Tuberous sclerosis is a genetic multisystem disorder characterised by widespread hamartomas in several organs, including the brain, heart, skin, eyes, kidney, lung, and liver. The affected genes are TSC1 and TSC2, encoding hamartin and tuberin respectively. The hamartin-tuberin complex inhibits the mammalian-target-of-rapamycin pathway, which controls cell growth and proliferation. Variations in the distribution, number, size, and location of lesions cause the clinical syndrome to vary, even between relatives. Most features of tuberous sclerosis become evident only in childhood after 3 years of age, limiting their usefulness for early diagnosis. Identification of patients at risk for severe manifestations is crucial. Increasing understanding of the molecular abnormalities caused by tuberous sclerosis may enable improved management of this disease.

Modern management of acute myocardial infarction is built on a clinical evidence base drawn from many studies undertaken over the past three decades. The evolution in clinical practice has substantially reduced mortality and morbidity associated with the condition. Key to this success is the effective integration of antithrombotic therapy combined with timely reperfusion, either primary percutaneous coronary intervention or fibrinolysis for ST-elevation myocardial infarction, and invasive investigation and revascularisation for non-ST-elevation myocardial infarction, underpinned by risk stratification and optimised systems of care. After the development of troponin assays for the detection of myonecrosis, the universal definition and classification of myocardial infarction now indicates the underlying pathophysiology. Additionally, an increasing appreciation of the importance of adverse events, such as bleeding, has emerged. Remaining challenges include the effective translation of this evidence to all patients with myocardial infarction, especially to those not well represented in clinical trials who remain at increased risk of adverse events, such as elderly patients and those with renal failure. On a global level, the epidemic of diabetes and obesity in the developed world and the transition from infectious diseases to cardiovascular disease in the developing world will place an increasing demand on health-care infrastructures required to deliver time-dependent and resource-intensive care. This Seminar discusses the underlying pathophysiology, evolving perspectives on diagnosis, risk stratification, and the invasive and pharmacological management of myocardial infarction.

Primary immunodeficiencies comprise many diseases caused by genetic defects primarily affecting the immune system. About 150 such diseases have been identified with more than 120 associated genetic defects. Although primary immunodeficiencies are quite rare in incidence, the prevalence can range from one in 500 to one in 500 000 in the general population, depending on the diagnostic skills and medical resources available in different countries. Common variable immunodeficiency (CVID) is the primary immunodeficiency most commonly encountered in clinical practice, and appropriate diagnosis and management of patients will have a significant effect on morbidity and mortality as well as financial aspects of health care. Advances in diagnostic laboratory methods, including B-cell subset analysis and genetic testing, coupled with new insights into the molecular basis of immune dysfunction in some patients with CVID, have enabled advances in the clinical classification of this heterogeneous disease.

The HIV/AIDS pandemic has become part of the contemporary global landscape. Few predicted its effect on mortality and morbidity or its devastating social and economic consequences, particularly in sub-Saharan Africa. Successful responses have addressed sensitive social factors surrounding HIV prevention, such as sexual behaviour, drug use, and gender equalities, countered stigma and discrimination, and mobilised affected communities; but such responses have been few and far between. Only in recent years has the international response to HIV prevention gathered momentum, mainly due to the availability of treatment with antiretroviral drugs, the recognition that the pandemic has both development and security implications, and a substantial increase in financial resources brought about by new funders and funding mechanisms. We now require an urgent and revitalised global movement for HIV prevention that supports a combination of behavioural, structural, and biomedical approaches and is based on scientifically derived evidence and the wisdom and ownership of communities.

Recognition that social, economic, political, and environmental factors directly affect HIV risk and vulnerability has stimulated interest in structural approaches to HIV prevention. Progress in the use of structural approaches has been limited for several reasons: absence of a clear definition; lack of operational guidance; and limited data on the effectiveness of structural approaches to the reduction of HIV incidence. In this paper we build on evidence and experience to address these gaps. We begin by defining structural factors and approaches. We describe the available evidence on their effectiveness and discuss methodological challenges to the assessment of these often complex efforts to reduce HIV risk and vulnerability. We identify core principles for implementing this kind of work. We also provide recommendations for ensuring the integration of structural approaches as part of combined prevention strategies.

