Management of psoriasis begins with identification of the extent of cutaneous disease. However, a holistic, contractual approach to treatment is encouraged, with particular reference to psychosocial disability and quality-of-life issues. The presence of psoriasis on palms, soles, body folds, genitals, face, or nails, and concomitant joint disease, are also important when considering treatment options. An evidence-based approach is essential in delineating differences between the many available treatments. However, archaic approaches, especially combinational ones, are routinely used by some clinicians, with inadequate prospective or comparative evidence. Treatments currently available are: topical agents used predominantly for mild disease and for recalcitrant lesions in more severe disease; phototherapy for moderate disease; and systemic agents including photochemotherapy, oral agents, and newer injectable biological agents, which have revolutionised the management of severe psoriasis. Other innovative treatments are undergoing clinical studies, with the aim of maintaining safe, long-term control of the condition.

Psoriasis, a papulosquamous skin disease, was originally thought of as a disorder primarily of epidermal keratinocytes, but is now recognised as one of the commonest immune-mediated disorders. Tumour necrosis factor alpha, dendritic cells, and T-cells all contribute substantially to its pathogenesis. In early-onset psoriasis (beginning before age 40 years), carriage of HLA-Cw6 and environmental triggers, such as beta-haemolytic streptococcal infections, are major determinants of disease expression. Moreover, at least nine chromosomal psoriasis susceptibility loci have been identified. Several clinical phenotypes of psoriasis are recognised, with chronic plaque (psoriasis vulgaris) accounting for 90% of cases. Comorbidities of psoriasis are attracting interest, and include impairment of quality of life and associated depressive illness, cardiovascular disease, and a seronegative arthritis known as psoriatic arthritis. A more complete understanding of underlying pathomechanisms is leading to new treatments, which will be discussed in the second part of this Series.

Polar expeditions include treks and stays at summer camps or year-round research stations. People on such expeditions generally undergo psychological changes resulting from exposure to long periods of isolation and confinement, and the extreme physical environment. Symptoms include disturbed sleep, impaired cognitive ability, negative affect, and interpersonal tension and conflict. Seasonal occurrence of these symptoms suggests the existence of three overlapping syndromes: the winter-over syndrome, the polar T3 syndrome, and subsyndromal seasonal affective disorder. About 5% of people on expeditions meet DSM-IV or ICD criteria for psychiatric disorders. However, they also experience positive or so-called salutogenic outcomes resulting from successfully coping with stress and enhanced self-sufficiency, improved health, and personal growth. Prevention of pathogenic psychological outcomes is best accomplished by psychological and psychiatric screening procedures to select out unsuitable candidates, and by providing access to psychological support, including telephone counselling. Promotion of salutogenic experiences is best accomplished by screening for suitable personality traits, and training participants in individual coping strategies, group interaction, and team leadership.

Drug therapy is essential when caring for elderly patients, but clearly it is a double-edged sword. Elderly patients are at high risk of having drug interactions, but the prevalence of these interactions is not well documented. Several types of interactions exist: drug-drug, drug-disease, drug-food, drug-alcohol, drug-herbal products, and drug-nutritional status. Factors such as age-related changes in pharmacokinetics and pharmacodynamics, frailty, interindividual variability, reduced homoeostatic mechanisms, and psychosocial issues need to be considered when drug interactions are assessed. Software can help clinicians to detect drug interactions, but many programmes have not been updated with the evolving knowledge of these interactions, and do not take into consideration important factors needed to optimise drug treatment in elderly patients. Any generated recommendations have to be tempered by a holistic, geriatric, multiprofessional approach that is team-based. This second paper in a series of two on prescribing in elderly people proposes an approach to categorise drug interactions, along with strategies to assist in their detection, management, and prevention.

Prescription of medicines is a fundamental component of the care of elderly people, and optimisation of drug prescribing for this group of patients has become an important public-health issue worldwide. Several characteristics of ageing and geriatric medicine affect medication prescribing for elderly people and render the selection of appropriate pharmacotherapy a challenging and complex process. In the first paper in this series we aim to define and categorise appropriate prescribing in elderly people, critically review the instruments that are available to measure it and discuss their predictive validity, critically review recent randomised controlled intervention studies that assessed the effect of optimisation strategies on the appropriateness of prescribing in elderly people, and suggest directions for future research and practice.

