The trypanosomiases consist of a group of important animal and human diseases caused by parasitic protozoa of the genus Trypanosoma. In sub-Saharan Africa, the final decade of the 20th century witnessed an alarming resurgence in sleeping sickness (human African trypanosomiasis). In South and Central America, Chagas' disease (American trypanosomiasis) remains one of the most prevalent infectious diseases. Arthropod vectors transmit African and American trypanosomiases, and disease containment through insect control programmes is an achievable goal. Chemotherapy is available for both diseases, but existing drugs are far from ideal. The trypanosomes are some of the earliest diverging members of the Eukaryotae and share several biochemical peculiarities that have stimulated research into new drug targets. However, differences in the ways in which trypanosome species interact with their hosts have frustrated efforts to design drugs effective against both species. Growth in recognition of these neglected diseases might result in progress towards control through increased funding for drug development and vector elimination.

DNA microarrays are being used for many applications, including the prediction of cancer outcomes by simultaneous analysis of the expression of thousands of genes. We systematically assessed the predictive performance of this method for major clinical outcomes (death, metastasis, recurrence, response to therapy) and the correlation of gene profiling with other clinicopathological correlates of malignant disorders.

RNA interference (RNAi) is the sequence-specific gene-silencing induced by double-stranded RNA (dsRNA), and gives information about gene function quickly, easily, and inexpensively. The use of RNAi for genetic-based therapies is widely studied, especially in viral infections, cancers, and inherited genetic disorders. RNAi has been used to make tissue-specific knockdown mice for studying gene function in a whole animal. Combined with genomics data, RNAi-directed gene-silencing could allow functional determination of any gene expressed in a cell or pathway. The term RNAi came from the discovery that the injection of dsRNAs into Caenorhabditis elegans interferes with the expression of specific genes containing a complementary region to the delivered dsRNA. Although stalled for a time by the non-gene-specific interferon response elicited by dsRNA molecules longer than about 30 nucleotides in mammalian cells, Tom Tuschl's group found that transfection of synthetic 21-nucleotide small-interfering RNA (siRNA) duplexes were highly selective and sequence-specific inhibitors of endogenous genes.

Rickets, once thought vanquished, is reappearing. In some less developed countries it hardly went away. This seminar reviews the effects of genes, stage of development, and environment on clinical expression of the disease. Rickets can be secondary to disorders of the gut, pancreas, liver, kidney, or metabolism; however, it is mostly due to nutrient deficiency and we concentrate on this form. Although calcium deficiency contributes in communities where little cows' milk is consumed, deficiency of vitamin D is the main cause. There are three major problems: the promotion of exclusive breastfeeding for long periods without vitamin D supplementation, particularly for babies whose mothers are vitamin D deficient; reduced opportunities for production of the vitamin in the skin because of female modesty and fear of skin cancer; and the high prevalence of rickets in immigrant groups in more temperate regions. A safety net of extra dietary vitamin D should be re-emphasised, not only for children but also for pregnant women. The reason why many immigrant children in temperate zones have vitamin D deficiency is unclear. We speculate that in addition to differences in genetic factors, sun exposure, and skin pigmentation, iron deficiency may affect vitamin D handling in the skin or gut or its intermediary metabolism.

Making evidence from scientific studies available to clinical practice has been expected to directly improve quality of care, but this expectation has not been realised. The notion of quality of care is complex, and quality improvement needs medical, contextual, and policy evidence. In primary care, research is needed that takes into account the specific characteristics of its population and the presentation and prevalence of illness and disease. The context of the doctor-patient encounter plays a major part, and needs better understanding. At the policy level, issues of equity must be addressed. The knowledge base for family practice must be expanded by integration of multiple methods of comprehension, so we can bridge the gap between evidence and practice.

