Linkage analysis is used to map genetic loci by use of observations of related individuals. We provide an introduction to methods commonly used to map loci that predispose to disease. Linkage analysis methods can be applied to both major gene disorders (parametric linkage) and complex diseases (model-free or non-parametric linkage). Evidence for linkage is most commonly expressed as a logarithm of the odds score. We provide a framework for interpretation of these scores and discuss the role of simulation in assessment of statistical significance and estimation of power. Genetic and phenotypic heterogeneity can also affect the success of a study, and several methods exist to address such problems.

In low and middle income countries, health workers are essential for the delivery of health interventions. However, inadequate health-worker performance is a very widespread problem. We present an overview of issues and evidence about the determinants of performance and strategies for improving it. Health-worker practices are complex behaviours that have many potential influences. Reviews of intervention studies in low and middle income countries suggest that the simple dissemination of written guidelines is often ineffective, that supervision and audit with feedback is generally effective, and that multifaceted interventions might be more effective than single interventions. Few interventions have been evaluated with rigorous cost-effectiveness trials, and such studies are urgently needed to guide policy. We propose an international collaborative research agenda to generate knowledge about the true determinants of performance and about the effectiveness of strategies to improve performance. Furthermore, we recommend that ministries of health and international organisations should actively help translate research findings into action to improve health-worker performance, and thereby improve health.

Invasive mycoses pose a major diagnostic and therapeutic challenge. Advances in antifungal agents and diagnostic methods offer the potential for improved outcomes in patients with these infections, which are often lethal. Many fungal pathogens occur almost exclusively in opportunistic settings--in the immunocompromised host--and these infections are the focus of this review. Several areas of ongoing challenge remain, including the emergence of resistant organisms and the absence of reliable markers for early identification of patients at risk of developing invasive fungal disease. This Seminar reviews the changing epidemiology of invasive mycoses, new diagnostic methods, and recent therapeutic options and current management strategies for these opportunistic pathogens.

This article is the first in a series of seven that will provide an overview of central concepts and topical issues in modern genetic epidemiology. In this article, we provide an overall framework for investigating the role of familial factors, especially genetic determinants, in the causation of complex diseases such as diabetes. The discrete steps of the framework to be outlined integrate the biological science underlying modern genetics and the population science underpinning mainstream epidemiology. In keeping with the broad readership of The Lancet and the diverse background of today's genetic epidemiologists, we provide introductory sections to equip readers with basic concepts and vocabulary. We anticipate that, depending on their professional background and specialist knowledge, some readers will wish to skip some of this article.

Depressive disorders during youth occur frequently, are chronic and recurrent, and are associated with significant functional impairment, morbidity, and mortality. Two psychotherapeutic approaches-cognitive behavioural therapy and interpersonal therapy-are each better than wait-list or treatment-as-usual approaches. Several antidepressants have proven efficacious compared with placebo; however, more than half the studies comparing antidepressant treatment with placebo in children and adolescents with depression have not shown any benefit of the active compounds. Suicide rates are decreasing overall in adolescents, and there seems to be a correlation between the use of selective serotonin reuptake inhibitors (SSRIs) and a decrease in completed suicide. However, there was a signal for increase in suicide attempts and suicidal ideation in patients on acute antidepressant treatment when all antidepressants were assessed as a single group. Thus, there is substantial debate about the best approach to treat this serious disorder. Here, we discuss the treatment options for depression in children and adolescents.

Cluster headache is a stereotyped primary pain syndrome characterised by strictly unilateral severe pain, localised in or around the eye and accompanied by ipsilateral autonomic features. The syndrome is characterised by the circadian rhythmicity of the short-lived attacks, and the regular recurrence of headache bouts, which are interspersed by periods of complete remission in most individuals. Headaches often start about 1-2 h after falling asleep or in the early morning, and show seasonal variation, suggesting that the hypothalamus has a role in the illness. Consequently, the vascular theory has been superseded by recognition that neurovascular factors are more important. The increased familial risk suggests that cluster headache has a genetic component in some families. Neuroimaging has broadened our pathophysiological view and has led to successful treatment by deep brain stimulation of the hypothalamus. Although most patients can be treated effectively, some do not respond to therapy. Fortunately, time to diagnosis of cluster headache has improved. This is probably the result of a better understanding of the pathophysiology in combination with efficient treatment strategies, leading to a broader acceptance of the syndrome by doctors.

