Learning disability is common, affecting 1-2.5% of the general population in the Western world, and encompasses many different conditions. It usually leads to major functional impairment and lifelong need for support and interventions, not the least important of which are medical and health-care services. Rapid progress is being made in the understanding of the cause and pathogenesis of many learning disability syndromes, and these advances are likely to improve targeted interventions in the next decade. Many countries have abolished a learning disability specialty for medical professionals, but there is a great need to revive this niche of medical knowledge. We know little about quality of life and effects on families of people with learning disability, and research is needed to address these issues.

Twinning has fascinated human beings over the centuries. New technologies and large study groups have led to improved documentation of frequency and complications in twin pregnancies and long-term outcomes. Artificial reproductive technologies have led to a pronounced rise in numbers of dizygotic and monozygotic twins. Although spontaneous dizygotic twinning is clearly associated with increased concentration of follicle-stimulating hormone and ovulation of more than one egg, causes of monozygotic twinning remain illusive. Twin studies are used increasingly to study complex traits and disorders: however, caution is suggested, since twins might not be representative of a typical singleton pregnancy. Monozygotic twinning seems to represent an anomaly in itself, with an increased number of spontaneous abortions and structural congenital anomalies. Both monozygotic and dizygotic twins have growth rates that slow at 30 weeks in utero and might be programmed both developmentally and biochemically earlier in pregnancy to have different responses at birth and after birth compared with singletons.

The number of people with autism spectrum disorders has dramatically increased over the past decade, and problem behaviours in autism are an increasing challenge to families, schools, physicians, and other health-care professionals. Pharmacological treatments can effectively target problem behaviours associated with autism.

The lowering of serum cholesterol is increasingly recognised as essential in the prevention of coronary heart disease and other atherosclerotic disease. The success of statin trials and the need to deploy these drugs effectively in the population has led increasingly to the identification of many people whose serum cholesterol, triglycerides, and HDL-cholesterol require clinical assessment, and frequently treatment. Lipid disorders are mainly straightforward, but some are complex or resistant to simple treatment strategies. I have reviewed the clinical manifestations of disordered lipid metabolism (dyslipidaemia) and its management.

Many of the developmental mechanisms and molecular pathways that underlie fundamental features of body patterning are shared by all vertebrates, and some have even been conserved across evolution from invertebrates to vertebrates. Defects in such processes are a common cause of congenital malformation syndromes, and rapid progress is being made in elucidating their embryological and genetic basis. Here, I focus on three examples, each of which has been the subject of recent advances, and which together illustrate many of the most interesting and important aspects of these disorders. The first example is the development of the pharyngeal apparatus and its perturbation in DiGeorge's syndrome; the second is the induction and differentiation of the forebrain and its perturbation in holoprosencephaly; and the third is the role played by the human HOX genes in congenital malformations.

Fatigue is one of the most prevalent and distressing symptoms of cancer, and is a common side-effect of many of the treatments available for the management of malignant disease. We critically assess the evidence for cancer-related fatigue and its treatment in adults. Little is known about the cause and mechanisms of fatigue, and research into methods of alleviating the condition has focused on treatment for anaemia and behavioural interventions, such as exercise, both of which are effective in reducing fatigue. Although research into the condition has increased considerably in the past decade, important gaps in knowledge remain.

Childhood nephrotic syndromes are most commonly caused by one of two idiopathic diseases: minimal-change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS). A third distinct type, membranous nephropathy, is rare in children. Other causes of isolated nephrotic syndrome can be subdivided into two major categories: rare genetic disorders, and secondary diseases associated with drugs, infections, or neoplasia. The cause of idiopathic nephrotic syndrome remains unknown, but evidence suggests it may be a primary T-cell disorder that leads to glomerular podocyte dysfunction. Genetic studies in children with familial nephrotic syndrome have identified mutations in genes that encode important podocyte proteins. Patients with idiopathic nephrotic syndrome are initially treated with corticosteroids. Steroid-responsiveness is of greater prognostic use than renal histology. Several second-line drugs, including alkylating agents, ciclosporin, and levamisole, may be effective for complicated and steroid-unresponsive MCNS and FSGS patients. Nephrotic syndrome is associated with several medical complications, the most severe and potentially fatal being bacterial infections and thromboembolism. Idiopathic nephrotic syndrome is a chronic relapsing disease for most steroid-responsive patients, whereas most children with refractory FSGS ultimately develop end-stage renal disease. Research is being done to further elucidate the disorder's molecular pathogenesis, identify new prognostic indicators, and to develop better approaches to treatment.

Contrast nephropathy is associated with increased in-hospital morbidity and mortality and leads to extension of hospital stay in patients with chronic renal insufficiency. Acetylcysteine seems to be a safe and inexpensive way to reduce contrast nephropathy. We aimed to assess the efficacy of acetylcysteine to prevent contrast nephropathy after administration of radiocontrast media in patients with chronic renal insufficiency.

Manipulation of the mouse genome through mis-expressing, knocking out, and introducing mutations into genes of interest has provided important insights into the genetic pathways responsible for human skeletal development. These pathways contribute to the sequential phases of skeletal morphogenesis that include patterning, condensation, and overt organogenesis of the membranous and endochondral embryonic skeletons and to subsequent linear growth. Disturbances in these pathways account for many developmental syndromes and disorders of the human skeleton. Recurrent themes include establishment of interlocking regulatory circuits involving growth factors, receptors, signalling pathways, and transcription factors that control cellular programmes such as migration, adhesion, proliferation, differentiation, and apoptosis, and use of common molecules for different purposes. Technical advances suggest that genetic engineering in mice will continue to be highly instructive in the field of skeletal biology.

The larval stage of the pork tapeworm (Taenia solium) infects the human nervous system, causing neurocysticercosis. This disease is one of the main causes of epileptic seizures in many less developed countries and is also increasingly seen in more developed countries because of immigration from endemic areas. Little information is available on the natural evolution of taeniasis or cysticercosis. Available therapeutic measures include steroids, treatments for symptoms, surgery, and, more controversially, antiparasitic drugs to kill brain parasites. Efforts to control and eliminate this disease are underway through antiparasitic treatment of endemic populations, development of pig vaccines, and other measures.

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.