With the lack of effective drug treatments for amyotrophic lateral sclerosis (ALS), and compelling preclinical data, stem-cell research has highlighted this disease as a candidate for stem-cell treatment. Stem-cell transplantation is an attractive strategy for neurological diseases and early successes in animal models of neurodegnerative disease generated optimism about restoring function or delaying degeneration in human beings. The restricted potential of adult stem cells has been challenged over the past 5 years by reports on their ability to acquire new unexpected fates beyond their embryonic lineage (transdifferentiation). Therefore, autologous or allogeneic stem cells, undifferentiated or transdifferentiated and manipulated epigenetically or genetically, could be a candidate source for local or systemic cell-therapies in ALS.

Much excitement has surrounded recent breakthroughs in embryonic stem-cell research. Of lower profile, but no less exciting, are the advances in the field of adult stem-cell research, and their implications for cell therapy. Clinical experience from use of adult haemopoietic stem cells in haematology will facilitate and hasten transition from laboratory to clinic--indeed, clinical trials using adult human stem cells are already in progress in some disease states, including myocardial ischaemia. Here, with particular reference to neurology, we review processes that might underlie apparent changes in adult cell phenotype. We discuss implications these processes might have for the development of new therapeutic strategies using adult stem cells.

Stem-cell therapy provides the prospect of an exciting and powerful treatment to repair the heart. Although research has been undertaken in animals to analyse the safety and efficacy of this new approach, results have been inconclusive. The mechanism by which stem cells could improve cardiac function remains unclear. We describe the background to the concept of natural repair and the work that has been done to establish the role of stem cells in cardiac repair. Controversies have arisen in interpretation of experimental data. The important issues surrounding the application of stem-cell therapy to man are discussed critically. We discuss the future of this pioneering work in the setting of growing concerns about clinical studies in man without understanding the biological mechanisms involved, with the difficulties in funding this type of research.

In this review, we describe changes in dynamics of HIV transmission and shifts in affected populations in western Europe using HIV/AIDS surveillance data and published and unpublished reports. Despite substantial reductions in HIV-related morbidity and mortality since the introduction of highly active antiretroviral treatment, HIV continues to pose a major public health problem in western Europe. More than half a million people are living with an infection that remains incurable and requires costly lifelong treatment; many people remain unaware of their infection, and thousands of new infections continue to occur every year. Migrants from countries with a high prevalence of HIV/AIDS, notably sub-Saharan Africa, bear a disproportionate and increasing share of HIV throughout western Europe and, in most countries, account for the majority of heterosexually acquired HIV infections diagnosed in recent years. Prevention, treatment, and care must be adapted to reach migrant populations. Following a resurgence of risky sexual behaviour, HIV transmission may now be increasing among homosexual and bisexual men, and renewed safer sex campaigns are urgently needed.

HIV (ie, HIV-1) epidemics in Asia show great diversity, both in severity and timing. But epidemics in Asia are far from over and several countries including China, Indonesia, and Vietnam have growing epidemics. Several factors affect the rate and magnitude of growth of HIV prevalence, but two of the most important are the size of the sex worker population and the frequency with which commercial sex occurs. In view of the present state of knowledge, even countries with low prevalence of infection might still have epidemics affecting a small percentage of the population. Once HIV infection has become established, growing needs for care and treatment are unavoidable and even the so-called prevention-successful countries of Thailand and Cambodia are seeing burgeoning care needs. The manifestations of HIV disease in the region are discussed with the aim of identifying key issues in medical management and care of HIV/AIDS. In particular, issues relevant to developing appropriate highly active antiretroviral treatment programmes in the region are discussed. Although access to antiretroviral therapy is increasing globally, making it work effectively while simultaneously expanding prevention programmes to stem the flow of new infections remains a real challenge in Asia. Genuine political interest and commitment are essential foundations for success, demanding advocacy at all levels to drive policy, mobilise sufficient resources, and take effective action.

