Alpha1-antitrypsin deficiency is a genetic disorder that affects about one in 2000-5000 individuals. It is clinically characterised by liver disease and early-onset emphysema. Although alpha1 antitrypsin is mainly produced in the liver, its main function is to protect the lung against proteolytic damage from neutrophil elastase. The most frequent mutation that causes severe alpha1-antitrypsin deficiency arises in the SERPINA 1 gene and gives rise to the Z allele. This mutation reduces concentrations in serum of alpha1 antitrypsin by retaining polymerised molecules within hepatocytes: an amount below the serum protective threshold of 11 micromol/L increases risk for emphysema. In addition to the usual treatments for emphysema, infusion of purified alpha1 antitrypsin from pooled human plasma represents a specific treatment and raises the concentrations in serum and epithelial-lining fluid above the protective threshold. Evidence suggests that this approach is safe, slows the decline of lung function, could reduce infection rates, and might enhance survival. However, uncertainty about the cost-effectiveness of this expensive treatment remains.

Use of illicit drugs in clubs and large dance parties (so-called raves) is a burgeoning cultural trend. Such recreational drug use is associated with several medical complications, both acute and longlasting. Although few, if any, of the drugs currently used in recreational venues are truly new, their patterns and context of use have changed (a great deal in some instances). For some of these substances, this cultural repackaging of the drug experience has resulted in various medical disorders that have previously gone undocumented. This review aims to help treating physicians recognise and manage complications associated with the use of new drugs in clubs, including methylenedioxymethamfetamine, ephedrine, gamma-hydroxybutyrate; gamma-butyrolactone, 1,4-butanediol, flunitrazepam, ketamine, and nitrites. We also alert researchers to specific toxic effects of club-drugs on which more basic information is needed.

Congenital adrenal hyperplasia (CAH) due to deficiency of 21-hydroxylase is a disorder of the adrenal cortex characterised by cortisol deficiency, with or without aldosterone deficiency, and androgen excess. Patients with the most severe form also have abnormalities of the adrenal medulla and epinephrine deficiency. The severe classic form occurs in one in 15,000 births worldwide, and the mild non-classic form is a common cause of hyperandrogenism. Neonatal screening for CAH and gene-specific prenatal diagnosis are now possible. Standard hormone replacement fails to achieve normal growth and development for many children with CAH, and adults can experience iatrogenic Cushing's syndrome, hyperandrogenism, infertility, or the development of the metabolic syndrome. This Seminar reviews the epidemiology, genetics, pathophysiology, diagnosis, and management of CAH, and provides an overview of clinical challenges and future therapies.

Antiviral prophylaxis is commonly used in recipients of solid-organ transplants with the aim of preventing the clinical syndrome associated with cytomegalovirus infection. We undertook a systematic review to investigate whether this approach affects risks of cytomegalovirus disease and death.

Incidence of nasopharyngeal carcinoma has remained high in endemic regions. Diagnosing the disease in the early stages requires a high index of clinical acumen and, although most cross-sectional imaging investigations show the tumour with precision, confirmation is dependent on histology. Epstein-Barr virus (EBV)-encoded RNA signal is present in all nasopharyngeal carcinoma cells, and early diagnosis of the disease is possible through the detection of raised antibodies against EBV. The quantity of EBV DNA detected in blood indicates the stage and prognosis of the disease. Radiotherapy with concomitant chemotherapy has increased survival, and improved techniques (such as intensity-modulated radiotherapy), early detection of recurrence, and application of appropriate surgical salvage procedures have contributed to improved therapeutic results. Screening of high-risk individuals in endemic regions together with developments in gene therapy and immunotherapy might further improve outcome.

Valid information about cause-specific child mortality and morbidity is an essential foundation for national and international health policy. We undertook a systematic review to investigate the geographical dispersion of and time trends in publication for policy-relevant information about children's health and to assess associations between the availability of reliable data and poverty.

Control of pain and symptoms and terminal care are necessary for quality HIV and cancer care in sub-Saharan Africa. However, what constitutes feasible, accessible, and effective palliative care, and how to develop such services, remains to be resolved. Africa-specific palliative care includes components that carry resource implications. Home and community-based care has been largely successful, but community capacity and the resources and clinical supervision necessary to sustain quality care are lacking. Coverage and referrals must be primary concerns. Simple lay and professional protocols have been developed, but opioid availability remains a major constraint. Areas of good practice, and areas where further success may be achieved include: attention to community needs and capacity; explicit frameworks for service development and palliative-care integration throughout the disease course (including antiretroviral provision); further education and protocols; strengthening and dissemination of diverse referral and care systems; increasing advocacy; and funding and technical skills to build audit and quality assessment.

