High blood lactate concentration (hyperlactacidaemia) in trauma or sepsis is thought to indicate tissue hypoxia and anaerobic glycolysis even when blood pressure, cardiac output, and urine output are within clinically acceptable ranges. However, mechanisms of lactate generation by well-oxygenated tissues have received little attention. Within cells, oxidative and glycolytic energy production can proceed in separate, independent compartments. In skeletal muscle and other tissues, aerobic glycolysis is linked to ATP provision for the Na+-K+ pump, the activity of which is stimulated by epinephrine. In injured patients, hypokalaemia may reflect increased Na+,K+-ATPase activity. We propose that increased blood lactate often reflects increased aerobic glycolysis in skeletal muscle secondary to epinephrine-stimulated Na+,K+-ATPase activity and not anaerobic glycolysis due to hypoperfusion. The hypothesis explains why hyperlactacidaemia often neither correlates with traditional indicators of perfusion nor diminishes with increased oxygen delivery. When other variables have returned to normal, continued attempts at resuscitation based on elevated blood lactate may lead to unnecessary use of blood transfusion and inotropic agents in an effort to increase oxygen delivery and lactate clearance.

Outcome in acute respiratory distress syndrome (ARDS) is influenced by a number of factors, including the nature of the precipitating condition and the extent to which multiorgan failure ensues. Most studies of potential therapeutic interventions have been unsuccessful due to the enrollment of limited numbers of patients with a wide variety of pathologies of varying severity. Moreover, the value of initiating single-agent interventions at varying time points in what is an evolving and complex inflammatory process must be questioned. Mortality may therefore represent an inappropriate end-point for clinical trials, which are increasingly focusing on ventilator-free days. Despite these uncertainties, survival appears to be improving, possibly due to the application of supportive techniques in a protocol-driven fashion to patients in whom the underlying condition has been rigorously treated.

Effective, feasible interventions to prevent perinatal transmission of HIV-1 in developing nations are an urgent necessity. Scientific issues of concern include a need to identify other effective antiretroviral agents; to define the shortest effective course of therapy; to assess interventions other than antiretroviral agents; and to investigate interventions that may reduce HIV-1 transmission via breastfeeding. Sound scientific design is fundamental to all research studies. Ethical standards must guide such studies and include the necessity that the problem studied be a health priority in the host country; that the highest standard of care attainable in the country be assured to participants; that the health-care resources of the country not be harmed; that the informed consent of participants be obtained; and that a process of discussion ensure that a successful intervention will be considered for implementation. There are circumstances in which a no-antiretroviral comparison may be ethically justified.

Peritoneal dialysis has now become an established form of renal replacement therapy; nearly half the patients on dialysis in the UK are treated in this way. Survival of patients is now equal to that with haemodialysis. However, long-term peritoneal dialysis (>8 years) is limited to a small percentage of patients because of dropout to haemodialysis for inherent complications of peritoneal dialysis--peritonitis, peritoneal access, inadequate dialysis, and patient-related factors. However, improvements in the understanding of the pathophysiological processes involving the peritoneal membrane have paved the way for advances in the delivery of adequate dialysis, more biocompatible dialysis fluids, and automated peritoneal dialysis. Other technical advances have led to a reduction in peritonitis. Peritoneal dialysis is an important dialysis modality and should be used as an integral part of RRT programmes.

Beneficial clinical effects of treatment with antihypertensive drugs have been shown in middle-aged patients and in those hypertensive patients over 60 years old, but whether treatment is beneficial in patients over 80 years old is not known.

Reliable prognostic factors are lacking for multiple sclerosis (MS). Gadolinium enhancement in magnetic resonance imaging (MRI) of the brain detects with high sensitivity disturbance of the blood-brain barrier, an early event in the development of inflammatory lesions in MS. To investigate the prognostic value of gadolinium-enhanced MRI, we did a meta-analysis of longitudinal MRI studies.