This paper makes five key points. First is that the aggregate effect of radical and sustained behavioural changes in a sufficient number of individuals potentially at risk is needed for successful reductions in HIV transmission. Second, combination prevention is essential since HIV prevention is neither simple nor simplistic. Reductions in HIV transmission need widespread and sustained efforts, and a mix of communication channels to disseminate messages to motivate people to engage in a range of options to reduce risk. Third, prevention programmes can do better. The effect of behavioural strategies could be increased by aiming for many goals (eg, delay in onset of first intercourse, reduction in number of sexual partners, increases in condom use, etc) that are achieved by use of multilevel approaches (eg, couples, families, social and sexual networks, institutions, and entire communities) with populations both uninfected and infected with HIV. Fourth, prevention science can do better. Interventions derived from behavioural science have a role in overall HIV-prevention efforts, but they are insufficient when used by themselves to produce substantial and lasting reductions in HIV transmission between individuals or in entire communities. Fifth, we need to get the simple things right. The fundamentals of HIV prevention need to be agreed upon, funded, implemented, measured, and achieved. That, presently, is not the case.

Intensive research efforts for more than two decades have not yet resulted in an HIV vaccine of even moderate effectiveness. However, some progress has been made with other biomedical interventions, albeit on the basis of inconsistent levels of evidence. The male condom, if used correctly and consistently, has been proven in observational studies to be very effective in blocking HIV transmission during sexual intercourse; and, in three randomised trials, male circumcision was protective against HIV acquisition among men. Treatment of sexually transmitted infections, a public health intervention in its own right, has had mixed results, depending in part on the epidemic context in which the approach was assessed. Finally, oral and topical antiretroviral compounds are being assessed for their role in reduction of HIV transmission during sexual intercourse. Research on biomedical interventions poses formidable challenges. Difficulties with product adherence and the possibility of sexual disinhibition are important concerns. Biomedical interventions will need to be part of an integrative package that includes biomedical, behavioural, and structural interventions. Assessment of such multicomponent approaches with moderate effects is difficult. Issues to be considered include the nature of control groups and the effect of adherence on the true effectiveness of the intervention.

For more than 20 years, the abnormally thick mucus (mucoviscidosis) in cystic fibrosis has been widely shown to be linked to a genetic defect in the cystic fibrosis transmembrane conductance regulator Cl(-) channel. The defect is widely thought to cause mucus to become dehydrated as a result of basic defects in Cl(-) dependent fluid transport. However, this widely held explanation is inconsistent with the known physiological properties and functions of organs affected by cystic fibrosis. During the process of releasing highly condensed mucins from intracellular granules, Ca(2+) and H(+) cations must be removed to enable the mucins to expand by as much as 1000 times, forming extracellular mucus-gel networks. Over the past few years, that HCO(3)(-) transport is also defective in patients with cystic fibrosis has become apparent. I propose that HCO(3)(-) is crucial to normal mucin expansion because it forms complexes with these cations. Thus, because HCO(3)(-) secretion is defective in cystic fibrosis, mucins in organs affected by cystic fibrosis tend to remain aggregated, poorly solubilised, and less transportable. If the hypothesis is valid, pathogenesis in cystic fibrosis could be due as much to defective transport of HCO(3)(-) as to defective Cl(-) transport.

Meniere's disease is a chronic illness that affects a substantial number of patients every year worldwide. The disease is characterised by intermittent episodes of vertigo lasting from minutes to hours, with fluctuating sensorineural hearing loss, tinnitus, and aural pressure. Although there is currently no cure, more than 85% of patients with Meniere's disease are helped by either changes in lifestyle and medical treatment, or minimally invasive surgical procedures such as intratympanic steroid therapy, intratympanic gentamicin therapy, and endolymphatic sac surgery. Vestibular neurectomy has a very high rate of vertigo control and is available for patients with good hearing who have failed all other treatments. Labyrinthectomy is undertaken as a last resort and is best reserved for patients with unilateral disease and deafness.

