Permanent cardiac pacing remains the only effective treatment for chronic, symptomatic bradycardia. In recent years, the role of implantable pacing devices has expanded substantially. At the beginning of the 21st century, exciting developments in technology seem to happen at an exponential rate. Major advances have extended the use of pacing beyond the arrhythmia horizon. Such developments include dual-chamber pacers, rate-response algorithms, improved functionality of implantable cardioverter defibrillators, combinations of sensors for optimum physiological response, and advances in lead placement and extraction. Cardiac pacing is poised to help millions of patients worldwide to live better electrically. We review pacing studies of sick-sinus syndrome, neurocardiogenic syncope, hypertrophic obstructive cardiomyopathy, and cardiac resynchronisation therapy, which are common or controversial indications for cardiac pacing. We also look at the benefits and complications of implantation in specific arrhythmias, suitability of different pacing modes, and the role of permanent pacing in the management of patients with heart failure.

Atenolol is one of the most widely used beta blockers clinically, and has often been used as a reference drug in randomised controlled trials of hypertension. However, questions have been raised about atenolol as the best reference drug for comparisons with other antihypertensives. Thus, our aim was to systematically review the effect of atenolol on cardiovascular morbidity and mortality in hypertensive patients.

An increasing number of interventions have been developed for patients to better manage their chronic illnesses. They are characterised by substantial responsibility taken by patients, and are commonly referred to as self-management interventions. We examine the background, content, and efficacy of such interventions for type 2 diabetes, arthritis, and asthma. Although the content and intensity of the programmes were affected by the objectives of management of the illness, the interventions differed substantially even within the three illnesses. When comparing across conditions, it is important to recognise the different objectives of the interventions and the complexity of the issues that they are attempting to tackle. For both diabetes and asthma, the objectives are concerned with the underlying control of the condition with clear strategies to achieve the desired outcome. By contrast, strategies to deal with symptoms of pain and the consequences of disability in arthritis can be more complex. The interventions that were efficacious provide some guidance as to the components needed in future programmes to achieve the best results. But to ensure that these results endure over time remains an important issue for self-management interventions.

Bacterial, fungal, viral, and parasitic pathogens all cause systemic infection and can spread to the eye. Dissemination of pathogens via the bloodstream can lead to direct involvement of the eye. Visual loss is common in bacterial or fungal endophthalmitis, and toxoplasmosis is a major cause of ocular morbidity and poor vision after congenital or acquired infection. Some infections cause intraocular damage by indirect mechanisms (eg, HIV-mediated immunosuppression), leading to opportunistic infections such as cytomegalovirus infection, periocular nerve involvement due to leprosy, and hypersensitivity reactions in tuberculosis. Eye symptoms might indicate the outcome of an underlying infection, such as development of retinal ischaemia in severe malaria, which is associated with a poor prognosis. Successful outcome for patients with ocular infection depends on close collaboration between clinicians identifying and treating underlying disease, specialist ophthalmic review, and ophthalmic interventional skills (when needed).

In this article we outline research since 1995 on the impact of various financing strategies on access to health services or health outcomes in low income countries. The limited evidence available suggests, in general, that user fees deterred utilisation. Prepayment or insurance schemes offered potential for improving access, but are very limited in scope. Conditional cash payments showed promise for improving uptake of interventions, but could also create a perverse incentive. The largely African origin of the reports of user fees, and the evidence from Latin America on conditional cash transfers, demonstrate the importance of the context in which studies are done. There is a need for improved quality of research in this area. Larger scale, upfront funding for evaluation of health financing initiatives is necessary to ensure an evidence base that corresponds to the importance of this issue for achieving development goals.

National prospective collection of tonsillar tissue to be tested anonymously for abnormal lymphoreticular accumulation of prion protein (PrP) was approved to begin in the UK in 2004. The UK is not, however, testing autopsy specimens attributably for abnormal PrP (PrP(SC)) so that recipients at risk after a blood transfusion from, or exposed to surgical instruments from, a deceased carrier of variant Creutzfeldt-Jakob disease (vCJD) can be followed up to quantify transmission risks. In Switzerland, surveillance for subclinical vCJD includes unconsented testing in autopsies: consented testing of tonsillar tissue is potentially attributable to interrupt human-to-human vCJD transmission or treat it.

With the global scope of sickle-cell disease, knowledge of the countless clinical presentations and treatment of this disorder need to be familiar to generalists, haematologists, internists, and paediatricians alike. Additionally, an underlying grasp of sickle-cell pathophysiology, which has rapidly accrued new knowledge in areas related to erythrocyte and extra-erythrocyte events, is crucial to an understanding of the complexity of this molecular disease with protean manifestations. We highlight studies from past decades related to such translational research as the use of hydroxyurea in treatment, as well as the therapeutic promise of red-cell ion-channel blockers, and antiadhesion and anti-inflammatory therapy. The novel role of nitric oxide in sickle-cell pathophysiology and the range of its potential use in treatment are also reviewed. Understanding of disease as the result of a continuing interaction between basic scientists and clinical researchers is best exemplified by this entity.

