People with diabetes develop foot ulcers because of neuropathy (sensory, motor, and autonomic deficits), ischaemia, or both. The initiating injury may be from acute mechanical or thermal trauma or from repetitively or continuously applied mechanical stress. Patients with clinically significant limb ischaemia should be assessed by a vascular surgeon to determine the need for angioplasty, stenting, or femorodistal bypass. When infection complicates a foot ulcer, the combination can be limb or life-threatening. Infection is defined clinically, but wound cultures reveal the causative pathogens. Tissue specimens are strongly preferred to wound swabs for wound cultures. Antimicrobial therapy should be guided by culture results, and should aim to cure the infection, not to heal the wound. Alleviation of the mechanical load on ulcers (off-loading) should always be a part of treatment. Neuropathic ulcers typically heal in 6 weeks with total contact casting, because it effectively relieves pressure at the ulcer site and enforces patient compliance. The success of other approaches to off-loading similarly depends on the patients' adherence to the effectiveness of pressure relief. Surgery to heal ulcers and prevent recurrence can include tenotomy, tendon lengthening, reconstruction, or removal of bony prominences. However, these procedures may result in secondary ulceration and other complications. Ulcer recurrence rates are high, but appropriate education for patients, the provision of posthealing footwear, and regular foot care can reduce rates of re-ulceration.

Diabetic foot problems are common throughout the world, resulting in major economic consequences for the patients, their families, and society. Foot ulcers are more likely to be of neuropathic origin, and therefore eminently preventable, in developing countries, which will experience the greatest rise in the prevalence of type 2 diabetes in the next 20 years. People at greatest risk of ulceration can easily be identified by careful clinical examination of the feet: education and frequent follow-up is indicated for these patients. When assessing the economic effects of diabetic foot disease, it is important to remember that rates of recurrence of foot ulcers are very high, being greater than 50% after 3 years. Costing should therefore include not only the immediate ulcer episode, but also social services, home care, and subsequent ulcer episodes. A broader view of total resource use should include some estimate of quality of life and the final outcome. An integrated care approach with regular screening and education of patients at risk requires low expenditure and has the potential to reduce the cost of health care.

The scientific knowledge to achieve a new global goal for the prevention of chronic diseases--a 2% yearly reduction in rates of death from chronic disease over and above projected declines during the next 10 years--already exists. However, many low-income and middle-income countries must deal with the practical realities of limited resources and a double burden of infectious and chronic diseases. This paper presents a novel planning framework that can be used in these contexts: the stepwise framework for preventing chronic diseases. The framework offers a flexible and practical public health approach to assist ministries of health in balancing diverse needs and priorities while implementing evidence-based interventions such as those recommended by the WHO Framework Convention on Tobacco Control and the WHO Global Strategy on Diet, Physical Activity and Health. Countries such as Indonesia, the Philippines, Tonga, and Vietnam have applied the stepwise planning framework: their experiences illustrate how the stepwise approach has general applicability to solving chronic disease problems without sacrificing specificity for any particular country.

Guillain-Barré syndrome consists of at least four subtypes of acute peripheral neuropathy. Major advances have been made in understanding the mechanisms of some of the subtypes. The histological appearance of the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) subtype resembles experimental autoimmune neuritis, which is predominantly caused by T cells directed against peptides from the myelin proteins P0, P2, and PMP22. The role of T-cell-mediated immunity in AIDP remains unclear and there is evidence for the involvement of antibodies and complement. Strong evidence now exists that axonal subtypes of Guillain-Barré syndrome, acute motor axonal neuropathy (AMAN), and acute motor and sensory axonal neuropathy (AMSAN), are caused by antibodies to gangliosides on the axolemma that target macrophages to invade the axon at the node of Ranvier. About a quarter of patients with Guillain-Barré syndrome have had a recent Campylobacter jejuni infection, and axonal forms of the disease are especially common in these people. The lipo-oligosaccharide from the C jejuni bacterial wall contains ganglioside-like structures and its injection into rabbits induces a neuropathy that resembles acute motor axonal neuropathy. Antibodies to GM1, GM1b, GD1a, and GalNac-GD1a are in particular implicated in acute motor axonal neuropathy and, with the exception of GalNacGD1a, in acute motor and sensory axonal neuropathy. The Fisher's syndrome subtype is especially associated with antibodies to GQ1b, and similar cross-reactivity with ganglioside structures in the wall of C jejuni has been discovered. Anti-GQ1b antibodies have been shown to damage the motor nerve terminal in vitro by a complement-mediated mechanism. Results of international randomised trials have shown equivalent efficacy of both plasma exchange and intravenous immunoglobulin, but not corticosteroids, in hastening recovery from Guillain-Barré syndrome. Further research is needed to discover treatments to prevent 20% of patients from being left with persistent and significant disability.