The global burden of injuries is enormous, but has often been overlooked in attempts to improve health. We review measures that would strengthen existing efforts to prevent and treat injuries worldwide. Scientifically-based efforts to understand risk factors for the occurrence of injury are needed and they must be translated into prevention programmes that are well designed and assessed. Areas for potential intervention include environmental modification, improved engineering features of motor vehicle and other products, and promotion of safe behaviours through social marketing, legislation, and law enforcement. Treatment efforts need to better define the most high-yield services and to promote these in the form of essential health services. To achieve these changes, there is a need to strengthen the capacity of national institutions to do research on injury control; to design and implement countermeasures that address injury risk factors and deficiencies in injury treatment; and to assess the effectiveness of such countermeasures. Although much work remains to be done in high-income countries, even greater attention is needed in less-developed countries, where injury rates are higher, few injury control activities have been undertaken, and where most of the world's population lives. In almost all areas, injury rates are especially high in the most vulnerable sections of the community, including those of low socioeconomic status. Injury control activities should, therefore, be undertaken in a context of attention to human rights and other broad social issues.

Rapid progress has been made in cardiac MRI (CMRI) over the past decade, which has firmly established it as a reliable and clinically important technique for assessment of cardiac structure, function, perfusion, and myocardial viability. Its versatility and accuracy is unmatched by any other individual imaging modality. CMRI is non-invasive and has high spatial resolution and avoids use of potentially nephrotoxic contrast agent or radiation. It has been extensively studied against other established non-invasive imaging modalities and has been shown to be superior in many scenarios, particularly with respect to assessment of cardiac and great vessel morphology and left ventricular function. Furthermore, its clinical use continues to expand with increasing experience and proliferation of CMRI centres. As worldwide prevalence of cardiovascular disease continues to rise, CMRI provides opportunity for improved and cost-effective non-invasive assessment. Continued progress in CMRI technology promises to further widen its clinical application in coronary imaging, myocardial perfusion, comprehensive assessment of valves, and plaque characterisation.

With the development of trauma systems, improved resuscitation, and organ system support, survival after severe injury is common, but is often complicated by nosocomial infection and organ failure. These complications are costly, and can lead to death or disability. Although much is known about the pathophysiology of post-traumatic nosocomial infection and organ failure, findings have been limited by our ability to generate and analyse large amounts of experimental and observational data. However, technological advances in nucleic acid and protein analysis, coupled with increased computational capacity, provide an opportunity to characterise the determinants of and the responses to injury and sepsis on a genome-wide scale. New large-scale collaborative efforts aim to investigate the genome for variation (gene polymorphisms), characterise multiple levels of the biological response to injury (transcriptome and proteome), and relate these to clinical phenotypes. In this article, we summarise recent findings and explore where promising new technologies might have the greatest potential for increasing our knowledge. It will now be important to determine how these recent technological advances can be used and integrated with our existing approaches, to reduce death, disability, and the economic consequences of trauma.

Dengue, Japanese encephalitis, tick-borne encephalitis, yellow fever, and West Nile viruses cause substantial morbidity and mortality each year. Modern transportation and the relaxation of mosquito-control measures are largely responsible for the increase of disease caused by flaviviruses. Without effective antiviral drugs, vaccination offers the best chance of decreasing the incidence of these diseases, and live virus vaccines are the most promising and cost effective. However, flaviviruses can recombine, which raises the possibility of recombination between a vaccine strain and wild-type virus resulting in a new virus with potentially undesirable properties.

Schizophrenia is a mental illness that is among the world's top ten causes of long-term disability. The symptoms of schizophrenia include psychosis, apathy and withdrawal, and cognitive impairment, which lead to problems in social and occupational functioning, and self-care. About 1% of the population is affected by schizophrenia, with similar rates across different countries, cultural groups, and sexes. The illness tends to develop between the ages of 16 and 30 years, and mostly persists throughout the patient's lifetime. The cause of schizophrenia is unknown, but evidence suggests that genetic factors, early environmental influences (eg, obstetric complications), and social factors (eg, poverty) contribute. No biological alterations are pathognomonic of schizophrenia, although several pathophysiological differences exist in a wide range of brain structures. Antipsychotic medications are the mainstay for managing schizophrenia. A range of psychosocial treatments are also helpful, including family intervention, supported employment, cognitive-behaviour therapy for psychosis, social skills training, teaching illness self-management skills, assertive community treatment, and integrated treatment for co-occurring substance misuse.