DDT (bis[4-chlorophenyl]-1,1,1-trichloroethane) is a persistent insecticide that was used worldwide from the mid 1940s until its ban in the USA and other countries in the 1970s. When a global ban on DDT was proposed in 2001, several countries in sub-Saharan Africa claimed that DDT was still needed as a cheap and effective means for vector control. Although DDT is generally not toxic to human beings and was banned mainly for ecological reasons, subsequent research has shown that exposure to DDT at amounts that would be needed in malaria control might cause preterm birth and early weaning, abrogating the benefit of reducing infant mortality from malaria. Historically, DDT has had mixed success in Africa; only the countries that are able to find and devote substantial resources towards malaria control have made major advances. DDT might be useful in controlling malaria, but the evidence of its adverse effects on human health needs appropriate research on whether it achieves a favourable balance of risk versus benefit.

Phaeochromocytomas are rare neuroendocrine tumours with a highly variable clinical presentation but most commonly presenting with episodes of headaches, sweating, palpitations, and hypertension. The serious and potentially lethal cardiovascular complications of these tumours are due to the potent effects of secreted catecholamines. Biochemical testing for phaeochromocytoma is indicated not only in symptomatic patients, but also in patients with adrenal incidentalomas or identified genetic predispositions (eg, multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and mutations of the succinate dehydrogenase genes). Imaging techniques such as CT or MRI and functional ligands such as (123)I-MIBG are used to localise biochemically proven tumours. After the use of appropriate preoperative treatment to block the effects of secreted catecholamines, laparoscopic tumour removal is the preferred procedure. If removal of phaeochromocytoma is timely, prognosis is excellent. However, prognosis is poor in patients with metastases, which especially occur in patients with large, extra-adrenal tumours.

Stem cells derived from adult and embryonic sources have great therapeutic potential, but much research is still needed before their clinical use becomes commonplace. There is debate about whether adult stem cells can be used instead of those derived from embryos. Rationalisation is needed but can be exercised only once the various cells have been carefully compared and contrasted under appropriate experimental conditions. Some characteristics that might help resolve the issue of cell source can already be applied to the debate. Accessibility is important; some adult cells, such as neural stem cells, are difficult to obtain, at least from living donors. Other factors include the frequency and abundance of adult stem cells and their numbers and potency, which might decline with age or be affected by disease. For embryonic stem cells, ethical concerns have been raised, and the proposed practice of therapeutic cloning tends to be misrepresented in the lay media. For both adult and embryonic stem cells, stability, potential to transmit harmful pathogens or genetic mutations, and risk of forming unwanted tissues or even teratocarcinomas have yet to be fully assessed.

Ectopic pregnancy is an important cause of morbidity and mortality worldwide. Use of transvaginal ultrasonography and quantitative measurement of the beta subunit of human chorionic gonadotropin (beta-hCG) has led to a reduction in the need for diagnostic laparoscopy. Furthermore, with earlier diagnosis, medical therapy with methotrexate can be offered and surgery avoided in some women, though the best regimen remains unclear. In the surgical management of ectopic pregnancy, the benefits of salpingectomy over salpingostomy are uncertain. Although there have been advances in the management of ectopic pregnancy there are still questions to be answered.

Each year, endometrial cancer develops in about 142,000 women worldwide, and an estimated 42,000 women die from this cancer. The typical age-incidence curve for endometrial cancer shows that most cases are diagnosed after the menopause, with the highest incidence around the seventh decade of life. The appearance of symptoms early in the course explains why most women with endometrial cancer have early-stage disease at presentation. For all stages taken together, the overall 5-year survival is around 80%. There is a substantial prognostic difference between the histological types of endometrial cancers. The most common lesions (type 1) are typically hormone sensitive and low stage and have an excellent prognosis, whereas tumours of type 2 are high grade with a tendency to recur, even in early stage. The cornerstone of treatment for endometrial cancer is surgery, which not only is important for staging purposes but also enables appropriate tailoring of adjuvant treatment modalities that benefit high-risk patients only. We review current concepts about epidemiology, pathology, pathogenesis, risk factors and prevention, diagnosis, staging, prognostic factors, treatment, and follow-up of endometrial cancer.