35 million people will die in 2005 from heart disease, stroke, cancer, and other chronic diseases. Only 20% of these deaths will be in high-income countries--while 80% will occur in low-income and middle-income countries. The death rates from these potentially preventable diseases are higher in low-income and middle-income countries than in high-income countries, especially among adults aged 30-69 years. The impact on men and women is similar. We propose a new goal for reducing deaths from chronic disease to focus prevention and control efforts among those concerned about international health. This goal-to reduce chronic disease death rates by an additional 2% annually--would avert 36 million deaths by 2015. An additional benefit will be a gain of about 500 million years of life over the 10 years from 2006 to 2015. Most of these averted deaths and life-years gained will be in low-income and middle-income countries, and just under half will be in people younger than 70 years. We base the global goal on worldwide projections of deaths by cause for 2005 and 2015. The data are presented for the world, selected countries, and World Bank income groups.

Governed by parasite and host factors and immunoinflammatory responses, the clinical spectrum of leishmaniasis encompasses subclinical (inapparent), localised (skin lesions), and disseminated infection (cutaneous, mucosal, or visceral). Symptomatic disease is subacute or chronic and diverse in presentation and outcome. Clinical characteristics vary further by endemic region. Despite T-cell-dependent immune responses, which produce asymptomatic and self-healing infection, or appropriate treatment, intracellular infection is probably life-long since targeted cells (tissue macrophages) allow residual parasites to persist. There is an epidemic of cutaneous leishmaniasis in Afghanistan and Pakistan and of visceral infection in India and Sudan. Diagnosis relies on visualising parasites in tissue or serology; culture and detection of parasite DNA are useful in the laboratory. Pentavalent antimony is the conventional treatment; however, resistance of visceral infection in India has spawned new treatment approaches--amphotericin B and its lipid formulations, injectable paromomycin, and oral miltefosine. Despite tangible advances in diagnosis, treatment, and basic scientific research, leishmaniasis is embedded in poverty and neglected. Current obstacles to realistic prevention and proper management include inadequate vector (sandfly) control, no vaccine, and insufficient access to or impetus for developing affordable new drugs.

The allele CHEK2*1100delC doubles the risk of breast cancer in unselected women, but could confer a greater risk in women with a family history of the disease, particularly of bilateral breast cancer. Our aim was to measure the risk of breast cancer in relatives of women with bilateral breast cancer who were carriers of this allele.

Beta blockers have been used widely in the treatment of hypertension and are recommended as first-line drugs in hypertension guidelines. However, a preliminary analysis has shown that atenolol is not very effective in hypertension. We aim to substantially enlarge the data on atenolol and analyse the effect of different beta blockers.

Genetic epidemiology is a rapidly expanding research field, but the implications of findings from such studies for individual or population health are unclear. The use of molecular genetic screening currently has some legitimacy in certain monogenic conditions, but no established value with respect to common complex diseases. Personalised medical care based on molecular genetic testing is also as yet undeveloped for common diseases. Genetic epidemiology can contribute to establishing the causal nature of environmentally modifiable risk factors, through the application of mendelian randomisation approaches and thus contribute to appropriate preventive strategies. Technological and other advances will allow the potential of genetic epidemiology to be revealed over the next few years, and the establishment of large population-based resources for such studies (biobanks) should contribute to this endeavour.

The term self-harm is commonly used to describe a wide range of behaviours and intentions including attempted hanging, impulsive self-poisoning, and superficial cutting in response to intolerable tension. As with suicide, rates of self-harm vary greatly between countries. 5-9% of adolescents in western countries report having self-harmed within the previous year. Risk factors include socioeconomic disadvantage, and psychiatric illness--particularly depression, substance abuse, and anxiety disorders. Cultural aspects of some societies may protect against suicide and self-harm and explain some of the international variation in rates of these events. Risk of repetition of self-harm and of later suicide is high. More than 5% of people who have been seen at a hospital after self-harm will have committed suicide within 9 years. Assessment after self-harm includes careful consideration of the patient's intent and beliefs about the lethality of the method used. Strong suicidal intent, high lethality, precautions against being discovered, and psychiatric illness are indicators of high suicide risk. Management after self-harm includes forming a trusting relationship with the patient, jointly identifying problems, ensuring support is available in a crisis, and treating psychiatric illness vigorously. Family and friends may also provide support. Large-scale studies of treatments for specific subgroups of people who self-harm might help to identify more effective treatments than are currently available. Although risk factors for self-harm are well established, aspects that protect people from engaging in self-harm need to be further explored.

Designs that involve families (the traditional strength of genetic epidemiology) and population-based sampling (the traditional strength of environmental epidemiology) allow investigation of both genes and environment, separately or together, and allow valid inference to the population. These case-control-family designs (including those involving twin pairs), can be regarded as retrospective cohort studies of relatives, and can be used for: determining familial risks and genetic models; estimating risk (penetrance) for measured genotypes; genetic association studies; stratifying risks by family history and known mutation status; and studying modifiers of risk in genetically susceptible individuals. Follow-up of families allows genetic and environmental risks to be studied prospectively. We discuss statistical methods, theoretical and practical strengths, limitations, and other issues. Given their versatility, population-based family studies could become a principal framework in epidemiology, and move genetics from its traditional focus on high-risk families to give it a wider clinical and population health relevance.

