Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease.

Use of metformin in polycystic ovary syndrome (PCOS) is becoming increasingly accepted and widespread, but clinical practice is ahead of the evidence. Although a wide range of benefits in metabolic, reproductive, and clinical measures have been reported from non-randomised trials with metformin, close inspection of results from the adequately controlled studies shows that the benefits are modest. Our aim in this descriptive review is not to define practice guidelines but to improve clinicians' knowledge of the available published clinical evidence, concentrating on the few randomised controlled trials. We also highlight other issues, including hirsutism, acne, pregnancy, and neonatal outcome, that require more attention before clinical recommendations for the use of metformin in PCOS can be formalised. The potentially greater benefits achievable by lifestyle changes alone are also emphasised. We hope that the review will lead to more judicious use of metformin in PCOS and a more structured approach to research.

Varicocele repair is a widely used treatment for subfertility. Our aim was to identify and combine the results from randomised controlled trials published to ascertain whether the pregnancy rates after varicocele repair are higher than those with no treatment.

An association between polycystic ovary syndrome (PCOS)and endometrial carcinoma was first suggested in 1949, 14 years after the original description of the syndrome. Since then several studies have been published that seem to support this association. The prescription of hormonal treatment to reduce the risk of this complication is supported by the Guidelines for Good Clinical Practice of the Royal College of Obstetricians and Gynaecologists, UK, the Health Information website of the National Library of Medicine, USA, and in textbooks of gynaecological oncology.

The haemophilias are inherited disorders in which one of the coagulation factors is deficient. Although deficiencies of factor VIII (haemophilia A) and factor IX (haemophilia B) are well recognised, von Willebrand's disease is much more common. Rare defects can occur in any of the coagulation factors. In the past, men with haemophilia were likely to die in their youth. With advances in diagnosis, and especially with development of safe and effective treatment, affected individuals can now look forward to a normal life expectancy. Complications of the disorder, particularly the development of antibodies that make treatment ineffective, and of treatment, such as transfusion-transmitted infections, have taken a severe toll on these patients. The future holds the realistic possibility of gene therapy. However, we must not forget that haemophilia is a worldwide disorder that requires significant economic resources not available for the majority.

The first WHO essential drugs list, published in 1977, was described as a peaceful revolution in international public health. The list helped to establish the principle that some medicines were more useful than others and that essential medicines were often inaccessible to many populations. Since then, the essential medicines list (EML) has increased in size; defining an essential medicine has moved from an experience to an evidence-based process, including criteria such as public-health relevance, efficacy, safety, and cost-effectiveness. High priced medicines such as antiretrovirals are now included. Differences exist between the WHO model EML and national EMLs since countries face varying challenges relating to costs, drug effectiveness, morbidity patterns, and rationality of prescribing. Ensuring equitable access to and rational use of essential medicines has been promoted through WHO's revised drug strategy. This approach has required an engagement by WHO on issues such as the effect of international trade agreements on access to essential medicines and research and development to ensure availability of new essential medicines.

Melioidosis, which is infection with the gram-negative bacterium Burkholderia pseudomallei, is an important cause of sepsis in east Asia and northern Australia. In northeastern Thailand, melioidosis accounts for 20% of all community-acquired septicaemias, and causes death in 40% of treated patients. B pseudomallei is an environmental saprophyte found in wet soils. It mostly infects adults with an underlying predisposing condition, mainly diabetes mellitus. Melioidosis is characterised by formation of abscesses, especially in the lungs, liver, spleen, skeletal muscle, and prostate. In a third of paediatric cases in southeast Asia, the disease presents as parotid abscess. In northern Australia, 4% of patients present with brain stem encephalitis. Ceftazidime is the treatment of choice for severe melioidosis, but response to high dose parenteral treatment is slow (median time to abatement of fever 9 days). Maintenance antibiotic treatment is with a four-drug regimen of chloramphenicol, doxycycline, and trimethoprim-sulfamethoxazole, or with amoxicillin-clavulanate in children and pregnant women. However, even with 20 weeks' antibiotic treatment, 10% of patients relapse. With improvements in health care and diagnostic microbiology in endemic areas of Asia, and increased travel, melioidosis will probably be recognised increasingly during the next decade.