The number of patients with congenital cardiac disease reaching adulthood is increasing steadily. Many adults with such disease face both medical and surgical difficulties. Most clinicians know very little about basic cardiac defects, their natural history, complications after surgery, and adequate management of these patients. We aim to provide an overview of the most frequently encountered cardiac lesions and long-term complications and to outline an up-to-date approach to their management. We present a series of hypothetical cases and discuss their management.

Echinococcosis is a near-cosmopolitan zoonosis caused by adult or larval stages of cestodes belonging to the genus Echinococcus (family Taeniidae). The two major species of medical and public health importance are Echinococcus granulosus and Echinococcus multilocularis, which cause cystic echinococcosis and alveolar echinococcosis, respectively. Both are serious and severe diseases, the latter especially so, with high fatality rates and poor prognosis if managed incorrectly. Several reports have shown that both diseases are of increasing public health concern and that both can be regarded as emerging or re-emerging diseases. In this review we discuss aspects of the biology, life cycle, aetiology, distribution, and transmission of the Echinococcus organisms, and the epidemiology, clinical features, treatment, and diagnosis of the diseases they cause. We also discuss the countermeasures available for the control and prevention of these diseases. E granulosus still has a wide geographical distribution, although effective control against cystic echinococcosis has been achieved in some regions. E multilocularis and alveolar echinococcosis are more problematic, since the primary transmission cycle is almost always sylvatic so that efficient and cost-effective methods for control are unavailable.

Major difficulties arise when introducing evidence and clinical guidelines into routine daily practice. Data show that many patients do not receive appropriate care, or receive unnecessary or harmful care. Many approaches claim to offer solutions to this problem; which ones are as yet the most effective and efficient is unclear. We aim to provide an overview of present knowledge about initiatives to changing medical practice. Substantial evidence suggests that to change behaviour is possible, but this change generally requires comprehensive approaches at different levels (doctor, team practice, hospital, wider environment), tailored to specific settings and target groups. Plans for change should be based on characteristics of the evidence or guideline itself and barriers and facilitators to change. In general, evidence shows that none of the approaches for transferring evidence to practice is superior to all changes in all situations.

Stroke is a major public-health burden worldwide. Prevention programmes are essential to reduce the incidence of stroke and to prevent the all but inevitable stroke epidemic, which will hit less developed countries particularly hard as their populations age and adopt lifestyles of the more developed countries. Efficient, effective, and rapid diagnosis of stroke and transient ischaemic attack is crucial. The diagnosis of the exact type and cause of stroke, which requires brain imaging as well as traditional clinical skills, is also important when it will influence management. The treatment of acute stroke, the prevention and management of the many complications of stroke, and the prevention of recurrent stroke and other serious vascular events are all improving rapidly. However, stroke management will only be most effective when delivered in the context of an organised, expert, educated, and enthusiastic stroke service that can react quickly to the needs of patients at all stages from onset to recovery.

The echinocandins are large lipopeptide molecules that are inhibitors of beta-(1,3)-glucan synthesis, an action that damages fungal cell walls. In vitro and in vivo, the echinocandins are rapidly fungicidal against most Candida spp and fungistatic against Aspergillus spp. They are not active at clinically relevant concentrations against Zygomycetes, Cryptococcus neoformans, or Fusarium spp. No drug target is present in mammalian cells. The first of the class to be licensed was caspofungin, for refractory invasive aspergillosis (about 40% response rate) and the second was micafungin. Adverse events are generally mild, including (for caspofungin) local phlebitis, fever, abnormal liver function tests, and mild haemolysis. Poor absorption after oral administration limits use to the intravenous route. Dosing is once daily and drug interactions are few. The echinocandins are widely distributed in the body, and are metabolised by the liver. Results of studies of caspofungin in candidaemia and invasive candidiasis suggest equivalent efficacy to amphotericin B, with substantially fewer toxic effects. Absence of antagonism in combination with other antifungal drugs suggests that combination antifungal therapy could become a general feature of the echinocandins, particularly for invasive aspergillosis.