Small-cell lung carcinoma is an aggressive form of lung cancer that is strongly associated with cigarette smoking and has a tendency for early dissemination. Increasing evidence has implicated autocrine growth loops, proto-oncogenes, and tumour-suppressor genes in its development. At presentation, the vast majority of patients are symptomatic, and imaging typically reveals a hilar mass. Pathology, in most cases of samples obtained by bronchoscopic biopsy, should be undertaken by pathologists with pulmonary expertise, with the provision of additional tissue for immunohistochemical stains as needed. Staging should aim to identify any evidence of distant disease, by imaging of the chest, upper abdomen, head, and bones as appropriate. Limited-stage disease should be treated with etoposide and cisplatin and concurrent early chest irradiation. All patients who achieve complete remission should be considered for treatment with prophylactic cranial irradiation, owing to the high frequency of brain metastases in this disease. Extensive-stage disease should be managed by combination chemotherapy, with a regimen such as etoposide and cisplatin administered for four to six cycles. Thereafter, patients with progressive or recurrent disease should be treated with additional chemotherapy. For patients who survive long term, careful monitoring for development of a second primary tumour is necessary, with further investigation and treatment as appropriate.

Cholangiocarcinoma is a devastating malignancy that presents late, is notoriously difficult to diagnose, and is associated with a high mortality. The incidence of intrahepatic cholangiocarcinoma is increasing worldwide. The cause for this rise is unclear, although it could be related to an interplay between predisposing genetic factors and environmental triggers. MRI and CT with endoscopic ultrasound and PET provide useful diagnostic information in certain patients. Surgical resection is the only chance for cure, with results depending on careful technique and patient selection. Data suggest that liver transplantation could offer long-term survival in selected patients when combined with neoadjuvant chemoradiotherapy. Chemotherapy and radiotherapy have been ineffective for patients with inoperable tumours. For most of these patients biliary drainage is the mainstay of palliation. However, controversy exists over the type and positioning of biliary stents. Photodynamic treatment is a new palliative technique that might improve quality of life.

Physicians and other health-care professionals are rapidly adopting personal digital assistants (PDA). Palm pilots and other hand-held computers are also increasingly popular among medical students. PDAs can be used for medical student education and physician training, daily clinical practice, and research. PDAs and their increasing integration with information technology in hospitals could change the way health care is delivered in the future. But despite the increasing use of PDAs, evidence from well-designed research studies is still needed to show how much these devices can improve the quality of care, save patients' lives, and ultimately reduce health-care expenses. In this Review of PDA use in health care, the operating systems, basic functionality, security and safety, limitations, and future implications of PDAs are examined. A personal perspective and an introduction to medical PDA applications, software, guidelines, and programmes for health-care professionals is also provided.

Excess bodyweight is the sixth most important risk factor contributing to the overall burden of disease worldwide. 1.1 billion adults and 10% of children are now classified as overweight or obese. Average life expectancy is already diminished; the main adverse consequences are cardiovascular disease, type 2 diabetes, and several cancers. The complex pathological processes reflect environmental and genetic interactions, and individuals from disadvantaged communities seem to have greater risks than more affluent individuals partly because of fetal and postnatal imprinting. Obesity, with its array of comorbidities, necessitates careful clinical assessment to identify underlying factors and to allow coherent management. The epidemic reflects progressive secular and age-related decreases in physical activity, together with substantial dietary changes with passive over-consumption of energy despite the neurobiological processes controlling food intake. Effective long-term weight loss depends on permanent changes in dietary quality, energy intake, and activity. Neither the medical management nor the societal preventive challenges are currently being met.

Influenza vaccination of elderly individuals is recommended worldwide. Our aim was to review the evidence of efficacy and effectiveness of influenza vaccines in individuals aged 65 years or older.

The inevitable deterioration in hearing ability that occurs with age--presbycusis--is a multifactorial process that can vary in severity from mild to substantial. Left untreated, presbycusis of a moderate or greater degree affects communication and can contribute to isolation, depression, and, possibly, dementia. These psychological effects are largely reversible with rehabilitative treatment. Comprehensive rehabilitation is widely available but underused because, in part, of social attitudes that undervalue hearing, in addition to the cost and stigma of hearing aids. Remediation of presbycusis is an important contributor to quality of life in geriatric medicine and can include education about communication effectiveness, hearing aids, assistive listening devices, and cochlear implants for severe hearing loss. Primary care physicians should screen and refer their elderly patients for assessment and remediation. Where hearing aids no longer provide benefit, cochlear implantation is the treatment of choice with excellent results even in octogenarians.