Symptomatic acute hepatitis C occurs in only about 15% of patients who are infected with hepatitis C virus (HCV). Acute hepatitis C is most often diagnosed in the setting of post-exposure surveillance, or seroconversion in high-risk individuals (eg, health-care professionals or injecting drug users) previously known to be seronegative. Although transmission via transfusion and injecting drug use has declined in developed countries, unsafe blood products and medical practices continue to increase transmission of HCV in many developing countries. Clinically, acute hepatitis C can increase concentrations of alanine aminotransferase to ten times the upper limit of normal but almost never causes fulminant hepatic failure. Diagnosis of HCV infection in the acute phase is difficult since production of antibodies against HCV can be delayed by up to 12 weeks, and about a third of infected individuals might not have detectable antibody at the onset of symptoms. Therefore, testing for HCV RNA by PCR is the only reliable test for the diagnosis of acute infection. Symptomatic patients with jaundice have a higher likelihood of spontaneous viral clearance than do asymptomatic patients, and thus should be monitored for at least 12 weeks before initiating antiviral therapy. By contrast, asymptomatic patients have a much lower chance of spontaneous clearance, and might benefit from early antiviral therapy. Antiviral therapy for 12 weeks is generally effective in treating patients who are HCV RNA negative after 4 weeks of treatment; lengthier courses could be needed for those who relapse or fail to show early virological clearance.

This Review discusses physiological, emotional, behavioural, and cognitive aspects of psychological adjustment to chronic illness. Reviewing the reports of the past decade, we identify four innovative and promising themes that are relevant for understanding and explaining psychological adjustment. In particular, the emphasis on the reasons why people fail to achieve a healthy adjustment has shifted to the identification of factors that help patients make that adjustment. To promote psychological adjustment, patients should remain as active as is reasonably possible, acknowledge and express their emotions in a way that allows them to take control of their lives, engage in self-management, and try to focus on potential positive outcomes of their illness. Patients who can use these strategies have the best chance of successfully adjusting to the challenges posed by a chronic illness.

Polymyalgia rheumatica and giant-cell arteritis are closely related disorders that affect people of middle age and older. They frequently occur together. Both are syndromes of unknown cause, but genetic and environmental factors might have a role in their pathogenesis. The symptoms of polymyalgia rheumatica seem to be related to synovitis of proximal joints and extra-articular synovial structures. Giant-cell arteritis primarily affects the aorta and its extracranial branches. The clinical findings in giant-cell arteritis are broad, but commonly include visual loss, headache, scalp tenderness, jaw claudication, cerebrovascular accidents, aortic arch syndrome, thoracic aorta aneurysm, and dissection. Glucocorticosteroids are the cornerstone of treatment of both polymyalgia rheumatica and giant-cell arteritis. Some patients have a chronic course and might need glucocorticosteroids for several years. Adverse events of glucocorticosteroids affect more than 50% of patients. Trials of steroid-sparing drugs have yielded conflicting results. A greater understanding of the molecular mechanisms involved in the pathogenesis should provide new targets for therapy.

A third of the world's population is infected with Mycobacterium tuberculosis, and 2 million people die from tuberculosis every year even though the bacille Calmette Guérin (BCG) vaccine has been available for more than 75 years. In order to reduce the immense burden of tuberculosis, new vaccines or vaccination strategies, or both, are urgently needed. Why BCG vaccination has not reduced disease prevalence, especially in the developing world, is not yet understood. Important contributing factors might include background immunity induced by non-tuberculous environmental mycobacteria, diversity of BCG strains, and overattenuation of presently used strains. This review provides a summary of the immune responses thought to be important for protective tuberculosis immunity; various mycobacterial antigens that seem to be promising targets for vaccine-induced immunity; different vaccination approaches being developed for use in people; and the key issues involved in the selection of new vaccines for expanded phase II or III testing.