Resuscitation of the severely injured patient who presents in shock has improved greatly, following focused wartime experience and insight from laboratory and clinical studies. Further benefit is probable from technologies that are being brought into clinical use, especially hypertonic saline dextran, haemoglobin-based oxygen carriers, less invasive early monitors, and medical informatics. These technologies could improve the potential of prehospital and early hospital care to pre-empt or more rapidly reverse hypoxaemia, hypovolaemia, and onset of shock. Damage control surgery and definitive interventional radiology will probably combine with more real-time detection and intervention for hypothermia, coagulopathy, and acidosis, to avoid extreme pathophysiology and the "bloody vicious cycle". Although now widely practised as standard of care in the USA and Europe, shock resuscitation strategies involving haemoglobin replacement and fluid volume loading to regain tissue perfusion and oxygenation vary between trauma centres. One of the difficulties is the scarcity of published evidence for or against seemingly basic intervention strategies, such as early or large-volume fluid loading. Standardised protocols for resuscitation, representing the best and most current knowledge of the clinical process, could be devised and widely implemented as interactive computerised applications among trauma centres in the USA and Europe. Prevention of injury is preferable and feasible, but early care of the severely injured patient and modulation of exaggerated systemic inflammatory response due to transfusion and other complications of traditional strategies will probably provide the next generation of improvements in shock resuscitation.

Advances in molecular biology have led to the identification of mutations within several novel genes associated with the phenotype of isolated growth hormone deficiency, combined pituitary hormone deficiency, and syndromes such as septo-optic dysplasia. Progress has also been made in terms of the optimum diagnosis of disorders of stature and their treatment. The use of growth hormone for the treatment of adults with growth hormone deficiency and conditions such as Turner's syndrome, Prader-Willi syndrome, intrauterine growth restriction, and chronic renal failure has changed the practice of endocrinology, although cost-benefit implications remain to be established.

Toxoplasma gondii is a protozoan parasite that infects up to a third of the world's population. Infection is mainly acquired by ingestion of food or water that is contaminated with oocysts shed by cats or by eating undercooked or raw meat containing tissue cysts. Primary infection is usually subclinical but in some patients cervical lymphadenopathy or ocular disease can be present. Infection acquired during pregnancy may cause severe damage to the fetus. In immunocompromised patients, reactivation of latent disease can cause life-threatening encephalitis. Diagnosis of toxoplasmosis can be established by direct detection of the parasite or by serological techniques. The most commonly used therapeutic regimen, and probably the most effective, is the combination of pyrimethamine with sulfadiazine and folinic acid. This Seminar provides an overview and update on management of patients with acute infection, pregnant women who acquire infection during gestation, fetuses or infants who are congenitally infected, those with ocular disease, and immunocompromised individuals. Controversy about the effectiveness of primary and secondary prevention in pregnant women is discussed. Important topics of current and future research are presented.

Severe burn causes metabolic disturbances that can last for a year after injury; persistent and profound catabolism hampers rehabilitative efforts and delays the meaningful return of individuals to society. The simplest, effective anabolic strategies for severe burn injuries are: early excision and grafting of the wound; prompt treatment of sepsis; maintenance of environmental temperature at 30-32 degrees C; continuous feeding of a high carbohydrate, high protein diet, preferably by the enteral route; and early institution of vigorous and aerobic resistive exercise programmes. To further keep erosion of lean body mass to a minimum, administration of anabolic agents, recombinant human growth hormone, insulin, oxandrolone, or anticatabolic drugs such as propranolol are alternative approaches. Exogenous continuous low-dose insulin infusion, beta blockade with propranolol, and use of the synthetic testosterone analogue oxandrolone are the most cost effective and least toxic pharmacological treatments to date.

