The triptans, selective serotonin 5-HT(1B/1D) agonists, are very effective acute migraine drugs with a well- developed scientific rationale. Seven different triptans will soon be clinically available, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis; this will provide a foundation for using triptans in clinical practice.

Cardiomyopathies are defined as diseases of the myocardium associated with cardiac dysfunction ranging from lifelong symptomless forms to major health problems such as progressive heart failure, arrhythmia, thromboembolism, and sudden cardiac death. They are classified by morphological characteristics as hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular (ARVC), and restrictive cardiomyopathy (RCM). A familial cause has been shown in 50% of patients with HCM, 35% with DCM, and 30% with ARVC. In HCM, nine genetic loci and more than 130 mutations in ten different sarcomeric genes and in the gamma 2 subunit of AMP-activated protein kinase (AMPK) have been identified, suggesting impaired force production associated with inefficient use of ATP as the crucial disease mechanism. In DCM, 16 chromosomal loci with defects of several proteins also involved in the development of skeletal myopathies have been detected. These mutated cytoskeletal and nuclear transporter proteins may alter force transmission or disrupt nuclear function, resulting in cell death. Further DCM mutations have also been identified in sarcomeric genes, which indicates that different defects of the same protein can result in either HCM or DCM. In ARVC, six genetic loci and mutations in the cardiac ryanodine receptor, which controls electromechanical coupling, and in plakoglobin and desmoglobin (molecules involved in desmosomal cell-junction integrity), have been identified. Yet, no genetic linkage has been shown in RCM. Apart from disease-causing mutations, other factors, such as environment, genetic background, and the recently identified modifier genes of the renin-angiotensin, adrenergic, and endothelin systems are likely to result in the wide variety of RCM clinical presentations. Treatment options are symptomatic and are mainly focused on treatment of heart failure and prevention of thromboembolism and sudden death. Identification of patients with high risk for major arrhythmic events is important because implantable cardioverter defibrillators can prevent sudden death. Clinical and genetic risk stratification may lead to prospective trials of primary implantation of cardioverter defibrillators in people with hereditary cardiomyopathy.

Pharmacological therapy has an important role in the management of insomnia. Although older drugs are highly effective for initiating and maintaining sleep, tolerance and withdrawal effects as well as impairment of daytime performance are commonly troublesome and limit their use. Aided by increased knowledge of gamma-aminobutyric acid (GABA) and its receptors, new hypnotic sedatives have been developed that are increasingly selective for the various subunits of the GABA receptor. This development has produced newer agents with very favourable hypnotic profiles and side-effect profiles that provide better treatment options for medical practitioners. The pyrazolopyrimidines, the latest in this area, seem to offer some advantages over other agents.

Unstable angina and non-ST-segment-elevation myocardial infarction have in recent years been recognised as frequent and important clinical manifestations of coronary-artery disease. The European (ESC) and American (ACC/AHA) professional societies last year released guidelines on diagnosis, risk stratification, and treatment of these disorders. These guidelines summarise similarly the current evidence and translate them to clinical practice. Most important changes relate to the inclusion of troponins into the risk stratification algorithm, the addition of low-molecular-weight heparin and glycoprotein IIb/IIIa antagonists to medical treatment, and the role of invasive management for improved long-term outcome. Guidelines are constantly challenged by newly emerging study results. Recently, early invasive management and clopidogrel have been found to exert further benefit to this high-risk group of patients. Accordingly, the societies on both sides of the Atlantic will work together closely to update and implement these guidelines.

Vasopeptidase inhibitors are a new class of cardiovascular drug that simultaneously inhibit both neutral endopeptidase and angiotensin-converting enzyme (ACE). They increase the availability of peptides that have vasodilatory and other vascular effects; they also inhibit production of angiotensin II. In animal models vasopeptidase inhibitors decrease blood pressure in low, medium, and high renin forms of hypertension, and they also appear to confer benefits in models of heart failure and ischaemic heart disease. Studies in human hypertension show that these agents are effective in decreasing blood pressure regardless of race or age. Experience with omapatrilat, the most clinically advanced of these drugs, has shown it to be more effective than currently available ACE inhibitors or other widely used antihypertensive agents. Studies with omapatrilat in congestive heart failure have shown beneficial effects on haemodynamics and symptoms. The vasopeptidase inhibitors appear to have safety profiles similar to ACE inhibitors, though the frequency of side-effects such as angio-oedema and cough remains to be established. Large trials with clinical endpoints, some already in progress, are needed to establish the place of this class of drug beside that of established therapies in conditions such as hypertension, heart failure, ischaemic heart disease, and nephropathy.

Autosomal dominant polycystic kidney disease is a common inherited disorder, which is characterised by the formation of fluid-filled cysts in both kidneys that leads to progressive renal failure. Mutations in two genes, PKD1 and PKD2, are associated with the disorder. We describe the various factors that cause variation in disease progression between patients. These include whether the patient has a germline mutation in the PKD1 or in the PKD2 gene, and the nature of the mutation. Detection of mutations in PKD1 is complicated, but the total number identified is rising and will enable genotype-to-phenotype studies. Another factor affecting disease progression is the occurrence of somatic mutations in PKD genes. Furthermore, modifying genes might directly affect the function of polycystins by affecting the rate of somatic mutations or the rate of protein interactions, or they might affect cystogenesis itself or clinical factors associated with disease progression. Finally, environmental factors that speed up or slow down progress towards chronic renal failure have been identified in rodents.

Women with a family history of breast cancer are at increased risk of the disease, but no study has been large enough to characterise reliably how, over women's lives, this risk is influenced by particular familial patterns of breast cancer. This report, on the relevance of breast cancer in first-degree relatives, is based on combined data from 52 epidemiological studies.

