Studies of human birth defects and developmental disorders have made major contributions to our understanding of development. Rare human syndromes have allowed identification of important developmental genes, and revealed mechanisms such as uniparental disomy and unstable trinucleotide repeats that were not suspected from animal studies. Some aspects of development, in particular cognitive development, can only be studied in human beings. Basic developmental mechanisms are very highly conserved across a very wide range of animals, making for a rich interplay between animal and human studies. Often, clinical studies identify a gene, or suggest a hypothesis, that can then be investigated in animals.

Hyperthyroidism is a pathological syndrome in which tissue is exposed to excessive amounts of circulating thyroid hormone. The most common cause of this syndrome is Graves' disease, followed by toxic multinodular goitre, and solitary hyperfunctioning nodules. Autoimmune postpartum and subacute thyroiditis, tumours that secrete thyrotropin, and drug-induced thyroid dysfunction, are also important causes. The diagnosis of hyperthyroidism is generally straightforward, with raised serum thyroid hormones and suppressed serum thyrotropin in almost all cases. Appropriate treatment of hyperthyroidism relies on identification of the underlying cause. Antithyroid drugs, radioactive iodine, and surgery are the traditional treatments for the three common forms of hyperthyroidism. Beta-adrenergic blocking agents are used in most patients for symptomatic relief, and might be the only treatment needed for thyroiditis, which is transient. The more unusual causes of hyperthyroidism, including struma ovarii, thyrotropin-secreting tumours, choriocarcinoma, and amiodarone-induced thyrotoxicosis are, more often than not, a challenge to diagnose and treat.

Right ventricular involvement in acute myocardial infarction and cardiogenic shock has received little attention by clinicians and researchers, although its pathophysiology, clinical presentation, and natural history are distinctly different from those of left ventricular infarction and associated cardiogenic shock. Right ventricular shock has important therapeutic implications for the management of patients, which need to be recognised.

Coeliac disease is a genetically-determined chronic inflammatory intestinal disease induced by an environmental precipitant, gluten. Patients with the disease might have mainly non-gastrointestinal symptoms, and as a result patients present to various medical practitioners. Epidemiological studies have shown that coeliac disease is very common and affects about one in 250 people. The disease is associated with an increased rate of osteoporosis, infertility, autoimmune diseases, and malignant disease, especially lymphomas. The mechanism of the intestinal immune-mediated response is not completely clear, but involves an HLA-DQ2 or HLA-DQ8 restricted T-cell immune reaction in the lamina propria as well as an immune reaction in the intestinal epithelium. An important component of the disease is the intraepithelial lymphocyte that might become clonally expanded in refractory sprue and enteropathy-associated T-cell lymphoma. Study of the mechanism of the immune response in coeliac disease could provide insight into the mechanism of inflammatory and autoimmune responses and lead to innovations in treatment.

The past decade has seen many advances in knowledge about gastric cancer. Notably, tumour biology and lymphatic spread are now better understood, and treatment by surgical and medical oncologists has become more standardised. Since refrigerators have replaced other methods of food conservation, Helicobacter pylori has become a factor in the cause of gastric cancer. Cancers that arise at the oesophagogastric junction might be further examples of wealth-associated disease. To tailor treatment better, the western hemisphere needs to borrow from the East by establishing screening programmes for early diagnosis, through careful surgical resection, and through detailed analysis of tumour spread. In Europe and the USA, most patients reach treatment with cancers already at an advanced stage. For these patients, three important randomised trials are underway that evaluate combined therapy. Cytostatic drugs, especially angiogenesis inhibitors have proved disappointing; however, basic research efforts to detect familial gastric cancers and to assess minimally residual disease look more hopeful.

Colorectal cancer is the second most common cause of cancer-related mortality in the west. The high incidence and mortality make effective prevention an important public-health and economic issue. Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit colorectal carcinogenesis and are among the few agents known to be chemopreventive. Randomised trials have shown that sulindac and celecoxib suppress the development of adenomatous polyps and cause regression of existing polyps in patients with familial adenomatous polyposis (FAP), who have a high risk for developing colorectal cancer. The mechanisms by which NSAIDs inhibit neoplastic growth are not fully known.

Trachoma is the most common infectious cause of blindness. It is caused by ocular serovars of Chlamydia trachomatis. Transmission is favoured in poor communities, where crowding is common and access to water and sanitation inadequate. Repeated reinfection over many years causes dense scarring of the upper eyelid. The resultant inversion of the lashes abrades the eyeball, and the abrasion leads to corneal opacification and visual impairment. The host immune response is probably at least partly the cause of this process. The "SAFE" strategy is used for the control of trachoma: surgery for in-turned lashes, antibiotics for active disease, facial cleanliness, and environmental improvement. The demonstration that a single oral dose of the antibiotic azithromycin is as effective as 6 weeks of topical tetracycline was an important advance in trachoma control. By means of the SAFE strategy, WHO and its partners aim to eliminate trachoma as a public-health problem by the year 2020.