Autism is a disorder characterised by severe difficulties in social interaction and communication, and with unusual behaviours. Once thought of as rare, autism is now recognised as being common. The role of CNS factors in pathogenesis is suggested by high rates of seizure disorder; research has highlighted the role of several specific brain regions in syndrome pathogenesis. Autism is a strongly genetic disorder and probably arises because of multiple genes; recurrence rates in families with one child are high. Early intervention with various techniques is helpful in many cases. Some pharmacological agents may help with certain problematic behaviours but do not address the underlying cause of the disorder.

Hepatitis A is one of the most common vaccine-preventable infectious diseases in the world. Effective vaccines against hepatitis A have been available since 1992, and they provide long-term immunity against the infection. However, there is no worldwide consensus on how long protection will last or whether there will be a need for hepatitis A virus (HAV) booster vaccinations in the future. In most countries, booster-vaccination policy is guided by manufacturers' recommendations, national authorities, or both. In June, 2002, a panel of international experts met to review the long-term immunogenicity and protection conferred by HAV vaccine in different population groups. Data have shown that after a full primary vaccination course, protective antibody amounts persist beyond 10 years in healthy individuals, and underlying immune memory provides protection far beyond the duration of anti-HAV antibodies. The group concluded that there is no evidence to lend support to HAV booster vaccination after a full primary vaccination course in a healthy individual. However, further investigations are needed before deciding if boosters can be omitted in special patient-groups.

Mycobacterium ulcerans causes devastating necrotic lesions in affected individuals. The disease, commonly called Buruli ulcer, is increasing in prevalance in western African countries. Treatment is mainly surgical; no clinical trials have been done to support the use of antimycobacterial drugs. A secreted polyketide toxin, mycolactone, is responsible for the tissue damage; its chemical structure has been elucidated.

Chronic obstructive pulmonary disease (COPD) is a major cause of death and disability worldwide. Recognition that the burden of this disorder will continue to increase over the next 20 years despite medical intervention has stimulated new research into the underlying mechanisms, leading to a rational basis for evaluation of existing therapies, and has suggested novel treatment approaches. Tobacco exposure remains the main but not exclusive cause of COPD. Whether the lung is injured by changes in the balance of proteases and antiproteases, tissue damage by oxidative stress, or a combination of the two is still not known. The genetic basis of susceptibility to COPD is now being studied as is the role of computed tomography in the identification of structural damage in individuals with less symptomatic disease. Clinical diagnosis still relies heavily on an appropriate history confirmed by abnormal spirometry. Smoking cessation is possible in a substantial proportion of individuals with symptoms but is most effective if withdrawal is supported by pharmacological treatment. Treatment with long-acting inhaled bronchodilators and, in more severe disease, inhaled corticosteroids reduces symptoms and exacerbation frequency and improves health status. Rehabilitation can be even more effective, at least for a year after the treatment. Recent guidelines have made practical suggestions about how to optimise these treatments and when to consider addition of oxygen, surgery, and non-invasive ventilation. Regular review of this guidance is important if future management advances are to be implemented effectively.

The proliferative capacity of human cells is regulated by telomerase, an enzyme uniquely specialised for telomeric DNA synthesis. The critical role of telomerase activation in tumour progression and tumour maintenance has been well established in studies of cancer and of oncogenic transformation in cell culture. New evidence suggests that telomerase activation has an important role in normal somatic cells, and that failure to activate sufficient telomerase also promotes disease. We review the evidence for premature telomere attrition in proliferative deficiencies of the human haemopoietic system, and discuss the potential use of telomerase activation in telomere-restorative gene therapy.

