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.

Primary open-angle glaucoma is a progressive optic neuropathy and, perhaps, the most common form of glaucoma. Because the disease is treatable, and because the visual impairment caused by glaucoma is irreversible, early detection is essential. Early diagnosis depends on examination of the optic disc, retinal nerve fibre layer, and visual field. New imaging and psychophysical tests can improve both detection and monitoring of the progression of the disease. Recently completed long-term clinical trials provide convincing evidence that lowering intraocular pressure prevents progression at both the early and late stages of the disease. The degree of protection is related to the degree to which intraocular pressure is lowered. Improvements in therapy consist of more effective and better-tolerated drugs to lower intraocular pressure, and more effective surgical procedures. New treatments to directly treat and protect the retinal ganglion cells that are damaged in glaucoma are also in development.

Preimplantation genetic diagnosis (PGD) was introduced at the beginning of the 1990s as an alternative to prenatal diagnosis, to prevent termination of pregnancy in couples with a high risk for offspring affected by a sex-linked genetic disease. At that time, embryos obtained in vitro were tested to ascertain their sex, and only female embryos were transferred. Since then, techniques for genetic analysis at the single-cell level, involving assessment of first and second polar bodies from oocytes or blastomeres from cleavage-stage embryos, have evolved. Fluorescence in-situ hybridisation (FISH) has been introduced for the analysis of chromosomes and PCR for the analysis of genes in cases of monogenic diseases. In-vitro culture of embryos has also improved through the use of sequential media. Here, we provide an overview of indications for, and techniques used in, PGD, and discuss results obtained with the technique and outcomes of pregnancies. A brief review of new technologies is also included.

Cerebral palsy, a range of non-progressive syndromes of posture and motor impairment, is a common cause of disability in childhood. The disorder results from various insults to different areas within the developing nervous system, which partly explains the variability of clinical findings. Management options include physiotherapy, occupational and speech therapy, orthotics, device-assisted modalities, pharmacological intervention, and orthopaedic and neurosurgical procedures. Since 1980, modification of spasticity by means of orally administered drugs, intramuscular chemodenervation agents (alcohol, phenol, botulinum toxin A), intrathecally administered drugs (baclofen), and surgery (neurectomy, rhizotomy) has become more frequent. Family-directed use of holistic approaches for their children with cerebral palsy includes the widespread adoption of complementary and alternative therapies; however, the prevalence of their use and the cost of these options are unknown. Traditional medical techniques (physiotherapy, bracing, and orthopaedic musculoskeletal surgery) remain the mainstay of treatment strategies at this time. This seminar addresses only the musculoskeletal issues associated with cerebral palsy and only indirectly discusses the cognitive, medical, and social issues associated with this diagnosis.

Adherence difficulties and psychological problems are associated with poor glycaemic control in diabetes. We undertook a systematic review and meta-analysis of psychological therapies to assess their effectiveness in improving glycaemic control in type 2 diabetes.

Use of illicit drugs, particularly cannabis, by young people is widespread and is associated with several types of psychological and social harm. These relations might not be causal. Causal relations would suggest that recreational drug use is a substantial public health problem. Non-causal relations would suggest that harm-reduction policy based on prevention of drug use is unlikely to produce improvements in public health. Cross-sectional evidence cannot clarify questions of causality; longitudinal or interventional evidence is needed. Past reviews have generally been non-systematic, have often included cross-sectional data, and have underappreciated the extent of methodological problems associated with interpretation.

Many human diseases are the result of autoimmune attack, presumably related to a loss of tolerance to self. Autoimmune disease can be divided into either organ-specific illnesses, such as thyroid disease, type 1 diabetes, and mysasthenia gravis, or systemic illnesses, such as rheumatoid arthritis and systemic lupus erythematosus. The pathogenesis of autoimmune damage also segregates autoimmune disease in that some diseases or manifestations are mainly induced by autoantibodies. Pathogenesis may be mainly mediated by autoimmune T lymphocytes. Notwithstanding the underlying mechanism of disease, virtually all autoimmune diseases are associated with circulating autoantibodies, which bind self-protein. Furthermore, for many diseases these autoantibodies are found in serum samples many years before disease onset.

