Multiple myeloma is a malignant disease of plasma cells that manifests as one or more of lytic bone lesions, monoclonal protein in the blood or urine, and disease in the bone marrow. Treatment for myeloma has changed beyond recognition in the past decade, and now includes state of the art supportive treatment and infusional chemotherapy courses, followed for younger patients by high-dose melphalan and an autologous transplant. Patients younger than 70 years can now expect a doubling of median survival to 5 years, a 20% chance of surviving longer than 10 years, and a 50% chance of attaining complete morphological and biochemical remission. Bisphosphonate control of bone disease is essential. Exploitation of the understanding of the biology of myeloma has led to the development of biological treatments, such as thalidomide, CC-5013, and bortezomib, which target the myeloma cell and the bone-marrow microenvironment, which plays a crucial part in the disease's pathogenesis. These treatments will hold the key to future success.

Cerebrovascular diseases are an important cause of morbidity and mortality worldwide. Endovascular treatment has emerged as a minimally invasive approach to treat cerebrovascular diseases and possibly intracranial neoplasms. Practice patterns for selection of patients for endovascular treatment are continuously being modified on the basis of new information derived from clinical studies. In this review, I discuss the various endovascular treatments for diseases such as ischaemic stroke, carotid and intracranial stenosis, intracranial aneurysms, arteriovenous malformations, malignant gliomas, and meningiomas.

Hypothyroidism is common, potentially serious, often clinically overlooked, readily diagnosed by laboratory testing, and eminently treatable. The condition is particularly prevalent in older women, in whom autoimmune thyroiditis is common. Other important causes include congenital thyroid disorders, previous thyroid surgery and irradiation, drugs such as lithium carbonate and amiodarone, and pituitary and hypothalamic disorders. Worldwide, dietary iodine deficiency remains an important cause. Hypothyroidism can present with nonspecific constitutional and neuropsychiatric complaints, or with hypercholesterolaemia, hyponatraemia, hyperprolactinaemia, or hyperhomocysteinaemia. Severe untreated hypothyroidism can lead to heart failure, psychosis, and coma. Although these manifestations are neither specific nor sensitive, the diagnosis is confirmed or excluded by measurements of serum thyrotropin and free thyroxine. Thyroxine replacement therapy is highly effective and safe, but suboptimal dosing is common in clinical practice. Patient noncompliance, drug interactions, and pregnancy can lead to inadequate treatment. Iatrogenic thyrotoxicosis can cause symptoms, and, even when mild, provoke atrial fibrillation and osteoporosis. We summarise present understanding of the history, epidemiology, pathophysiology, and clinical diagnosis and management of hypothyroidism.

Sunlight is the main environmental cause of most cutaneous melanomas. Exposure to intense bursts of ultraviolet radiation, especially in childhood, starts the transformation of benign melanocytes into a malignant phenotype. Paradoxically, outdoor workers have a decreased risk of melanoma compared with indoor workers, suggesting that chronic sunlight exposure can have a protective effect. Further, some melanomas form on sun-exposed regions; others do not. Although some melanomas arise from pre-existing melanocytic naevi (moles), many arise de novo. These observations suggest that melanoma arises from multiple pathways, with initiating and promoting factors differing for each.

By contrast with patients with asthma, those with chronic obstructive pulmonary disease (COPD) are poorly responsive to the anti-inflammatory actions of corticosteroids, and these drugs provide little clinical benefit. In both diseases, multiple inflammatory genes are activated, which results from acetylation of core histones around which DNA is wound. This acetylation opens up the chromatin structure allowing gene transcription and synthesis of inflammatory proteins to proceed. Corticosteroids recruit histone deacetylase 2 (HDAC2) to the actively transcribing gene, which reverses this process and switches off inflammatory gene transcription. We propose that in patients with COPD, HDAC2 function is impaired by cigarette smoking and oxidative stress, leading to a pronounced reduction in responsiveness to corticosteroids. Oxidative stress could generate peroxynitrite, which impairs HDAC2 activity through nitration of critical tyrosine residues. This hypothesis raises the possibility that novel therapeutic approaches might unlock this corticosteroid resistance, leading to more effective anti-inflammatory treatments for COPD and other severe inflammatory diseases.

Pericarditis is a common disorder that has multiple causes and presents in various primary-care and secondary-care settings. New diagnostic techniques have improved the sampling and analysis of pericardial fluid and allow comprehensive characterisation of cause. Despite this advance, pericarditis is most commonly idiopathic, and radiation therapy, cardiac surgery, and percutaneous procedures have become important causes. Pericarditis is frequently self-limiting, and non-steroidal anti-inflammatory agents remain the first-line treatment for uncomplicated cases. Integrated use of new imaging methods facilitates accurate detection and management of complications such as pericardial effusion or constriction. Differentiation of constrictive pericarditis from restrictive cardiomyopathy remains a clinical challenge but is facilitated by tissue doppler and colour M-mode echocardiography. Most pericardial effusions can be safely managed with an echo-guided percutaneous approach. Pericardiectomy remains the definitive treatment for constrictive pericarditis and provides symptomatic relief in most cases. In the future, the pericardial space might become a conduit for treatments directed at the pericardium and myocardium.