Paget's disease of bone is a common disease characterised by focal areas of increased bone turnover, affecting one or several bones throughout the skeleton. Paget's disease is often asymptomatic but can be associated with bone pain and other complications such as osteoarthritis, pathological fracture, bone deformity, deafness, and nerve compression syndromes. Genetic factors have an important role in this disease, and mutations have been identified in four genes that cause Paget's disease and related syndromes. The most important of these is Sequestosome 1 (SQSTM1), which is a scaffold protein in the nuclear factor kappaB (NFkappaB) signalling pathway. Patients with SQSTM1 mutations have severe Paget's disease of bone and a high degree of penetrance with increasing age. Environmental factors also contribute. Most research has focused on paramyxovirus infection as a possible trigger, but evidence for this notion is conflicting. Other potential triggers include deficiency of dietary calcium and repetitive mechanical loading of the skeleton. Medical management of Paget's disease of bone is based on giving inhibitors of osteoclastic bone resorption, and bisphosphonates are the treatment of first choice. Bisphosphonate therapy is primarily indicated for patients who have bone pain arising from increased metabolic activity in affected bones. Bisphosphonate therapy is highly effective at reducing bone turnover, and it has been shown to heal radiological lesions and restore normal histology; however, the long-term effects of bisphosphonates on disease progression have not been adequately studied. No firm evidence as yet exists to show that bisphosphonates can prevent the development of complications of Paget's disease of bone, and further work is needed to address the effects of treatment on long-term clinical outcome.

Rwanda is making substantial progress towards improvement of health and is working towards achievement of the Millennium Development Goals, which is a challenging task because the country has had genocide in 1994, has few natural resources, is landlocked, and has high population growth. Like many impoverished sub-Saharan countries, Rwanda's health system has had an uncoordinated plethora of donors, shortage of health staff, inequity of access, and poor quality of care in health facilities. This report describes three health system developments introduced by the Rwandan government that are improving these barriers to care-ie, the coordination of donors and external aid with government policy, and monitoring the effectiveness of aid; a country-wide independent community health insurance scheme; and the introduction of a performance-based pay initiative. If these innovations are successful, they might be of interest to other sub-Saharan countries. However, Rwanda still does not have sufficient financial resources for health and will need additional external aid for some time to attain the Millennium Development Goals.

In the past few years, antagonists of tumour necrosis factor have resulted in unforetold therapeutic benefits in Crohn's disease, but the magnitude and duration of responses are variable. New agents are therefore needed. Their development has benefited from advances in the understanding of the pathophysiology of this disease. Uncontrolled activation of the acquired immune system has an important role, and lymphocytes, cytokines, and adhesion molecules are broadly targeted for therapeutic intervention. With increasing evidence of an implication of the innate immune system and the intestinal epithelium, the therapeutic paradigm is also shifting from mere immunosuppression to the reinforcement of the intestinal barrier. We review mechanisms of actions of new drugs and the efficacy and adverse events from data from clinical trials. We discuss future directions, including new strategies with optimum endpoints.

We summarise advances in the epidemiology, presentation, pathogenesis, diagnosis, and management of acute aortic dissection. Improved understanding of this problem has been assisted not only by establishment of an international registry but also by progress in molecular biology and genetics of connective-tissue diseases. Advances in endovascular products and techniques have provided new treatment options. Open surgical repair remains the main treatment for dissection in the ascending aorta, whereas endovascular treatment is increasingly being used in dissection that is limited to other parts of the aorta.

Juvenile dermatomyositis, the most common inflammatory myopathy of childhood, is a rare systemic autoimmune vasculopathy that is characterised by weakness in proximal muscles and pathognomonic skin rashes. The length of time before the initiation of treatment affects presenting symptoms, laboratory measures, and pathophysiology. It also affects disease outcomes, including the development of pathological calcifications, which are associated with increased morbidity. Both genetic and environmental risk factors seem to have a role in the cause of juvenile dermatomyositis; HLA B8-DRB1*0301 ancestral haplotype is a strong immunogenetic risk factor, and antecedent infections and birth seasonality suggest that environmental stimuli might increase risk. Activation of dendritic cells with upregulation of genes induced by type-1 interferon (alpha) in muscle and peripheral blood seems to be central to disease pathogenesis. Treatment often includes combinations of corticosteroids, methotrexate, and other immunosuppressive agents. Disease outcome, if treatment is initiated early, is generally good. Randomised controlled trials are needed to define the most effective treatments.