Huntington's disease is a late onset neurodegenerative disorder for which the mutation is a CAG/polyglutamine (polyQ) repeat expansion in the gene encoding the huntingtin protein. The disease is one of nine inherited neurodegenerative disorders that are caused by this type of mutation, and which include dentatorubral pallidoluysian atrophy, spinal and bulbar muscular atrophy, and the spinocerebellar ataxias 1, 2, 3, 6, 7, and 17. The mutant proteins are unrelated except for the polyQ tract, and aggregated polyQ is a major component of the proteinaceous deposits that are found in patients' brains for all of these diseases.

Hypertension is a frequent, chronic, age-related disorder, which often entails debilitating cardiovascular and renal complications. Blood pressure is usually noted in combination with other cardiovascular risk factors. Diagnosis of hypertension increasingly relies on automated techniques of blood pressure measurement. The pathophysiology of essential hypertension depends on the primary or secondary inability of the kidney to excrete sodium at a normal blood pressure. The central nervous system, endocrine factors, the large arteries, and the microcirculation also have roles in the disorder. Although monogenic forms of blood pressure dysregulation exist, hypertension mostly arises as a complex quantitative trait that is affected by varying combinations of genetic and environmental factors. Non-pharmacological strategies can reduce blood pressure. Antihypertensive drug treatment diminishes the complications of hypertension. The concept that a few major genes will provide the final clue to the pathogenesis of essential hypertension is an oversimplification that contradicts the heterogeneous nature of this disorder. Further integration of genetic, molecular, clinical, and epidemiological research could disclose subsets of patients in whom specific combinations of genetic and environmental factors raise blood pressure, and might lead to more individualised treatment.

Enzyme-replacement therapy has been assessed as a treatment for patients who have mucopolysaccharidosis I (alpha-L-iduronidase deficiency). We aimed to investigate the humoral immune response to recombinant human alpha-L-iduronidase among these patients.

The clearest advantage of new generation, atypical antipsychotics is a reduced risk of extrapyramidal side-effects (EPS), compared with conventional compounds. These findings might have been biased by the use of the high-potency antipsychotic haloperidol as a comparator in most of the trials. We aimed to establish whether the new drugs induce fewer EPS than low-potency conventional antipsychotics.

Ulceration of the foot in diabetes is common and disabling and frequently leads to amputation of the leg. Mortality is high and healed ulcers often recur. The pathogenesis of foot ulceration is complex, clinical presentation variable, and management requires early expert assessment. Interventions should be directed at infection, peripheral ischaemia, and abnormal pressure loading caused by peripheral neuropathy and limited joint mobility. Despite treatment, ulcers readily become chronic wounds. Diabetic foot ulcers have been neglected in health-care research and planning, and clinical practice is based more on opinion than scientific fact. Furthermore, the pathological processes are poorly understood and poorly taught and communication between the many specialties involved is disjointed and insensitive to the needs of patients.

Primary pulmonary hypertension (PPH) is a rare disorder characterised by raised pulmonary-artery pressure in the absence of secondary causes. Precapillary pulmonary arteries are affected by medial hypertrophy, intimal fibrosis, microthrombosis, and plexiform lesions. Most individuals present with dyspnoea or evidence of right heart failure. Echocardiography is the best non-invasive test to screen for suspected pulmonary hypertension. The discovery of mutations in the coding region of the gene for bone morphogenetic protein receptor 2 in patients with familial and sporadic PPH may help not only to elucidate pathogenesis but also to direct future treatment options. The pathogenesis is not completely understood, but recent investigations have revealed many possible candidate modifier genes. Without treatment, the disorder progresses in most cases to right heart failure and death. With current therapies such as epoprostenol, progression of disease is slowed, but not halted. Many promising new therapeutic options, including prostacyclin analogues, endothelin-1-receptor antagonists, and phosphodiesterase inhibitors, improve clinical function and haemodynamic measures and may prolong survival.