Chronic heart failure is an increasingly common cause of premature death and poor quality of life. Community-based epidemiological studies have provided much-needed information on the demography of chronic heart failure, providing insight into its influence on public health. In most patients, chronic heart failure is accompanied by a range of concomitant disorders that both contribute to the cause of the disease and have a key role in its progression and response to treatment. Information on the most common comorbidities in chronic heart failure--ischaemic heart disease, hypertension, and diabetes mellitus--is presented for prespecified subgroups in the reports of many large-scale, multicentre trials; despite their limitations, these subanalyses provide guidance in therapeutic decision-making. Similarly, because chronic heart failure is commonly an endpoint in intervention trials of both hypertension and diabetes, such studies afford important information on the prevention of chronic heart failure in these common diseases.

Non-Hodgkin lymphoma is a non-specific term that includes several lymphoproliferative malignant diseases with different clinical and histological appearances. Here, we concentrate on adult lymphomas. We look at their molecular basis, at the development of a classification system based on a better understanding of the biology of the various subgroups, and at how refinement of adverse prognostic factor groupings helps in clinical management. Lymphomas can present in various ways and be difficult to diagnose. About a quarter of cases arise extranodally and might present special problems. Developments in cytotoxic chemotherapy have led to good long-term survival prospects for aggressive lymphoma; introduction of novel approaches, including monoclonal antibody therapy, offers promise for indolent lymphoma, and should further improve prognosis for aggressive tumours.

This is the second of five papers in the child survival series. The first focused on continuing high rates of child mortality (over 10 million each year) from preventable causes: diarrhoea, pneumonia, measles, malaria, HIV/AIDS, the underlying cause of undernutrition, and a small group of causes leading to neonatal deaths. We review child survival interventions feasible for delivery at high coverage in low-income settings, and classify these as level 1 (sufficient evidence of effect), level 2 (limited evidence), or level 3 (inadequate evidence). Our results show that at least one level-1 intervention is available for preventing or treating each main cause of death among children younger than 5 years, apart from birth asphyxia, for which a level-2 intervention is available. There is also limited evidence for several other interventions. However, global coverage for most interventions is below 50%. If level 1 or 2 interventions were universally available, 63% of child deaths could be prevented. These findings show that the interventions needed to achieve the millennium development goal of reducing child mortality by two-thirds by 2015 are available, but that they are not being delivered to the mothers and children who need them.

Aberrant signalling through the epidermal growth factor receptor (EGFR) is associated with neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, and angiogenesis. The high frequency of abnormalities in EGFR signalling in human carcinomas and gliomas and laboratory studies showing that inhibition of EGFRcan impair tumour growth means that EGFR is an attractive target for the development of cancer therapeutics. Among the classes of agents targeting EGFR in clinical development are monoclonal antibodies against the extracellular ligand-binding domain of the receptor, and small molecules that inhibit activation of the receptor tyrosine kinase. Although there are pharmacological and mechanistic differences between the two classes of inhibitor, preclinical studies suggest they both inhibit cell proliferation and have additive or synergistic cytotoxicity with standard therapies. Results from early clinical trials indicate that these agents are well tolerated and have anti-tumour activity.

Primary biliary cirrhosis is a chronic cholestatic liver disease of adults. This disorder is characterised histologically by chronic non-suppurative destruction of interlobular bile ducts leading to advanced fibrosis, cirrhosis, and liver failure. The precise aetiopathogenesis of primary biliary cirrhosis remains unknown, although dysregulation of the immune system and genetic susceptibility both seem to be important. Affected patients are typically middle-aged women with abnormal serum concentrations of alkaline phosphatase. Presence of antimitochondrial antibody in serum is almost diagnostic of the disorder. Identification of primary biliary cirrhosis is important, because effective treatment with ursodeoxycholic acid has been shown to halt disease progression and improve survival without need for liver transplantation. However, therapeutic options for disease-related complications-including fatigue and metabolic bone disease-remain unavailable. Mathematical models have been developed that accurately predict the natural history of primary biliary cirrhosis in individuals. Despite advances in understanding of the disease, it remains one of the major indications for liver transplantation worldwide.

Supported by detailed understanding of their mechanism of action, and facilitated by chemical manipulations that have amplified their solubility, the camptothecins have advanced to the forefront of several areas of therapeutic and developmental chemotherapy. Additive and synergistic laboratory interactions with other cytotoxic drugs have been exploited to allow development of camptothecin-based multidrug regimens, which are showing important activity in several malignancies. Topotecan and irinotecan are already in widespread use in clinical practice, and newer agents with promising preclinical activity are in various stages of clinical assessment. As knowledge of molecular and biochemical mechanisms of action and resistance continues to expand, newer and better camptothecin-based strategies for treatment of malignant disease are likely to evolve.