In elderly people, depression mainly affects those with chronic medical illnesses and cognitive impairment, causes suffering, family disruption, and disability, worsens the outcomes of many medical illnesses, and increases mortality. Ageing-related and disease-related processes, including arteriosclerosis and inflammatory, endocrine, and immune changes compromise the integrity of frontostriatal pathways, the amygdala, and the hippocampus, and increase vulnerability to depression. Heredity factors might also play a part. Psychosocial adversity-economic impoverishment, disability, isolation, relocation, caregiving, and bereavement-contributes to physiological changes, further increasing susceptibility to depression or triggering depression in already vulnerable elderly individuals. Treatment with antidepressants is well tolerated by elderly people and is, overall, as effective as in young adults. Evidence-based guidelines for prevention of new episodes of depression are available as are care-delivery systems that increase the likelihood of diagnosis, and improve the treatment of, late-life depression. However, in North America at least, public insurance covers these services inadequately.

Erythropoietin (EPO), which is used clinically as recombinant human EPO (rHuEPO) for anaemia associated with end-stage renal failure and cancer chemotherapy, also has pleiotropic properties. Although EPO and its receptor are primary mediators of the normal physiological response to hypoxia, rHuEPO can provide impressive protection against acute ischaemic injury in several organs and tissues. The longer-acting hyperglycosylated derivative of EPO, darbepoetin-alpha, is also used for anaemia and has pleiotropic properties. However, the ability of EPO or its analogues to act directly to reduce the severity of renal injury associated with chronic renal failure is not known.

Although heart failure is common, disabling, and deadly, there are now many effective treatments, at least for patients with low left-ventricular ejection fraction. For all, angiotensin-converting-enzyme inhibitors and beta blockers are the essential disease-modifying treatments, improving symptoms, reducing hospital admissions, and increasing survival. Implantable cardioverter defibrillators also improve survival. For patients with persistent symptoms, angiotensin-receptor blockers and aldosterone antagonists have additional benefits. These treatments are now preferred to digoxin, although this drug can still be useful at an earlier stage in patients with atrial fibrillation. In some patients with persistently severe symptoms and a wide QRS on the electrocardiogram, cardiac resynchronisation therapy also reduces mortality and morbidity. The role of other markers of ventricular dys-synchrony is under investigation. There is growing evidence that left-ventricular assist devices are indicated in some patients with end-stage heart failure. Organised delivery of care also improves outcome. However, there is still no firmly evidence-based treatment for heart failure with preserved ejection fraction. Many new pharmacological, device, and surgical treatments for heart failure are currently under evaluation in clinical trials, and other approaches, including stem-cell treatment, are at an earlier stage of investigation.

Assisted reproductive technologies (ARTs) aim to increase a woman's chances of becoming pregnant by bringing many female and male gametes into close proximity. Techniques to achieve this objective include ovarian hyperstimulation by maturation of several oocytes, intrauterine insemination (IUI) of concentrated sperm, or in-vitro fertilisation (IVF) by bringing gametes together outside the female body. The very nature of ovarian hyperstimulation--with or without IUI--enhances the risk of multiple pregnancy (eg, two or more babies). In most IVF cycles, more than one embryo is transferred, again resulting in an increased chance of multiple pregnancy. Developed societies have witnessed a large rise in prevalence of twin, triplet, and higher order multiple births, mainly resulting from ARTs. The primary aim of this Review is to increase awareness of the many implications of the present iatrogenic epidemic of multiple births. The background of ovarian hyperstimulation, trends supporting current practice, and strategies to reduce the chance of multiple pregnancy are highlighted.

The term glomerulonephritis encompasses a range of immune-mediated disorders that cause inflammation within the glomerulus and other compartments of the kidney. Studies with animal models have shown the crucial interaction between bone-marrow-derived inflammatory cells and cells intrinsic to the kidney that is both fundamental and unique to the pathogenesis of glomerulonephritis. The mechanisms of interaction between these cells and the mediators of their coordinated response to inflammation are being elucidated. Despite these pathophysiological advances, treatments for glomerulonephritis remain non-specific, hazardous, and only partly successful. Glomerulonephritis therefore remains a common cause of end-stage kidney failure worldwide. Molecule-specific approaches offer hope for more effective and safer treatments in the future.

Breast cancer remains a public-health issue on a global scale. We report new information about the disease from the past 5 years. Early age at first birth, increasing parity, and tamoxifen use are related to long-term lifetime reduction in breast-cancer risk. Ductal carcinomas in situ has been suggested to be renamed ductal intraepithelial neoplasia to emphasise its non-life-threatening nature. An alternative approach, the progenitor/stem cell theory, predicts that only some tumour cells cause cancer progression and that these should be targeted by treatment. Mammography and ultrasonography are still the most effective for women with non-dense and dense breast tissues, respectively. Additionally, MRI, lymphatic mapping, the nipple-sparing mastectomy, partial breast irradiation, neoadjuvant systemic therapy, and adjuvant treatments are promising for subgroups of breast-cancer patients. Although tamoxifen can be offered for endocrine-responsive disease, aromatase inhibitors are increasingly used. Assessment of potential molecular targets is now important in primary diagnosis. Tyrosine-kinase inhibitors and other drugs with anti-angiogenesis properties are currently undergoing preclinical investigations.