Non-esterified fatty acids in plasma originate from adipose tissue. Delivery of fatty acids to the liver provides the substrate for VLDL triglycerides. Insulin-sensitive organs, overburdened by high concentrations of non-esterified fatty acids, may develop resistance to insulin action. In addition, insulin secretion from pancreatic beta-cells may be impaired by long-standing elevation of concentrations of non-esterified fatty acid in plasma. Normally, such concentrations fluctuate over the day depending on the transient suppression of lipolysis from adipose tissue by insulin released after meals. Diurnal concentrations of non-esterified fatty acid are often elevated in obesity, in particular in male-pattern upper-body fat accumulation. Nicotinic acid is the only drug that primarily lowers concentrations of non-esterified fatty acids and thereby lowers VLDL triglycerides. Nicotinic acid, or its analogues, seems to alleviate insulin resistance in the short-term whereas, paradoxically, the long-term effect is often the opposite. Suppression of lipolysis by nicotinic acid gives rise to a prominent rebound and the degree to which this occurs might explain this paradox.

Hypertrophic cardiomyopathy is a common genetically transmitted disease, defined clinically by the presence of unexplained left ventricular hypertrophy. The disease has a varied clinical course and outcome; many patients have little or no discernible cardiovascular symptoms, whereas others have profound exercise limitation and recurrent arrhythmias. The overall risk of disease-related complications such as sudden death, endstage heart failure, and fatal stroke is roughly 1-2% per year, but the absolute risk in individuals varies as a function of underlying genetic abnormality, age, myocardial pathology, and other pathophysiological abnormalities such as impaired peripheral vascular responses. Genetic counselling and clinical risk stratification are relevant to all patients, but many therapeutic interventions, including septal alcohol ablation, septal myectomy, and implantable cardioverter defibrillators, are appropriate only in particular patient subsets. We review the management of patients with unexplained myocardial hypertrophy, considering the influence of underlying genetic and pathophysiological substrates on clinical decision-making.

Despite its history as a human teratogen, thalidomide is emerging as a treatment for cancer and inflammatory diseases. Although the evolution of its clinical application could not have been predicted from the tragedy associated with its misuse in the past, its history serves as a lesson in drug development that underscores the need to understand the molecular pharmacology of a compound's activity, including associated toxicities. Here, we summarise the applications for thalidomide with an emphasis on clinical trials published over the past 10 years, and consider our knowledge of the molecular pharmacology of the drug in the context of clinical trial data, attempting to provide a mechanism-guided understanding of its activity.

Parkinson's disease is the most common serious movement disorder in the world, affecting about 1% of adults older than 60 years. The disease is attributed to selective loss of neurons in the substantia nigra, and its cause is enigmatic in most individuals. Symptoms of Parkinson's disease respond in varying degrees to drugs, and surgery offers hope for patients no longer adequately controlled in this manner. The high prevalence of the disease, and important advances in its management, mean that generalists need to have a working knowledge of this disorder. This Seminar covers the basics, from terminology to aspects of diagnosis, treatment, and pathogenesis.

Important advances have been made in our understanding of severe sepsis. Outcome can be improved by targeted interventions, including early and appropriate antibiotic therapy and goal-directed resuscitation, and might be further improved by selective decontamination of the digestive tract, tight control of glucose, and possibly by giving corticosteroids to selected patients. Drugs that target specific steps in the septic cascade include cytokine inhibitors, anti-endotoxins, and the three naturally occurring anticoagulants. Only one of these trials, which assessed the efficacy of activated protein C, reported significant improvements in outcome. Translation of these results into practice has been hampered by high drug costs, and by apparent discrepancies between interim results and final outcomes in two of the trials with natural anticoagulants.