It is clear that the prion strain causing bovine spongiform encephalopathy (BSE) in cattle has infected human beings, manifesting itself as a novel human prion disease, variant Creutzfeldt-Jakob disease (CjD). Studies of the incubation periods seen in previous epidemics of human prion disease and of the effect of transmission barriers limiting spread of these diseases between species, suggest that the early variant CJD cases may have been exposed during the preclinical phase of the BSE epidemic. It must therefore be considered that many cases may follow from later exposure in an epidemic that would be expected to evolve over decades. Since the number of people currently incubating this disease is unknown, there are concerns that prions might be transmitted iatrogenically via blood transfusion, tissue donation, and, since prions resist routine sterilisation, contamination of surgical instruments. Such risks remain unquantified. Although variant CJD can be diagnosed during life by tonsil biopsy, a prion-specific blood test is needed to assess and manage this potential threat to public health. The theoretical possibility that BSE prions might have transferred to other species and continue to present a risk to human health cannot be excluded at present.

For more than 20 years, moderately raised concentrations of total homocysteine (tHcy) have been associated with an increased risk of atherothrombotic vascular events but only recently has evidence mounted to suggest that the association may be causal. The association is independent of other factors, it is fairly consistent across many studies, it is strong and dose-related, and it is biologically plausible. However, the evidence needs to be strengthened by a systematic review of all comparable studies and the demonstration, in randomised trials, that lowering tHcy is followed by a significant reduction in atherothrombotic vascular disease. In addition, the measurement of tHcy needs to be standardised. If these can be achieved then tHcy measurement will become another useful marker of vascular risk, multivitamin therapy will be another therapeutic option for people at risk of atherothrombotic vascular disease, and fortification of food with folic acid will rise high on the political and public health agenda.

The prevalence of psychiatric disorders is increased in children and adults with intellectual disability. Brain damage or dysfunction interact with social and family factors to increase susceptibility to mental illness. Psychiatric disorders in the context of genetic syndromes are commonly overlooked, and there is substantial underdiagnosis of mental disorders because of the atypical and non-specific clinical presentations, and the frequent assumption that psychiatric symptoms are an inherent part of the underlying intellectual disability. There is a strong need for evidence-based practice in the prescribing and monitoring of drugs in this population, especially since many of the drugs are unlicensed for use in children. There is an urgent need to understand and establish the pharmacokinetics, pharmacodynamics, and side-effect profiles of psychotropic medication in this population. Positive trends in pharmacotherapy include the use of atypical antipsychotics instead of the classic antipsychotics, serotonin-specific reuptake inhibitors (SSRIs) rather than tricyclic antidepressants, and newer antiepileptic drugs. Another welcome trend is the use of SSRIs instead of antipsychotics in the long-term management of challenging behaviour in this population.

Peroxisome proliferator-activated receptors (PPAR) were discovered in 1990, ending 25 years of uncertainty about the molecular mechanisms of peroxisome proliferation. Subsequently, PPARs have improved our understanding of adipocyte differentiation. But there is more to PPARs than solving a puzzle about an organelle (the peroxisome) long considered an oddity, and their medical significance goes beyond obesity too. Enhanced PPAR type alpha expression protects against cardiovascular disorders though the role of enhanced PPARgamma expression seems less favourable. PPAR mechanisms, mainly via induction of more differentiated cell phenotypes, protect against some cancers. The differentiation of many cell types (hepatocyte, fibroblast, adipocyte, keratinocyte, myocyte, and monocyte/macrophage) involves PPARs, and these nuclear receptors are now attracting the attention of many medical specialties and the pharmaceutical industry.

Tissue repair involves a close interplay between growth factors and cell adhesion molecules. The normal healing process may be disrupted by pathophysiological states such as inflammation, due to loss of growth factors, cell adhesion molecules, or both, which results in a reduced rate of healing. Such events may occur in inflammatory bowel disease during mucosal restitution. We postulate that the beneficial response to heparin observed in inflammatory bowel disease may result from mechanisms in addition to anticoagulation. These include the restoration of high-affinity receptor binding by antiulcerogenic growth factors, such as basic fibroblast growth factor, that normally rely on the presence of heparan sulphate proteoglycans, such as syndecan-1, as co-receptors. Loss of syndecan-1 has been observed in the ulcerated mucosa of patients with inflammatory bowel disease. This loss may lead to impaired binding of basic fibroblast growth factor and a reduced rate of ulcer healing. We suggest that heparin restores high-affinity receptor binding of basic fibroblast growth, and so increases the rate of mucosal recovery.