During the past few years, many women and doctors have revised their opinions of hormone replacement therapy (HRT) for menopausal symptoms, and a substantial number of individuals have discontinued its use because of concerns about side-effects. Numerous alternatives to HRT are promoted, and assessment of the quality of evidence about the safety and effectiveness of these compounds can be difficult. In this Review, we summarise the data from studies addressing the efficacy, risks, and benefits of frequently prescribed treatments, and offer evidence-based clinical guidelines for the management of menopausal symptoms. Although few comparative studies exist, oestrogen alone or combinations of oestrogen and progestagen are likely to be the most effective treatments for menopausal hot flushes and vaginal dryness. Tibolone is as effective as HRT, however, and might also improve libido. For those who wish to avoid hormonal treatments, there are few effective options. Selective serotonin reuptake inhibitors might be effective in the very short term (less than 12 weeks) and are well tolerated. There is not enough evidence that any of the complementary therapies available are any better than placebo for menopausal vasomotor symptoms, and few safety data exist.

Malignant mesothelioma is an aggressive, treatment-resistant tumour, which is increasing in frequency throughout the world. Although the main risk factor is asbestos exposure, a virus, simian virus 40 (SV40), could have a role. Mesothelioma has an unusual molecular pathology with loss of tumour suppressor genes being the predominant pattern of lesions, especially the P16INK4A, and P14ARF, and NF2 genes, rather than the more common p53 and Rb tumour suppressor genes. Cytopathology of mesothelioma effusions or fine-needle aspirations are often sufficient to establish a diagnosis, but histopathology is also often required. Patients typically present with breathlessness and chest pain with pleural effusions. Median survival is now 12 months from diagnosis. Palliative chemotherapy is beneficial for mesothelioma patients with high performance status. The role of aggressive surgery remains controversial and growth factor receptor blockade is still unproven. Gene therapy and immunotherapy are used on an experimental basis only. Patterns identified from microarray studies could be useful for diagnosis as well as prognostication.

Sjögren's syndrome is a chronic autoimmune disorder of the exocrine glands with associated lymphocytic infiltrates of the affected glands. Dryness of the mouth and eyes results from involvement of the salivary and lacrimal glands. The accessibility of these glands to biopsy enables study of the molecular biology of a tissue-specific autoimmune process. The exocrinopathy can be encountered alone (primary Sjögren's syndrome) or in the presence of another autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, or progressive systemic sclerosis. A new international consensus for diagnosis requires objective signs and symptoms of dryness including a characteristic appearance of a biopsy sample from a minor salivary gland or autoantibody such as anti-SS-A. Exclusions to the diagnosis include infections with HIV, human T-lymphotropic virus type I, or hepatitis C virus. Therapy includes topical agents to improve moisture and decrease inflammation. Systemic therapy includes steroidal and non-steroidal anti-inflammatory agents, disease-modifying agents, and cytotoxic agents to address the extraglandular manifestations involving skin, lung, heart, kidneys, and nervous system (peripheral and central) and haematological and lymphoproliferative disorders. The most difficult challenge in diagnosis and therapy is patients with symptoms of fibromyalgia (arthralgia, myalgia, fatigue) and oral and ocular dryness in the presence of circulating antinuclear antibodies.

Elucidation of the biology of stem cells of the lung parenchyma could revolutionise treatment of patients with lung disorders such as cancer, acute respiratory distress syndrome, emphysema, and fibrotic lung disease. How close is this goal? Despite remarkable observations and ensuing advances, more questions than answers have been generated. Progenitors of the alveolar epithelium remain largely mysterious, so the prospect of isolating enough of these cells and delivering them effectively to cure disease remains remote. Similarly, the bone-marrow-derived cell that might most effectively engraft the lung remains unknown. If this mechanism is an important process for lung repair, why will the administration of additional cells be more effective? Finally, there is an issue of control of multipotent cells to avoid the generation of multiple teratomas, longevity of the graft, and possible immunological reactions to gene products inserted to replace a deficiency. The biology is exciting but not yet well enough understood to support therapeutic advances.