Exploration of the human genome presents new challenges and opportunities for epidemiological research. Although the case-control design is quicker and cheaper for study of associations between genotype and risk of disease than the cohort design, cohort studies have been recommended because they can be used to study gene-environment interactions. Although the scientific relevance of statistical interaction is pertinent, the main disadvantage of the case-control design-susceptibility to bias when estimating effects of exposures that are measured retrospectively-does not necessarily apply when studying statistical interaction between genotype and environmental exposure. Because correctly designed genetic association studies are equivalent to randomised comparisons between genotypes, conclusions about cause can be drawn from genetic associations even when the risk ratio is modest. For adequate statistical power to detect such modest risk ratios, the case-control design is more feasible than the cohort design.

Rates of caesarean sections in more-developed countries have been rising since 1970, and vary greatly between less-developed countries. Present estimates, based on data from more-developed countries need to be validated with data from less-developed countries. We estimated the need for caesarean section for maternal indication in a population of pregnant women in west Africa (MOMA survey).

Whether antihypertensive drugs offer cardiovascular protection beyond blood pressure lowering has not been established. We aimed to investigate whether pharmacological properties of antihypertensive drugs or reduction of systolic pressure accounted for cardiovascular outcome in hypertensive or high-risk patients.

At least 28 randomised, controlled trials have compared outcomes of surgery for rectal cancer combined with preoperative or postoperative radiotherapy with those of surgery alone. We have done a collaborative meta-analysis of these results to give a more balanced view of the total evidence and to increase statistical precision.

Lower extremity peripheral arterial disease (PAD) most frequently presents with pain during ambulation, which is known as "intermittent claudication". Some relief of symptoms is possible with exercise, pharmacotherapy, and cessation of smoking. The risk of limb-loss is overshadowed by the risk of mortality from coexistent coronary artery and cerebrovascular atherosclerosis. Primary therapy should be directed at treating the generalised atherosclerotic process, managing lipids, blood sugar, and blood pressure. By contrast, the risk of limb-loss becomes substantial when there is pain at rest, ischaemic ulceration, or gangrene. Interventions such as balloon angioplasty, stenting, and surgical revascularisation should be considered in these patients with so-called "critical limb ischaemia". The choice of the intervention is dependent on the anatomy of the stenotic or occlusive lesion; percutaneous interventions are appropriate when the lesion is focal and short but longer lesions must be treated with surgical revascularisation to achieve acceptable long-term outcome.

Today's society places a great emphasis on value for money, so medical interventions must not only be shown to be effective but also be proved to be costeffective. Drug treatment is no exception. In health economics, costeffectiveness is calculated differently depending on the indication and the perspective. For cholesterol-lowering drugs (as an example) there is a difference between primary and secondary intervention. In primary prevention, the cut off value for absolute risk when treatment is costeffective varies with age and sex, but in secondary prevention, although treatment is costeffective for all groups of patients, costeffectiveness varies with age, sex, cholesterol concentration, and other risk factors. There are three complementary approaches to economic assessment of secondary prevention-analysis of the whole population, subgroup analysis, and modelling.

The time has come to subject surgery to the same rigours of economic assessment that other health-care sectors are already receiving--namely, the comparative assessment of costs and benefits. The surgical management of gallstones provides a good example of the role of economics in surgery. Gallstone disease is common and patients are usually referred to a surgeon, but the threshold for intervention is not agreed and varies widely, with considerable implications for resources. Gallstone removal has been subject to much innovation over the past 10 years, yet economic assessment of laparoscopic and "mini" cholecystectomy and of gallstone lithotripsy is rare, despite the fact that operation rates have increased by up to 50% in some countries. For surgery to compete with other interventions, economic assessment of new surgical techniques will be increasingly important. This assessment should be based on well-conducted clinical trials in which interventions are provided in a routine service setting, and in which benefits are assessed among other things on the basis of the patient's perceived quality of life. Economic assessment often needs data beyond those collected in a clinical trial, however pragmatic the trial design, so modelling will often be required, incorporating a range of sources of evidence. Finally, evidence alone will not be enough to promote cost-effective practices. The take-up of surgical techniques will always be affected by the way hospitals and surgeons are remunerated. Affecting practice requires a realistic system of reimbursement that reflects evidence on cost effectiveness.

Progress in the Human Genome Project, availability of cochlea-specific cDNA libraries, and development of murine models of deafness have resulted in rapid discovery of many loci and corresponding genes for deafness. Up to now, the chromosomal locations of about 70 genes for non-syndromic deafness have been mapped, and the genes of more than 20 loci have been identified and characterised. Mutations in one gene, connexin 26 (CX26GJB2), are responsible for most cases of recessive non-syndromic deafness, accounting for 30-40% of all childhood genetic deafness in some populations (eg, white people of western European descent). We summarise advances in identification of genes for deafness and provide a guide to the clinical approach to diagnosis of patients with hearing loss.

With increasing economic and social demands, we are rapidly evolving into a 24-h society. In any urban economy, about 20% of the population are required to work outside the regular 0800-1700 h working day and this figure is likely to increase. Although the increase in shiftwork has led to greater flexibility in work schedules, the ability to provide goods and services throughout the day and night, and possibly greater employment opportunities, the negative effects of shiftwork and chronic sleep loss on health and productivity are now being appreciated. For example, sleepiness surpasses alcohol and drugs as the greatest identifiable and preventable cause of accidents in all modes of transport. Industrial accidents associated with night work are common, perhaps the most famous being Chernobyl, Three Mile Island, and Bhopal.