The molecular basis of many leukaemias is now known, allowing precise diagnosis. Treatment of chronic myeloid leukaemia is now possible by targeting of the BCR-ABL tyrosine kinase. The underlying molecular abnormalities in acute leukaemias allow the outlook for individual patients to be assessed at diagnosis and therapy tailored accordingly. Analysis of V(H) genes in B-cell malignant disorders allows these to be placed in the hierarchy of B-cell development and may provide prognostically valuable information.

The prevalence and incidence of epilepsy are highest in later life with around 25% of new cases occurring in elderly people, many of whom will have concomitant neurodegenerative, cerebrovascular, or neoplastic disease. Difficulties accepting the diagnosis are frequently compounded by its unpredictable nature. Those affected commonly lose confidence and independence. Seizures in older people can result in physical injury, adding to low morale. Complete control is achievable in around 70% of patients with antiepileptic drug treatment. Optimum management requires rapid investigation, accurate diagnosis, effective treatment, sympathetic education, and assured support. The emergence of seizure disorders in old age places an increasing burden on health-care facilities and costs. A coordinated programme among health-care workers is advised to maintain the independence and improve the quality of life of this vulnerable patient population.

The taxanes are anticancer cytotoxics that stabilise cellular microtubules. Two members, paclitaxel and docetaxel have substantial activity. One or both agents are widely accepted as evidence-based components of therapy for advanced breast, lung, and ovarian carcinomas. Paclitaxel has recently been approved in the USA for the adjuvant treatment of early stage node-positive breast carcinoma.

Examination of the genetic mechanisms underlying the thalassaemias has led to a clearer understanding of the control of eukaryotic genes in general. Inherited disorders of haemoglobin synthesis are an important cause worldwide of morbidity and mortality, and place a large burden on patients, families, and ultimately communities. The haemoglobin disorders can be controlled, by counselling and prenatal diagnosis. Treatment is usually symptomatic, though bone-marrow transplantation for beta-thalassaemia may be successful in suitable patients.

Disorders of white cells are very common in clinical practice. White-cell development and numbers are controlled by a mixture of external stimuli including cytokines, matrix proteins, and accessory cells. Several different white-cell lineages are recognised; each has a role in host defence. Both white-cell deficiency and overproduction can lead to disease. Some forms of inherited white-cell deficiency are potentially treatable with gene therapy.

Direct observation of patients taking their medication is a strategy to improve completion rates for tuberculosis treatment, but the programmes to implement this approach consist of a complex array of inputs aimed at influencing adherence. Policy makers need a clear understanding of these inputs to succeed. We systematically identified and reviewed published reports of direct observation therapy (DOT) programmes and compared inputs with WHO's short-course DOT programme. DOT programmes frequently consist of more than the five elements of WHO's strategy, including incentives, tracing of defaulters, legal sanctions, patient-centred approaches, staff motivation, supervision, and additional external funds. Focusing on direct observation as a key factor in the promotion of adherence seems inappropriate. Multiple components might account for the success of DOT programmes, and WHO should make these explicit.

Iron deficiency affects 30% of the world's population. Iron metabolism is tightly regulated, with both gut transport and storage being coordinated. Hereditary haemochromatosis due to mutations in the HFE gene leads to increased absorption of iron and multiple end-organ damage. Myelodysplastic disorders are acquired clonal stem-cell disorders that cause ineffective erythropoiesis. Aplastic anaemia is caused by an intrinsic defect of haemopoietic stem cells; both inherited and acquired forms occur. Primary polycythaemia is a myeloproliferative disorder, a non-malignant stem-cell disease.

Despite more than 70 randomised trials, the effect of chemotherapy on non-metastatic head and neck squamous-cell carcinoma remains uncertain. We did three meta-analyses of the impact of survival on chemotherapy added to locoregional treatment.

Developments in synthetic and analytical chemistry have provided the tools to differentiate between two enantiomers (mirror images) of drugs or between the parent compound and metabolite(s) with respect to desired and undesired pharmacological effects. Several drugs are now marketed or being developed as single enantiomers in place of a previous racemic mixture, a process known as "chiral switching". It is easier to understand "pure" as opposed to "mixture" pharmacology but whether the promise of chiral (and metabolite) switches will translate into real clinical advances remains to be seen.

Neuraminidase promotes influenza virus release from infected cells and facilitates virus spread within the respiratory tract. Several potent and specific inhibitors of this enzyme have been developed, and two (zanamivir and oseltamivir) have been approved for human use. Unlike amantadine and rimantadine that target the M2 protein of influenza A viruses, these drugs inhibit replication of both influenza A and B viruses. Zanamivir is delivered by inhalation because of its low oral bioavailability whereas oseltamivir is administered by mouth. Early treatment with either drug reduces the severity and duration of influenza symptoms and associated complications. Both agents are effective for chemoprophylaxis. Because of a broader antiviral spectrum, better tolerance, and less potential for emergence of resistance than is seen with the M2 inhibitors, the neuraminidase inhibitors represent an important advance in the treatment of influenza.