More than 10 million children die each year, most from preventable causes and almost all in poor countries. Six countries account for 50% of worldwide deaths in children younger than 5 years, and 42 countries for 90%. The causes of death differ substantially from one country to another, highlighting the need to expand understanding of child health epidemiology at a country level rather than in geopolitical regions. Other key issues include the importance of undernutrition as an underlying cause of child deaths associated with infectious diseases, the effects of multiple concurrent illnesses, and recognition that pneumonia and diarrhoea remain the diseases that are most often associated with child deaths. A better understanding of child health epidemiology could contribute to more effective approaches to saving children's lives.

Cervical cancer is a serious health problem, with nearly 500000 women developing the disease each year worldwide. Most cases occur in less developed countries where no effective screening systems are available. Risk factors include exposure to human papillomavirus, smoking, and immune-system dysfunction. Most women with early-stage tumours can be cured, although long-term morbidity from treatment is common. Results of randomised clinical trials have shown that for women with locally advanced cancers, chemoradiotherapy should be regarded as the standard of care; however, the applicability of this treatment to women in less developed countries remains largely untested. Many women with localised (stage IB) tumours even now receive various combinations of surgery and radiotherapy, despite unresolved concern about the morbidity of this approach compared with definitive radiotherapy or radical surgery. Treatment of recurrent cervical cancer remains largely ineffective. Quality of life should be taken into account in treatment of women with primary and recurrent cervical cancer.

This review comprises aspects of the epidemiology, microbiology, pathophysiology, clinical manifestations, diagnosis, management, prognosis, and prevention of bacterial meningitis, with emphasis on the paediatric population. The beginning of this millennium has witnessed the virtual disappearance of Haemophilus invasive disease in some countries, emergence of pneumococcal strains that are resistant to multiple antibiotics, isolation of pneumococci with tolerance to vancomycin, outbreaks and clusters of meningococcal meningitis in several geographical areas, and intense research in development of effective conjugate pneumococcal and meningococcal vaccines. Bacterial meningitis has become an uncommon disease in the developed world. Unfortunately, because of limited economic resources and poor living conditions, many developing countries are still affected by the devastating consequences of this life-threatening systemic infection. Basic and clinical research is needed to discover new antimicrobial and anti-inflammatory agents to improve outcome from disease. Novel strategies are needed to distribute and implement effective vaccines worldwide to prevent bacterial meningitis.

Nosocomial infections affect about 30% of patients in intensive-care units and are associated with substantial morbidity and mortality. Several risk factors have been identified, including the use of catheters and other invasive equipment, and certain groups of patients-eg, those with trauma or burns-are recognised as being more susceptible to nosocomial infection than others. Awareness of these factors and adherence to simple preventive measures, such as adequate hand hygiene, can limit the burden of disease. Management of nosocomial infection relies on adequate and appropriate antibiotic therapy, which should be selected after discussion with infectious-disease specialists and adapted as microbiological data become available.

von Hippel-Lindau disease is a heritable multisystem cancer syndrome that is associated with a germline mutation of the VHL tumour suppressor gene on the short arm of chromosome 3. This disorder is not rare (about one in 36000 livebirths) and is inherited as a highly penetrant autosomal dominant trait (ie, with a high individual risk of disease). Affected individuals are at risk of developing various benign and malignant tumours of the central nervous system, kidneys, adrenal glands, pancreas, and reproductive adnexal organs. Because of the complexities associated with management of the various types of tumours in this disease, treatment is multidisciplinary. We present an overview of the clinical aspects, management, and treatment options for von Hippel-Lindau disease.

During the past two decades, assisted reproductive technologies (ARTs) have revolutionised the treatment of infertility. ARTs now account for between 1% and 3% of annual births in many western countries and in-vitro fertilisation (IVF) services are growing worldwide. In general, the incidence of abnormalities at birth is reassuringly low and children develop normally. Nevertheless, it is important to monitor the safety of ARTs as clinical protocols evolve and new technologies emerge.

High-altitude illness is the collective term for acute mountain sickness (AMS), high-altitude cerebral oedema (HACE), and high-altitude pulmonary oedema (HAPE). The pathophysiology of these syndromes is not completely understood, although studies have substantially contributed to the current understanding of several areas. These areas include the role and potential mechanisms of brain swelling in AMS and HACE, mechanisms accounting for exaggerated pulmonary hypertension in HAPE, and the role of inflammation and alveolar-fluid clearance in HAPE. Only limited information is available about the genetic basis of high-altitude illness, and no clear associations between gene polymorphisms and susceptibility have been discovered. Gradual ascent will always be the best strategy for preventing high-altitude illness, although chemoprophylaxis may be useful in some situations. Despite investigation of other agents, acetazolamide remains the preferred drug for preventing AMS. The next few years are likely to see many advances in the understanding of the causes and management of high-altitude illness.