Achondroplasia is the most common form of short limb dwarfism in human beings, affecting more than 250,000 individuals worldwide. More than 95% of patients have the same point mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) and more than 80% of these are new mutations. The mutation, which causes gain of FGFR3 function, affects many tissues, most strikingly the cartilaginous growth plate in the growing skeleton, leading to a variety of manifestations and complications. The biology of FGFR3 and the molecular and cellular consequences of the achondroplasia mutation are being elucidated, providing a more complete understanding of the disorder and a basis for future treatments targeted directly at relevant pathogenetic pathways. Furthermore, the natural history of the condition, which has been well delineated in childhood and adolescence, is being defined more fully in adults with achondroplasia; most of the serious complications can be modified favourably or prevented by anticipation and early treatment. Possible future treatments include chemical inhibition of receptor signalling, antibody blockade of receptor activation, and alteration of pathways that modulate the downstream propagation of FGFR3 signals.

The need for new classes of antiretroviral drugs has become apparent because of increasing concern about the long-term toxic effects of existing drugs, the need to combat HIV-1 variants that are resistant to treatment, and the frequency of treatment change in drug-experienced patients. Currently, most regimens are combinations of inhibitors of two viral enzymes--reverse transcriptase and protease. Nevertheless, several steps in the HIV replication cycle are potential targets for intervention. These steps can be divided into entry steps, in which viral envelope glycoproteins and their receptors are involved, and postentry steps, involving viral accessory gene products and the cellular proteins with which they interact. New treatment options target viral entry into the cell. These treatments include the HIV fusion inhibitor enfuvirtide, and new HIV coreceptor antagonists in advanced stages of clinical development or in different stages of preclinical development. Here, we review the development of new HIV entry inhibitors, their performance in clinical trials, and their possible role in anti-HIV therapy.

Paediatric HIV infection is a growing health challenge worldwide, with an estimated 1500 new infections every day. In developed countries, well established prevention programmes keep mother-to-child transmission rates at less than 2%. However, in developing countries, where transmission rates are 25-40%, interventions are available to only 5-10% of women. Children with untreated natural infection progress rapidly to disease, especially in resource-poor settings where mortality is greater than 50% by 2 years of age. As in adult infection, antiretroviral therapy has the potential to rewrite the natural history of HIV, but is accessible only to a small number of children needing therapy. We focus on the clinical and immunological features of HIV that are specific to paediatric infection, and the formidable challenges ahead to ensure that all children worldwide have access to interventions that have proved successful in developed countries.

Only a few types of cancer are recognised as being directly related to immune deficiency in people with HIV/AIDS. Large population-based studies in transplant recipients have shown that a wider range of cancers could be associated with immune deficiency. Our aim was to compare cancer incidence in population-based cohort studies of people with HIV/AIDS and people immunosuppressed after solid organ transplantation.

Meningococcus, an obligate human bacterial pathogen, remains a worldwide and devastating cause of epidemic meningitis and sepsis. However, advances have been made in our understanding of meningococcal biology and pathogenesis, global epidemiology, transmission and carriage, host susceptibility, pathophysiology, and clinical presentations. Approaches to diagnosis, treatment, and chemoprophylaxis are now in use on the basis of these advances. Importantly, the next generation of meningococcal conjugate vaccines for serogroups A, C, Y, W-135, and broadly effective serogroup B vaccines are on the horizon, which could eliminate the organism as a major threat to human health in industrialised countries in the next decade. The crucial challenge will be effective introduction of new meningococcal vaccines into developing countries, especially in sub-Saharan Africa, where they are urgently needed.

Violence and rape are believed to fuel the HIV epidemic in countries affected by conflict. We compared HIV prevalence in populations directly affected by conflict with that in those not directly affected and in refugees versus the nearest surrounding host communities in sub-Saharan African countries.

There is renewed interest in the potential contribution of community health workers to child survival. Community health workers can undertake various tasks, including case management of childhood illnesses (eg, pneumonia, malaria, and neonatal sepsis) and delivery of preventive interventions such as immunisation, promotion of healthy behaviour, and mobilisation of communities. Several trials show substantial reductions in child mortality, particularly through case management of ill children by these types of community interventions. However, community health workers are not a panacea for weak health systems and will need focussed tasks, adequate remuneration, training, supervision, and the active involvement of the communities in which they work. The introduction of large-scale programmes for community health workers requires evaluation to document the impact on child survival and cost effectiveness and to elucidate factors associated with success and sustainability.

The clinical hallmark of neuroblastoma is heterogeneity, with the likelihood of cure varying widely according to age at diagnosis, extent of disease, and tumour biology. A subset of tumours will undergo spontaneous regression while others show relentless progression. Around half of all cases are currently classified as high-risk for disease relapse, with overall survival rates less than 40% despite intensive multimodal therapy. This Seminar focuses on recent advances in our understanding of the biology of this complex paediatric solid tumour. We outline plans for the development of a uniform International Neuroblastoma Risk Group (INRG) classification system, and summarise strategies for risk-based therapies. We also update readers on new discoveries related to the underlying molecular pathogenesis of this tumour, with special emphasis on advances that are translatable to the clinic. Finally, we discuss new approaches to treatment, including recently discovered molecular targets that might provide more effective treatment strategies with the potential for less toxicity.