Scabies and pediculosis are ubiquitous, contagious, and debilitating parasitic dermatoses. They have been known since antiquity and are distributed worldwide. Clusters of infestation occur-for example, scabies affecting immunocompromised individuals or patients and staff in hospitals and nursing homes for the elderly, and pediculosis affecting schoolchildren or homeless people. Associations with other disorders are common: infections with human T-cell leukaemia/lymphoma virus I (HTLV-I) and HIV are associated with scabies, and trench fever and exanthematous typhus with pediculosis. Specific forms of scabies, including bullous scabies or localised crusted scabies, may be misdiagnosed. Moreover, definitive parasitic diagnosis can be difficult to obtain, and the value of new techniques remains to be confirmed. Difficulties in management have returned scabies and pediculosis to the limelight.

High blood glucose concentration may increase risk of death and poor outcome after acute myocardial infarction. We did a systematic review and meta-analysis to assess the risk of in-hospital mortality or congestive heart failure after myocardial infarction in patients with and without diabetes who had stress hyperglycaemia on admission.

Members of the superfamily of Ras GTPase signalling proteins (monomeric G proteins) require post-translational carboxy-terminal prenylation to function. Prenylation is the covalent attachment of a hydrophobic prenyl group (either farnesyl or geranylgeranyl), which localises the GTPase to cell membranes. Ras proteins exert substantial control on cell proliferation and gene-transcription events, and prenylation inhibitors are now included in clinical trials for cancer. Many renal diseases are highly proliferative and are driven by a range of profibrotic cytokines. We hypothesise that inhibition of prenylation could be of substantial therapeutic benefit in such diseases, providing greater selectivity against abnormal cytokine-driven proliferation and fibrogenesis than current treatments available to nephrologists.

The therapeutic potential of monoclonal antibodies (mAb) was quickly realised after the hybridoma technique allowed their development in the mid 1970s. Chimeric humanised and fully humanised mAb can now be made by recombinant engineering. About a quarter of all biotech drugs in development are mAb, and around 30 products are in use or being investigated. Licensed products are available for inhibition of alloimmune and autoimmune reactivity, and for antitumour, antiplatelet, or antiviral therapy. Short-term side-effects are tolerable and as expected, although long-term safety remains to be elucidated. The cost-effectiveness and quality-of-life benefits of the use of mAb in patients who are usually seriously and chronically ill also needs studying. The therapeutic use of mAb is now established, and is perhaps the first example of how the "new biology" and the understanding of underlying molecular mechanisms has benefited patients.

From the mid-1980s to mid-1990s, the WHO MONICA Project monitored coronary events and classic risk factors for coronary heart disease (CHD) in 38 populations from 21 countries. We assessed the extent to which changes in these risk factors explain the variation in the trends in coronary-event rates across the populations.

Blockade of the renin-angiotensin system began as a way of studying the pathogenesis of cardiovascular disease with specific pharmacological probes. Oral activity, achieved by shortening the original peptide structures, transformed the probes into therapeutic agents, the angiotensin-converting enzyme (ACE) inhibitors. However, ACE is a non-specific target for blocking the renin-angiotensin enzymatic cascade. The availability of orally active drugs turned ACE inhibition into a therapeutic breakthrough but more specific blockade always seemed desirable. This goal has now been achieved with the orally active angiotensin II receptor antagonists; six are on the market and more are under development. This new class of drugs is equal in efficacy to ACE inhibitors, at least in hypertensive patients. Trials now underway will demonstrate whether angiotensin II receptor antagonists can prevent target-organ damage and reduce cardiovascular morbidity and mortality. If they do, these compounds might one day replace ACE inhibitors.

Long-term protection against clinically significant breakthrough hepatitis B (HB) virus infection and chronic carriage depends on immunological memory, which allows a protective anamnestic antibody response to antigen challenge. Memory seems to last for at least 15 years in immunocompetent individuals. To date there are no data to support the need for booster doses of HB vaccine in immunocompetent individuals who have responded to a primary course. All adequately vaccinated individuals have shown evidence of immunity in the form of persisting anti-HBs and/or in vitro B-cell stimulation or an anamnestic response to a vaccine challenge. Nonetheless several countries and individuals currently have a policy of administering booster doses to certain risk groups. Boosters may be used to provide reassurance of protective immunity against benign breakthrough infection. For immunocompromised patients, regular testing for anti-HBs, and a booster injection when the titre falls below 10 mIU/mL, is advised. Long-term monitoring should continue, to confirm the absence of clinically significant breakthrough episodes of hepatitis B and to find out if a carrier state develops after 15 years. Also, non-responders to a primary course should continue to be studied.