Although there have been suggestions that serum paraoxonase is important in protecting against coronary heart disease (CHD), a large number of studies of genetic determinants of serum paraoxonase have reported apparently conflicting results about their association with CHD.

Despite much progress in the understanding of pathogenesis and of management, diarrhoeal illnesses remain one of the most important causes of global childhood mortality and morbidity. Infections account for most illnesses, with pathogens employing ingenious mechanisms to establish disease. In the developed world, an upsurge in immune-mediated gut disorders might have resulted from a disruption of normal bacterial-epithelial cross-talk and impaired maturation of the gut's immune system. Oral rehydration therapies are the mainstay of management of gastroenteritis, and their composition continues to improve. Malnutrition remains the major adverse prognostic indicator for diarrhoea-related mortality, emphasising the importance of nutrition in early management. Drugs are of little use, except for specific indications although new agents that target mechanisms of secretory diarrhoea show promise, as do probiotics. However, preventive strategies on a global scale might ultimately hold the greatest potential to reduce the burden of diarrhoeal disease. These strategies include vaccines and, most importantly, policies to address persisting inequalities between the developed and developing worlds with respect to nutrition, sanitation, and access to safe drinking water.

Colonic diverticulosis refers to small outpouchings from the colonic lumen due to mucosal herniation through the colonic wall at sites of vascular perforation. Abnormal colonic motility and inadequate intake of dietary fibre have been implicated in its pathogenesis. This acquired abnormality is typically found in developed countries, and its prevalence rises with age. Most patients affected will remain entirely asymptomatic; however, 10-20% of those affected can manifest clinical syndromes, mainly diverticulitis and diverticular haemorrhage. As our elderly population grows, we can anticipate a concomitant rise in the number of patients with diverticular disease. Here, we review the incidence, pathophysiology, clinical presentation, and management of diverticular disease of the colon and its complications.

Identification of asymptomatic high-risk individuals is integral to current policies for preventing coronary heart disease, but existing methods of estimating risk lack sensitivity. To overcome this limitation increasing use is being made of non-invasive methods to detect subclinical coronary artery disease--eg, computed tomography (CT) to scan for coronary artery calcification. The location and extent of calcification correlate closely with pathological and angiographic abnormalities, but whether such calcification predicts clinical events, especially in younger individuals, is equivocal. Most data on coronary calcification have been obtained with electron-beam CT, but recently multislice CT, which is more versatile, less expensive, and available in most large hospitals, has been increasingly used.

Sexually transmitted infections (STIs) are notable for their fastidious requirements for transmission and growth in the laboratory and for their high physical and psychosocial morbidity. The combination of subtle or absent symptoms and stigma preventing the seeking of health care, leaves many infections undiagnosed. The development of nucleic-acid amplification tests heralded a new era in sensitive and robust diagnostic procedures for STIs. Unfortunately, many of these tests are not commercially available or are too expensive for the populations that need them most. Single-dose oral azithromycin has improved the treatment of several bacterial STIs, but quinolones are rapidly becoming ineffective for gonorrhoea. Self-treatment of genital warts with podophyllotoxin or imiquimod preparations is attractive to patients and might be cost effective for health services. The prospect of effective vaccines against genital papillomaviruses in the near future is real. Such vaccines could reduce the global incidence of some anogenital cancers. Episodic treatment of genital herpes is getting easier and cheaper, and suppressive treatment can reduce transmission to regular sexual partners. A vaccine against herpes simplex virus type 2 has shown some limited efficacy. Ultimately, better control of STIs, and reduction of their contribution to the spread of HIV, will require a broad health-sector response with adequate resourcing, and a change in social and political attitudes.

Multidrug-resistant tuberculosis (MDR-TB) presents an increasing threat to global tuberculosis control. Many crucial management issues in MDR-TB treatment remain unanswered. We reviewed the existing scientific research on MDR-TB treatment, which consists entirely of retrospective cohort studies. Although direct comparisons of these studies are impossible, some insights can be gained: MDR-TB can and should be addressed therapeutically in resource-poor settings; starting of treatment early is crucial; aggressive treatment regimens and high-end dosing are recommended given the lower potency of second-line antituberculosis drugs; and strategies to improve treatment adherence, such as directly observed therapy, should be used. Opportunities to treat MDR-TB in developing countries are now possible through the Global Fund to Fight AIDS, TB, and Malaria, and the Green Light Committee for Access to Second-line Anti-tuberculosis Drugs. As treatment of MDR-TB becomes increasingly available in resource-poor areas, where it is needed most, further clinical and operational research is urgently needed to guide clinicians in the management of this disease.

Otitis media (OM) continues to be one of the most common childhood infections and is a major cause of morbidity in children. The pathogenesis of OM is multifactorial, involving the adaptive and native immune system, Eustachian-tube dysfunction, viral and bacterial load, and genetic and environmental factors. Initial observation seems to be suitable for many children with OM, but only if appropriate follow-up can be assured. In children younger than 2 years with a certain diagnosis of acute OM, antibiotics are advised. Surgical candidacy depends on associated symptoms, the child's developmental risk, and the anticipated chance of timely spontaneous resolution of the effusion. The recommended approach for surgery is to start with tympanostomy tube placement, eventually followed by adenoidectomy. The ideal intervention for OM, however, does not yet exist, and an urgent need remains to explore new and creative options based on modern insights into the pathophysiology of OM.