Attention-deficit hyperactivity disorder (ADHD) is a disorder of inattention, impulsivity, and hyperactivity that affects 8-12% of children worldwide. Although the rate of ADHD falls with age, at least half of children with the disorder will have impairing symptoms in adulthood. Twin, adoption, and molecular genetic studies show ADHD to be highly heritable, and other findings have recorded obstetric complications and psychosocial adversity as predisposing risk factors. Converging evidence from animal and human studies implicates the dysregulation of frontal-subcortical-cerebellar catecholaminergic circuits in the pathophysiology of ADHD, and molecular imaging studies suggest that abnormalities of the dopamine transporter lead to impaired neurotransmission. Studies during the past decade have shown the safety and effectiveness of new non-stimulant drugs and long-acting formulations of methylphenidate and amfetamine. Other investigations have also clarified the appropriate role of targeted psychosocial treatments in the context of ongoing pharmacotherapy.

Acute rheumatic fever (ARF) and its chronic sequela, rheumatic heart disease (RHD), have become rare in most affluent populations, but remain unchecked in developing countries and in some poor, mainly indigenous populations in wealthy countries. More than a century of research, mainly in North America and Europe, has improved our understanding of ARF and RHD. However, whether traditional views need to be updated in view of the epidemiological shift of the past 50 years is still to be established, and improved data from developing countries are needed. Doctors who work in populations with a high incidence of ARF are adapting existing diagnostic guidelines to increase their sensitivity. Group A streptococcal vaccines are still years away from being available and, even if the obstacles of serotype coverage and safety can be overcome, their cost could make them inaccessible to the populations that need them most. New approaches to primary prevention are needed given the limitations of primary prophylaxis as a population-based strategy. The most effective approach for control of ARF and RHD is secondary prophylaxis, which is best delivered as part of a coordinated control programme.

Leptin is an adipocyte-secreted hormone that plays a key part in energy homoeostasis. Advances in leptin physiology have established that the main role of this hormone is to signal energy availability in energy-deficient states. Studies in animals and human beings have shown that low concentrations of leptin are fully or partly responsible for starvation-induced changes in neuroendocrine axes, including low reproductive, thyroid, and insulin-like growth factor (IGF) hormones. Disease states such as exercise-induced hypothalamic amenorrhoea and anorexia nervosa are also associated with low concentrations of leptin and a similar spectrum of neuroendocrine abnormalities. We have recently shown in an interventional, proof-of-concept study that leptin can restore ovulatory menstrual cycles and improve reproductive, thyroid, and IGF hormones and bone markers in hypothalamic amenorrhoea. Further studies are warranted to establish the safety and effectiveness of leptin for the infertility and osteoporosis associated with hypothalamic amenorrhoea, and to clarify its role in anorexia nervosa.

Pemphigus is a rare autoimmune disease that results in blistering of the skin and oral cavity. It is caused by autoantibodies directed against cell-surface antigens on keratinocytes, which when targeted lose their cellular adhesion properties and separate from one another to form blisters within the epidermis. Differences in the particular antigens targeted by the antibodies and in the distribution of these antigens in the different regions of the body and in the separate layers of the epidermis result in different clinical manifestations of the disease. The disease is diagnosed based on its clinical manifestations (flaccid blisters and erosions on skin and oral mucosa), histology (epidermal acantholysis), and immunological abnormalities (circulating and tissue-fixed antibodies against keratinocyte surface antigens). Pemphigus, which if left untreated is almost always fatal, is generally managed with topical, oral, or intralesional corticosteroids. Other options include plasmapheresis and intravenous immunoglobulin (IVIg), coupled with cytotoxic drugs. Immunosupressants, anti-inflammatory drugs, and antibiotics are used as adjuvants, but apart from IVIg, these therapy options are non-specific and more research is needed to develop treatments with improved side-effect profiles.

Just a decade after the the calcium-sensing receptor (CaR) was identified, pharmacological manipulation of the CaR is about to enter routine practice. For hyperparathyroid states, calcimimetics, which increase activation of the CaR, have been licensed in Europe and the USA. Calcilytics, which decrease CaR function and increase secretion of parathyroid hormone (PTH), might allow the anabolic effects of PTH on bone to be harnessed for the prevention and treatment of osteoporosis.