Every year, millions of people travel abroad, exposing themselves to various diseases. Advice on risk avoidance and on self-medication is not always successful; sometimes travellers return home ill or become unwell soon afterwards. There are many possible causes for such illnesses, and physicians should try to establish whether the disease is specifically associated with the recent journey. The approach to assessment of the ill traveller should make use not only of signs and symptoms, but also of geography and epidemiology. Travellers with fever need immediate attention to rule out serious and potentially life-threatening conditions. Faced with a difficult diagnosis, physicians should consult with experts in tropical and travel medicine.

Hysterectomy is a common and effective treatment for menorrhagia but is associated with substantial post-operative convalescence time and morbidity. In the early 1990s endometrial resection or ablation became a well-established day-case alternative for the surgical treatment of menorrhagia. Both endometrial resection and ablation require general anaesthesia, a high level of skill in hysteroscopic surgery, and can be long procedures. More recently, various new techniques have been developed that can be done in an outpatient setting under local anaesthesia and with a low risk of complications. The effectiveness of most new second-generation ablation technologies has not been confirmed in randomised trials and it is possible that these techniques will not prove to be as effective or as safe as originally thought.

In the past decade, our understanding of the genetic basis, pathogenesis, and natural history of pancreatitis has grown strikingly. In severe acute pancreatitis, intensive medical support and non-surgical intervention for complications keeps patients alive; surgical drainage (necrosectomy) is reserved for patients with infected necrosis for whom supportive measures have failed. Enteral feeding has largely replaced the parenteral route; controversy remains with respect to use of prophylactic antibiotics. Although gene therapy for chronic pancreatitis is years away, our understanding of the roles of gene mutations in hereditary and sporadic pancreatitis offers tantalising clues about the disorder's pathogenesis. The division between acute and chronic pancreatitis has always been blurred: now, genetics of the disorder suggest a continuous range of disease rather than two separate entities. With recognition of pancreatic intraepithelial neoplasia, we see that chronic pancreatitis is a premalignant disorder in some patients. Magnetic resonance cholangiopancreatography and endoscopic ultrasound are destined to replace endoscopic retrograde cholangiopancreatography for many diagnostic indications in pancreatic disease.

More than a decade ago, a mammography screening programme for women aged 50-69 years was initiated in the Netherlands. Our aim was to assess the effect of this programme on breast-cancer mortality rates.

The four steps for giving travellers the foundation for healthy journeys are to assess their health, analyse their itineraries, select vaccines, and provide education about prevention and self-treatment of travel-related diseases. This process takes time. Since there is a risk of information overload, travellers should leave the clinic with some written advice for reinforcement. The order of these steps can be tailored to what best suits the travel clinic, but vaccinating early in the process allows monitoring for adverse reactions. Face-to-face discussion is vital for explaining the use and side-effects of medications. Those who provide a travel medicine service should be seeing many travellers and should seek specialist training. In 2003, the International Society of Travel Medicine introduced a certificate of knowledge examination in travel medicine. We cannot make travellers bullet-proof but it is possible to make them bullet-resistant. The pre-travel visit should minimise health risks specific to the journey, give travellers the capability to handle most minor medical problems, and allow them to identify when to seek local care during the trip or on return.

In both ageing men and women, there is an increasing incidence of lower urinary tract symptoms (LUTS) which are increasing. These infections have many possible causes, including smooth muscle dysfunction, neurological factors and benign prostatic hyperplasia. Up to 15% to 25% of men aged 50-65 years have LUTS of sufficient severity to interfere with their quality of life. Although benign prostatic hyperplasia is an important cause of these symptoms, and can have serious consequences, clinicians should be aware of these other causes so that the appropriate diagnosis is made before invasive treatments are started. New medical treatments, including alpha-adrenergic blocking agents and 5 alpha-reductase inhibitors mean that many men without complications such as infection, bleeding, or chronic retention, and with mild to moderate symptoms, should be managed in primary care. Combined local protocols between primary and secondary care will help to establish which men with persistent symptoms or complications need referral for a urological opinion to determine the need for further investigation and more invasive forms of management. We review the pathophysiology of the disease, and current approaches to investigation and management of this common problem.