This review summarises the psychiatry of the puerperium, in the light of publications during the past 5 years. A wide variety of disorders are seen. Recognition of disorders of the mother-infant relationship is important, because these have pernicious long-term effects but generally respond to treatment. Psychoses complicate about one in 1000 deliveries. The most common is related to manic depression, in which neuroleptic drugs should be used with caution. Post-traumatic stress disorder, obsessions of child harm, and a range of anxiety disorders all require specific psychological treatments. Postpartum depression necessitates thorough exploration. Cessation of breastfeeding is not necessary, because most antidepressant drugs seem not to affect the infant. Controlled trials have shown the benefit of involving the child's father in therapy and of interventions promoting interaction between mother and infant. Owing to its complexity, multidisciplinary specialist teams have an important place in postpartum psychiatry.

Many oncologists believe that patients with cancer who enroll in clinical trials have better outcomes than those who do not enroll. We aimed to assess the empirical evidence that such a trial effect exists.

Intestinal infection with Vibrio cholerae results in the loss of large volumes of watery stool, leading to severe and rapidly progressing dehydration and shock. Without adequate and appropriate rehydration therapy, severe cholera kills about half of affected individuals. Cholera toxin, a potent stimulator of adenylate cyclase, causes the intestine to secrete watery fluid rich in sodium, bicarbonate, and potassium, in volumes far exceeding the intestinal absorptive capacity. Cholera has spread from the Indian subcontinent where it is endemic to involve nearly the whole world seven times during the past 185 years. V cholerae serogroup O1, biotype El Tor, has moved from Asia to cause pandemic disease in Africa and South America during the past 35 years. A new serogroup, O139, appeared in south Asia in 1992, has become endemic there, and threatens to start the next pandemic. Research on case management of cholera led to the development of rehydration therapy for dehydrating diarrhoea in general, including the proper use of intravenous and oral rehydration solutions. Appropriate case management has reduced deaths from diarrhoeal disease by an estimated 3 million per year compared with 20 years ago. Vaccination was thought to have no role for cholera, but new oral vaccines are showing great promise.

A WHO expert consultation addressed the debate about interpretation of recommended body-mass index (BMI) cut-off points for determining overweight and obesity in Asian populations, and considered whether population-specific cut-off points for BMI are necessary. They reviewed scientific evidence that suggests that Asian populations have different associations between BMI, percentage of body fat, and health risks than do European populations. The consultation concluded that the proportion of Asian people with a high risk of type 2 diabetes and cardiovascular disease is substantial at BMIs lower than the existing WHO cut-off point for overweight (> or =25 kg/m2). However, available data do not necessarily indicate a clear BMI cut-off point for all Asians for overweight or obesity. The cut-off point for observed risk varies from 22 kg/m2 to 25 kg/m2 in different Asian populations; for high risk it varies from 26 kg/m2 to 31 kg/m2. No attempt was made, therefore, to redefine cut-off points for each population separately. The consultation also agreed that the WHO BMI cut-off points should be retained as international classifications. The consultation identified further potential public health action points (23.0, 27.5, 32.5, and 37.5 kg/m2) along the continuum of BMI, and proposed methods by which countries could make decisions about the definitions of increased risk for their population.

Large gains in the reduction of malaria mortality in the early 20th century were lost in subsequent decades. Malaria now kills 2-3 million people yearly. Implementation of malaria control technologies such as insecticide-treated bednets and chemotherapy could reduce mortality substantially, but an effective malaria vaccine is also needed. Advances in vaccine technology and immunology are being used to develop malaria subunit vaccines. Novel approaches that might yield effective vaccines for other diseases are being evaluated first in malaria. We describe progress in malaria vaccine development in the past 5 years: reasons for cautious optimism, the type of vaccine that might realistically be expected, and how the process could be hastened. Although exact predictions are not possible, if sufficient funding were mobilised, a deployable, effective malaria vaccine is a realistic medium-term to long-term goal.

Despite improvements in health care, the incidence of infective endocarditis has not decreased over the past decades. This apparent paradox is explained by a progressive evolution in risk factors; while classic predisposing conditions such as rheumatic heart disease have been all but eradicated, new risk factors for infective endocarditis have emerged. These include intravenous drug use, sclerotic valve disease in elderly patients, use of prosthetic valves, and nosocomial disease. Newly identified pathogens, which are difficult to cultivate--eg, Bartonella spp and Tropheryma whipplei--are present in selected individuals, and resistant organisms are challenging conventional antimicrobial therapy. Keeping up with these changes depends on a comprehensive approach, allying understanding of the pathogenesis of disease with the development of new drugs for infective endocarditis. Infection by staphylococci and streptococci is being dissected at the molecular level. New ideas for antimicrobial agents are being developed. These novel insights should help redefine preventive and therapeutic strategies against infective endocarditis.