Meningiomas are by far the most common tumours arising from the meninges. Progressive enlargement of the tumour leads to focal or generalised seizure disorders or neurological deficits caused by compression of adjacent neural tissue. Surgery remains the primary treatment of choice, although the use of fractionated radiotherapy or stereotactic single-dose radiosurgery is increasing for meningiomas that are incompletely excised, surgically inaccessible, or recurrent and either atypical or anaplastic. Although most meningiomas have good long-term prognosis after treatment, there are still controversies over management in a proportion of cases. We review various features of meningioma biology, diagnosis, and treatment and provide an overview of the current rationale and evidence base for the various therapeutic approaches.

The clinically and pathophysiologically distinct entities of portopulmonary hypertension and hepatopulmonary syndrome occur in a substantial proportion of patients who have advanced liver disease of different causes. These disorders are notoriously underdiagnosed, but they have a substantial impact on survival and require focused treatment. Abnormal intrapulmonary vascular dilatation, the hallmark of hepatopulmonary syndrome, can cause profound hypoxaemia that can be very difficult to treat. By contrast, portopulmonary hypertension results from excessive pulmonary vasoconstriction and vascular remodelling that eventually leads to right-heart failure. Insights into the pathogeneses of these syndromes have led to novel therapeutic approaches. However, in severely affected patients, effective treatment remains a difficult task. In selected patients, liver transplantation represents the only treatment option, but the decision to do isolated liver transplantation is particularly challenging in patients who have severe pulmonary disease involvement. Data from several centres have contributed to provide criteria that allow improved prediction of which patients may, or may not, benefit from liver transplantation alone.

Developmental dyslexia, or specific reading disability, is a disorder in which children with normal intelligence and sensory abilities show learning deficits for reading. Substantial evidence has established its biological origin and the preponderance of phonological disorders even though important phenotypic variability and comorbidity have been recorded. Diverse theories have been proposed to account for the cognitive and neurological aspects of dyslexia. Findings of genetic studies show that different loci affect specific reading disability although a direct relation has not been established between symptoms and a given genomic locus. In both children and adults with dyslexia, results of neuroimaging studies suggest defective activity and abnormal connectivity between regions crucial for language functions--eg, the left fusiform gyrus for reading--and changes in brain activity associated with performance improvement after various remedial interventions.

Malaria accounts for 1-3 million deaths yearly worldwide, mostly in children under 5 years of age in sub-Saharan Africa. Laboratory and clinical studies show an association between acute malaria and a decreased response to diphtheria and tetanus toxoids and to meningococcal, salmonella, and Haemophilus influenzae type b vaccinations. Malaria treatment, chemoprophylaxis, or other forms of parasite suppression might improve the immune response to childhood vaccinations. However, the antimalarial 4-aminoquinolones are immunodepressive, such that antimalarial drugs might depress the vaccine response.

Osteogenesis imperfecta is a genetic disorder of increased bone fragility, low bone mass, and other connective-tissue manifestations. The most frequently used classification outlines four clinical types, which we have expanded to seven distinct types. In most patients the disorder is caused by mutations in one of the two genes encoding collagen type 1, but in some individuals no such mutations are detectable. The most important therapeutic advance is the introduction of bisphosphonate treatment for moderate to severe forms of osteogenesis imperfecta. However, at present, the best treatment regimen and the long-term outcomes of bisphosphonate therapy are unknown. Although this treatment does not constitute a cure, it is an adjunct to physiotherapy, rehabilitation, and orthopaedic care. Gene-based therapy presently remains in the early stages of preclinical research.

Insulin-like growth factor (IGF)-I and its main binding protein, IGFBP-3, modulate cell growth and survival, and are thought to be important in tumour development. Circulating concentrations of IGF-I might be associated with an increased risk of cancer, whereas IGFBP-3 concentrations could be associated with a decreased cancer risk.

Questions concerning the safety of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression in children led us to compare and contrast published and unpublished data on the risks and benefits of these drugs.

Research into myocardial regeneration has an exciting future, shown by the results of experimental and clinical work challenging the dogma that the heart is a postmitotic non-regenerating organ. Such studies have initiated a lively debate about the feasibility of novel treatment approaches leading to the recovery of damaged myocardial tissue. The possibility of reconstituting dead myocardium by endogenous cardiomyocyte replication, transplantation, or activation of stem cells--or even cloning of an artificial heart--is being advanced, and will be a major subject of future research. Although health expenditure for heart failure in the industrial world is high, we are still a long way from being able to treat the cause of reduced myocardial contractility. Despite the hopes of some people, conventional treatment for heart failure does not achieve myocardial regeneration. We present a virtual case report of a patient with acute myocardial infarction; we discuss treatment options, including strategies aimed at organ regeneration.