Aplastic anaemia is a rare haemopoietic stem-cell disorder that results in pancytopenia and hypocellular bone marrow. Although most cases are acquired, there are unusual inherited forms. The pathophysiology of acquired aplastic anaemia is immune mediated in most cases; autoreactive lymphocytes mediate the destruction of haemopoietic stem cells. Environmental exposures, such as to drugs, viruses, and toxins, are thought to trigger the aberrant immune response in some patients, but most cases are classified as idiopathic. Similarly to other autoimmune diseases, aplastic anaemia has a varied clinical course; some patients have mild symptoms that necessitate little or no therapy, whereas others present with life-threatening pancytopenia representing a medical emergency. Paroxysmal nocturnal haemoglobinuria and myelodysplastic syndrome commonly arise in patients with aplastic anaemia, showing a pathophysiological link between these disorders. Acquired aplastic anaemia can be effectively treated by allogeneic bone-marrow transplantation, immunosuppression (generally antithymocyte globulin and ciclosporin), and high-dose cyclophosphamide.

Abdominal aortic aneurysms cause 1.3% of all deaths among men aged 65-85 years in developed countries. These aneurysms are typically asymptomatic until the catastrophic event of rupture. Repair of large or symptomatic aneurysms by open surgery or endovascular repair is recommended, whereas repair of small abdominal aortic aneurysms does not provide a significant benefit. Abdominal aortic aneurysm is linked to the degradation of the elastic media of the atheromatous aorta. An inflammatory cell infiltrate, neovascularisation, and production and activation of various proteases and cytokines contribute to the development of this disorder, although the underlying mechanisms are unknown. In this Seminar, we aim to provide an updated review of the pathophysiology, current and new diagnostic procedures, assessment, and treatment of abdominal aortic aneurysm to provide family practitioners with a working knowledge of this disorder.

Schistosomiasis is one of the world's most prevalent infections, yet its effect on the global burden of disease is controversial. Published disability-adjusted life-year (DALY) estimates suggest that the average effect of schistosome infection is quite small, although this is disputed. To develop an evidenced-based reassessment of schistosomiasis-related disability, we did a systematic review of data on disability-associated outcomes for all forms of schistosomiasis.

Malaria is the most important parasitic infection in people, accounting for more than 1 million deaths a year. Malaria has become a priority for the international health community and is now the focus of several new initiatives. Prevention and treatment of malaria could be greatly improved with existing methods if increased financial and labour resources were available. However, new approaches for prevention and treatment are needed. Several new drugs are under development, which are likely to be used in combinations to slow the spread of resistance, but the high cost of treatments would make sustainability difficult. Insecticide-treated bed-nets provide a simple but effective means of preventing malaria, especially with the development of longlasting nets in which insecticide is incorporated into the net fibres. One malaria vaccine, RTS,S/AS02, has shown promise in endemic areas and will shortly enter further trials. Other vaccines are being studied in clinical trials, but it will probably be at least 10 years before a malaria vaccine is ready for widespread use.

The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. The disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated. A proinflammatory state probably contributes to the syndrome. The increased risk for type 2 diabetes and cardiovascular disease demands therapeutic attention for those at high risk. The fundamental approach is weight reduction and increased physical activity; however, drug treatment could be appropriate for diabetes and cardiovascular disease risk reduction.

Type 2 diabetes mellitus has become an epidemic, and virtually no physician is without patients who have the disease. Whereas insulin insensitivity is an early phenomenon partly related to obesity, pancreas beta-cell function declines gradually over time already before the onset of clinical hyperglycaemia. Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for beta-cell dysfunction. Moreover, the disease has a strong genetic component, but only a handful of genes have been identified so far: genes for calpain 10, potassium inward-rectifier 6.2, peroxisome proliferator-activated receptor gamma, insulin receptor substrate-1, and others. Management includes not only diet and exercise, but also combinations of anti-hyperglycaemic drug treatment with lipid-lowering, antihypertensive, and anti platelet therapy.

About 13 million people are classified as refugees worldwide, and many more former refugees have been granted citizenship in their new countries. However, the prevalence of post-traumatic stress disorder, major depression, or psychotic illnesses in these individuals is not known. We did a systematic review of surveys about these disorders in general refugee populations in western countries.