Great efforts and expense have been expended in attempts to detect genetic polymorphisms contributing to susceptibility to complex human disease. Concomitantly, technology for detection and scoring of single nucleotide polymorphisms (SNPs) has undergone rapid development, extensive catalogues of SNPs across the genome have been constructed, and SNPs have been increasingly used as a means for investigation of the genetic causes of complex human diseases. For many diseases, population-based studies of unrelated individuals--in which case-control and cohort studies serve as standard designs for genetic association analysis--can be the most practical and powerful approach. However, extensive debate has arisen about optimum study design, and considerable concern has been expressed that these approaches are prone to population stratification, which can lead to biased or spurious results. Over the past decade, a great shift has been noted, away from case-control and cohort studies, towards family-based association designs. These designs have fewer problems with population stratification but have greater genotyping and sampling requirements, and data can be difficult or impossible to gather. We discuss past evidence for population stratification on genotype-phenotype association studies, review methods to detect and account for it, and present suggestions for future study design and analysis.

A "missed" case of congenital hip dislocation (CDH) can be a disaster for the patient and the outcome may be poor. Considerable resources are expended on screening programmes to identify appropriate cases early but a recent change in terminology to developmental dysplasia of the hip (DDH) and a realisation that neonatal hip maturation is poorly understood has made it difficult to know who should be screened and why.

Churg-Strauss syndrome is a rare diffuse vasculitis that is almost invariably accompanied by severe asthma. Although overall prognosis is good, and treatment with prednisone alone or in combination with immunosuppressive drugs is usually successful, severe asthma typically persists. Diffuse organ involvement of Churg-Strauss syndrome, especially cardiovascular and rare involvement of the CNS and renal system, suggests a poorer prognosis than usual, and can be fatal. The cause of Churg-Strauss syndrome is unknown, but its characteristic histological findings and association with asthma distinguish it from other vasculitides. Controversy surrounds the use of asthma drugs-especially antileukotrienes--and development of the disorder. We review the epidemiological evidence for an association of drug treatment with Churg-Strauss syndrome, the diverse diagnostic and pathological criteria for this syndrome, and treatment options.

Advances in human genetics could help us to assess prognosis on an individual basis and to optimise the management of complex diseases. However, different studies on the same genetic association sometimes have discrepant results. Our aim was to assess how often large studies arrive at different conclusions than smaller studies, and whether this situation arises more frequently when findings of first published studies disagree with those of subsequent research.

Recombinant interferons have been approved by many national regulatory agencies for treatment of relapsing remitting multiple sclerosis, but widespread discussion continues about their true effectiveness, benefits, side-effects, and costs.

The human gut is the natural habitat for a large and dynamic bacterial community, but a substantial part of these bacterial populations are still to be described. However, the relevance and effect of resident bacteria on a host's physiology and pathology has been well documented. Major functions of the gut microflora include metabolic activities that result in salvage of energy and absorbable nutrients, important trophic effects on intestinal epithelia and on immune structure and function, and protection of the colonised host against invasion by alien microbes. Gut flora might also be an essential factor in certain pathological disorders, including multisystem organ failure, colon cancer, and inflammatory bowel diseases. Nevertheless, bacteria are also useful in promotion of human health. Probiotics and prebiotics are known to have a role in prevention or treatment of some diseases.

Thyroid carcinomas are fairly uncommon and include disease types that range from indolent localised papillary carcinomas to the fulminant and lethal anaplastic disease. Several attempts to formulate a consensus about treatment of thyroid carcinoma have resulted in published guidelines for diagnosis and initial disease management. Multimodality treatments are widely recommended, although there is little evidence from prospective trials to support this approach. Surgical resection to achieve local disease control remains the cornerstone of primary treatment for most thyroid cancers, and is often followed by adjuvant radioiodine treatment for papillary and follicular types of disease. Thyroid hormone replacement therapy is used not only to rectify postsurgical hypothyroidism, but also because there is evidence to suggest that high doses that suppress thyroid stimulating hormone prevent disease recurrence in patients with papillary or follicular carcinomas. Treatment for progressive metastatic disease is often of limited benefit, and there is a pressing need for novel approaches in treatment of patients at high risk of disease-related death. In families with inherited thyroid cancer syndromes, early diagnosis and intervention based on genetic testing might prevent poor disease outcomes. Care should be carefully coordinated by members of an experienced multidisciplinary team, and patients should be provided with education about diagnosis, prognosis, and treatment options to allow them to make informed contributions to decisions about their care.

Schizophrenia is highly heritable, but the genes have remained elusive. Identifying the genes is essential if the pathogenesis and pathophysiology of schizophrenia is finally to be understood, and to give the prospect of more effective treatment.

Eating disorders are an important cause of physical and psychosocial morbidity in adolescent girls and young adult women. They are much less frequent in men. Eating disorders are divided into three diagnostic categories: anorexia nervosa, bulimia nervosa, and the atypical eating disorders. However, the disorders have many features in common and patients frequently move between them, so for the purposes of this Seminar we have adopted a transdiagnostic perspective. The cause of eating disorders is complex and badly understood. There is a genetic predisposition, and certain specific environmental risk factors have been implicated. Research into treatment has focused on bulimia nervosa, and evidence-based management of this disorder is possible. A specific form of cognitive behaviour therapy is the most effective treatment, although few patients seem to receive it in practice. Treatment of anorexia nervosa and atypical eating disorders has received remarkably little research attention.

