conventional two leads used for pacing, a third lead to pace the left ventricle has been advocated in some patients with heart failure. We review the evidence for pacing in heart failure.

Troglitazone, the first in the thiazolidinedione class of oral hypoglycaemic agents, was launched in the USA in March, 1997. It reached Europe later that year, only to be withdrawn within weeks on the grounds of liver toxicity. Meanwhile it went on to generate sales of over $2 billion in the USA, and caused at least 90 cases of liver failure (70 resulting in death or transplantation) before it was withdrawn in March, 2000. Rosiglitazone and pioglitazone reached the US market in 1999 as first-line agents to be used alone or in combination with other drugs, but in Europe the same dossiers were used one year later to apply for a limited licence as second-line agents restricted to oral combination therapy. How should we use the glitazones? And how did they achieve blockbuster status without any clear evidence of advantage over existing therapy?

Primary immunodeficiency diseases represent a vast array of inherited disorders of the immune system. Major advances in the understanding of genetic basis and molecular mechanisms have occurred within the past 10 years, as a result of the tools of modern genetics. About three quarters of 100 primary immunodeficiency diseases can now be reliably diagnosed with molecular probes. In many cases, gene identification has enabled significant insight into the physiopathology of the related conditions. Therapeutic progress based on protein engineering and possibly gene therapy will also ensue.

We are continually exposed to organisms that are inhaled, swallowed, or inhabit our skin and mucous membranes. Whether these organisms penetrate and cause disease is a result of both the pathogenicity of the organism (the virulence factors at its disposal) and the integrity of host defence mechanisms. The immune system is an interactive network of lymphoid organs, cells, humoral factors, and cytokines. The essential function of the immune system in host defence is best illustrated when it goes wrong; underactivity resulting in the severe infections and tumours of immunodeficiency, overactivity in allergic and autoimmune disease. In this review we have covered the normal function of the immune system in recognising, repelling, and eradicating pathogens and other foreign molecules.