The inflammatory myopathies, commonly described as idiopathic, are the largest group of acquired and potentially treatable myopathies. On the basis of unique clinical, histopathological, immunological, and demographic features, they can be differentiated into three major and distinct subsets: dermatomyositis, polymyositis, and inclusion-body myositis. Use of new diagnostic criteria is essential to discriminate between them and to exclude other disorders. Dermatomyositis is a microangiopathy affecting skin and muscle; activation and deposition of complement causes lysis of endomysial capillaries and muscle ischaemia. In polymyositis and inclusion-body myositis, clonally expanded CD8-positive cytotoxic T cells invade muscle fibres that express MHC class I antigens, which leads to fibre necrosis via the perforin pathway. In inclusion-body myositis, vacuolar formation with amyloid deposits coexists with the immunological features. The causative autoantigen has not yet been identified. Upregulated vascular-cell adhesion molecule, intercellular adhesion molecule, chemokines, and their receptors promote T-cell transgression, and various cytokines increase the immunopathological process. Early initiation of therapy is essential, since both polymyositis and dermatomyositis respond to immunotherapeutic agents. New immunomodulatory agents currently being tested in controlled trials may prove promising for difficult cases.

The Global Polio Eradication Initiative was launched in 1988. Assessment of the politics, production, financing, and economics of this international effort has suggested six lessons that might be pertinent to the pursuit of other global health goals. First, such goals should be based on technically sound strategies with proven operational feasibility in a large geographical area. Second, before launching an initiative, an informed collective decision must be negotiated and agreed in an appropriate international forum to keep to a minimum long-term risks in financing and implementation. Third, if substantial community engagement is envisaged, efficient deployment of sufficient resources at that level necessitates a defined, time-limited input by the community within a properly managed partnership. Fourth, although the so-called fair-share concept is arguably the best way to finance such goals, its limitations must be recognised early and alternative strategies developed for settings where it does not work. Fifth, international health goals must be designed and pursued within existing health systems if they are to secure and sustain broad support. Finally, countries, regions, or populations most likely to delay the achievement of a global health goal should be identified at the outset to ensure provision of sufficient resources and attention. The greatest threats to poliomyelitis eradication are a financing gap of US 210 million dollars and difficulties in strategy implementation in at most five countries.

The growing global burden of non-communicable diseases in poor countries and poor populations has been neglected by policy makers, major multilateral and bilateral aid donors, and academics. Despite strong evidence for the magnitude of this burden, the preventability of its causes, and the threat it poses to already strained health care systems, national and global actions have been inadequate. Globalisation is an important determinant of non-communicable disease epidemics since it has direct effects on risks to populations and indirect effects on national economies and health systems. The globalisation of the production and marketing campaigns of the tobacco and alcohol industries exemplify the challenges to policy makers and public health practitioners. A full range of policy responses is required from government and non-governmental agencies; unfortunately the capacity and resources for this response are insufficient, and governments need to respond appropriately. The progress made in controlling the tobacco industry is a modest cause for optimism.

Among communicable diseases, tuberculosis is the second leading cause of death worldwide, killing nearly 2 million people each year. Most cases are in less-developed countries; over the past decade, tuberculosis incidence has increased in Africa, mainly as a result of the burden of HIV infection, and in the former Soviet Union, owing to socioeconomic change and decline of the health-care system. Definitive diagnosis of tuberculosis remains based on culture for Mycobacterium tuberculosis, but rapid diagnosis of infectious tuberculosis by simple sputum smear for acid-fast bacilli remains an important tool, and more rapid molecular techniques hold promise. Treatment with several drugs for 6 months or more can cure more than 95% of patients; direct observation of treatment, a component of the recommended five-element DOTS strategy, is judged to be the standard of care by most authorities, but currently only a third of cases worldwide are treated under this approach. Systematic monitoring of case detection and treatment outcomes is essential to effective service delivery. The proportion of patients diagnosed and treated effectively has increased greatly over the past decade but is still far short of global targets. Efforts to develop more effective tuberculosis vaccines are under way, but even if one is identified, more effective treatment systems are likely to be required for decades. Other modes of tuberculosis control, such as treatment of latent infection, have a potentially important role in some contexts. Until tuberculosis is controlled worldwide, it will continue to be a major killer in less-developed countries and a constant threat in most of the more-developed countries.