Mechanical ventilation is indispensable in support of patients with respiratory failure who are critically ill. However, use of this technique has adverse effects, including increased risk of pneumonia, impaired cardiac performance, and difficulties associated with sedation and paralysis. Moreover, application of pressure to the lung, whether positive or negative, can cause damage known as ventilator-associated lung injury (VALI). Despite difficulties in distinguishing the effects of mechanical ventilation from those of the underlying disorder, VALI greatly assists patients with the most severe form of lung injury, acute respiratory distress syndrome (ARDS). Moreover, modification of mechanical ventilation so that VALI is kept to a minimum improves survival of patients with ARDS. Here, we outline the effects of mechanical ventilation on injured lungs and explore the underlying mechanisms.

The most frequent primary brain tumours in adults are gliomas and primary CNS lymphomas. In gliomas, molecular genetic analysis plays an increasing part in classification and treatment planning, a feature well illustrated by the chemosensitive oligodendrogliomas. Unfortunately, management of glioblastoma is still mainly palliative. Incidence of primary CNS lymphoma has increased strikingly in the past 20 years; substantial progress has been achieved in patients who are immunocompetent with the addition of methotrexate-based chemotherapy to radiotherapy, but the potential neurotoxic effects of this combination in elderly patients is worrisome.

Early findings on the use of tamoxifen or raloxifene as prophylaxis against breast cancer have been mixed; we update available data and overview the combined results.

Restenosis is the most important long-term limitation of stent implantation for coronary artery disease, occurring in 15-60% of patients. In-stent restenosis, a refractory coronary lesion resulting from neointimal hyperplasia, challenges both vascular biologist and interventional cardiologist. Various drugs and devices have been used tried to overcome restenosis but are not particularly successful. Over 1500000 percutaneous coronary interventions are done annually. Restenosis is not only important clinically but also for its impact on health-care costs.

Whipple's disease, or intestinal lipodystrophy, is a systemic infectious disorder affecting mostly middle-aged white men. Patients present with weight loss, arthralgia, diarrhoea, and abdominal pain. The disease is commonly diagnosed by small-bowel biopsy; the appearance of the sample is characterised by inclusions in the lamina propria staining with periodic-acid-Schiff, which represent the causative bacteria. Tropheryma whipplei has been classified as an actinomycete and has been propagated in vitro, which allows the possibility of improving diagnostic strategies, for example through antibody-based detection of the bacillus on duodenal tissue or in circulating monocytes. Cell-mediated immunity in active and inactive Whipple's disease has subtle defects that might predispose some individuals to symptomatic infection with this bacillus, which probably occurs ubiquitously. Although most patients respond well to empirical antibiotic treatment, some with relapsing disease have a poor outlook. The recent findings and concerted research might allow development of new strategies for diagnosis, treatment, and monitoring of patients with Whipple's disease.

The evolution of transfusion medicine into a clinically oriented discipline emphasising patient care has been accompanied by challenges that need to be faced as specialists look to the future. Emerging issues that affect blood safety and blood supply, such as pathogen inactivation and more stringent donor screening questions, bring new pressures on the availability of an affordable blood supply. Imminent alternatives for management of anaemia, such as oxygen carriers, hold great promise but, if available, will require close oversight. With current estimates of HIV or hepatitis C viral (HCV) transmission approaching one in 2000000 units transfused, keeping to a minimum bacterial contamination of platelet products (one in 2000) and errors in transfusion, with its estimated one in 800000 mortality rate, assume great urgency. Finally, serious difficulties in blood safety and availability for poor, developing countries require innovative strategies and commitment of resources.

Atopic dermatitis is a highly pruritic chronic inflammatory skin disorder affecting 10-20% of children worldwide. Symptoms can persist or begin in adulthood. It is also the most common cause of occupational skin disease in adults. This disease results from an interaction between susceptibility genes, the host's environment, pharmacological abnormalities, skin barrier defects, and immunological factors. New management approaches have evolved from advances in our understanding of the pathobiology of this common skin disorder.

Endarterectomy reduces risk of stroke in certain patients with recently symptomatic internal carotid stenosis. However, investigators have made different recommendations about the degree of stenosis above which surgery is effective, partly because of differences between trials in the methods of measurement of stenosis. To accurately assess the overall effect of surgery, and to increase power for secondary analyses, we pooled trial data and reassessed carotid angiograms.

Adverse events associated with dietary supplements are difficult to monitor in the USA, because such products are not registered before sale, and there is little information about their content and safety.

What is the effect of different treatment options for benign prostatic hyperplasia (BPH) on sexual function or dysfunction? With increasing age, sexual dysfunction and BPH become more prevalent. Some treatments for BPH can affect sexual function. Different surgical treatments have different effects on sexual function depending on how much the internal involuntary sphincter is affected. The same is true for medical therapies, each class of drug having a unique affect on sexual function.