The HIV epidemic has led to large increases in the frequency of smear-negative pulmonary tuberculosis, which has poor treatment outcomes and excessive early mortality compared with smear-positive disease. We used a combination of systematic review, document analysis, and global expert opinion to review the extent of this problem. We also looked at policies of national tuberculosis control programmes for the diagnosis of smear-negative pulmonary tuberculosis to assess their coverage, identify the diagnostic difficulties, and find ways to improve the diagnosis of this type of tuberculosis, with a focus on resource-constrained settings with high HIV infection rates. We propose that the internationally recommended algorithm for the diagnosis of smear-negative pulmonary tuberculosis should be revised to include HIV status, severity of AIDS and tuberculosis, and early use of chest radiography in the decision tree. Increased use of promising methods of diagnosis such as sputum liquefaction and concentration and increased availability of fluorescence microscopy should be explored and encouraged. Culturing of sputum in resource-constrained settings with high HIV infection rates should also be encouraged, existing facilities should be made full use of and upgraded, and effective quality-assurance systems should be used. Innovative ways to address human resources issues involved in addressing the diagnostic difficulties are also needed. The development of rapid, simple, and accurate tuberculosis diagnostic tools with applicability at point of care and remote location is essential. To achieve these goals, greater political commitment, scientific interest, and investment are needed.

Amyotrophic lateral sclerosis (known in the UK as motor neuron disease) is a devastating illness with uncertain pathogenesis. In this Seminar, we review its natural history, clinical features, diagnostic criteria, variant and mimic syndromes, genetic forms, and epidemiology. Several hypotheses about causes of the disorder are discussed, such as excitotoxicity and oxidant stress, and we review past and present putative disease-modifying treatments. Disease-management strategies, from telling the patient about their illness to end-of-life decisions and palliative care, are presented. We review options for control of the main symptoms of amyotrophic lateral sclerosis--including dysphagia, dysarthria, respiratory distress, pain, and psychological disorders--and care in the terminal phase. The need for good psychosocial and spiritual care of patients and families is emphasised. We conclude with an overview of some current major issues and future prospects, ranging from the search for disease markers to challenging developments such as stem-cell and gene therapy.

Rheumatoid arthritis is characterised by pain, swelling, and destruction of joints, with resultant disability. Only disease-modifying antirheumatic drugs can interfere with the disease process. In the past few years, biological agents, especially inhibitors of tumour necrosis factor, have allowed for hitherto unseen therapeutic benefit, although even with these drugs the frequency and degree of responses are restricted. Therefore, new agents are needed, and three novel biological compounds for treatment of rheumatoid arthritis have already been used in practice or are on the horizon: rituximab (anti-CD20), abatacept (cytotoxic T-lymphocyte antigen 4 immunoglobulin), and tocilizumab (anti-interleukin 6 receptor). We discuss the targets of these drugs, the roles of these targets in the pathogenesis of rheumatoid arthritis, and the efficacy and adverse effects of these agents from clinical trial data. Novel therapeutic strategies in conjunction with optimised disease assessment for better treatment of rheumatoid arthritis and an outlook into potential future targets are also presented.

Despite therapeutic advances, vulvovaginal candidosis remains a common problem worldwide, affecting all strata of society. Understanding of anti-candida host defence mechanisms in the vagina has developed slowly and, despite a growing list of recognised risk factors, a fundamental grasp of pathogenic mechanisms continues to elude us. The absence of rapid, simple, and inexpensive diagnostic tests continues to result in both overdiagnosis and underdiagnosis of vulvovaginal candidosis. I review the epidemiology and pathogenesis of this infection, and also discuss management strategies.

Statins are effective cholesterol-lowering drugs that reduce the risk of cardiovascular disease events (heart attacks, strokes, and the need for arterial revascularisation). Adverse effects from some statins on muscle, such as myopathy and rhabdomyolysis, are rare at standard doses, and on the liver, in increasing levels of transaminases, are unusual. Myopathy--muscle pain or weakness with blood creatine kinase levels more than ten times the upper limit of the normal range--typically occurs in fewer than one in 10,000 patients on standard statin doses. However, this risk varies between statins, and increases with use of higher doses and interacting drugs. Rhabdomyolysis is a rarer and more severe form of myopathy, with myoglobin release into the circulation and risk of renal failure. Stopping statin use reverses these side-effects, usually leading to a full recovery. Asymptomatic increases in concentrations of liver transaminases are recorded with all statins, but are not clearly associated with an increased risk of liver disease. For most people, statins are safe and well-tolerated, and their widespread use has the potential to have a major effect on the global burden of cardiovascular disease.