International consensus statements for resuscitation of newborn infants recommend provision of 100% oxygen with positive pressure if assisted ventilation is required. However, 100% oxygen exacerbates reperfusion injury in animals and reduces cerebral perfusion in newborn babies. We aimed to establish whether resuscitation with air decreased mortality or neurological disability in newborn infants compared with 100% oxygen.

Elder abuse has received increasing attention over the past decade as a common problem with serious consequences for the health and wellbeing of old people. Our aim is to assist clinicians by summarising recent international research and clinical findings about elder abuse, and to assess their quality, relevance, and feasibility for health-care providers in clinical practice. This seminar includes issues of definition and frequency of elder abuse and a summary of major known risk factors. The advantages and disadvantages of screening for elder abuse are discussed. We review clinical manifestations and diagnosis of elder abuse, and propose a protocol for medical assessment of a patient with confirmed or suspected abuse. Suggestions for treatment are offered on the basis that elder abuse is multifactorial and needs individual medical and social intervention strategies, preferably in the context of a multidisciplinary team.

Oxidative stress can cause cancer. Our aim was to establish whether antioxidant supplements reduce the incidence of gastrointestinal cancer and mortality.

The incidence of malignant pleural mesothelioma is increasing throughout most of the world. This cancer is uniformly fatal, and characterised by progressive breathlessness and unremitting pain in the chest wall. From the onset of symptoms, survival is from a few weeks to a few years. Desperation by patients and doctors has driven a search for effective treatments. Clinical benefits are marginal and evidence of a good quality is lamentably lacking.

Superficial fungal infections arise from a pathogen that is restricted to the stratum corneum, with little or no tissue reaction. In this Seminar, three types of infection will be covered: tinea versicolor, piedra, and tinea nigra. Tinea versicolor is common worldwide and is caused by Malassezia spp, which are human saprophytes that sometimes switch from yeast to pathogenic mycelial form. Malassezia furfur, Malassezia globosa, and Malassezia sympodialis are most closely linked to tinea versicolor. White and black piedra are both common in tropical regions of the world; white piedra is also endemic in temperate climates. Black piedra is caused by Piedraia hortae; white piedra is due to pathogenic species of the Trichosporon genus. Tinea nigra is also common in tropical areas and has been confused with melanoma.

Imatinib is approved worldwide for use in gastrointestinal stromal tumours (GIST). We aimed to assess dose dependency of response and progression-free survival with imatinib for metastatic GIST.

No currently available treatments have been shown to slow the progression of chronic obstructive pulmonary disease (COPD) or suppress the inflammation in small airways and lung parenchyma. However, several new treatments are in clinical development; some target the inflammatory process and others are directed against structural cells. A group of specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD; these include agents directed against adhesion molecules and chemokines, as well as therapies to oppose tumour necrosis factor alpha and increase interleukin 10. Broad-range anti-inflammatory drugs are now in phase III development for COPD; they include inhibitors of phosphodiesterase 4. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor kappaB, and phosphoinositide-3-kinase gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase, and antagonists of leukotriene B4 receptor. Inhibitors of epidermal-growth-factor-receptor kinase and calcium-activated chloride channels have the potential to prevent overproduction of mucus. Therapy to inhibit fibrosis is being developed against transforming growth factor beta1 and protease-activated receptor 2. There is also a search for inhibitors of serine proteinases and matrix metalloproteinases to prevent lung destruction and the development of emphysema, as well as drugs such as retinoids that might even reverse this process. Effective delivery of drugs to the sites of disease in the peripheral lung is an important consideration, and there is a need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD.

The Atkins diet books have sold more than 45 million copies over 40 years, and in the obesity epidemic this diet and accompanying Atkins food products are popular. The diet claims to be effective at producing weight loss despite ad-libitum consumption of fatty meat, butter, and other high-fat dairy products, restricting only the intake of carbohydrates to under 30 g a day. Low-carbohydrate diets have been regarded as fad diets, but recent research questions this view.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide, and the burden of the disorder will continue to increase over the next 20 years despite medical intervention. Apart from smoking cessation, no approach or agent affects the rate of decline in lung function and progression of the disease. Especially in the later phase, COPD is a multicomponent disorder, and various integrated intervention strategies are needed as part of the optimum management programme. This seminar describes largely non-pharmacological interventions aimed at improving health status and function of disabled patients. Exacerbations become progressively more troublesome as baseline lung function declines, commonly necessitating hospital admission and associated with the development of acute respiratory failure.

The imperative to undertake randomised trials in children arises from extraordinary advances in basic biomedical sciences, needing a matching commitment to translational research if child health is to reap the benefits from this new knowledge. Unfortunately, many prescribed treatments for children have not been adequately tested in children, sometimes resulting in harmful treatments being given and beneficial treatments being withheld. Government, industry, funding agencies, and clinicians are responsible for research priorities being adult-focused because of the greater burden of disease in adults, coupled with financial and marketing considerations. This bias has meant that the equal rights of children to participate in trials has not always been recognised. This is changing, however, as the need for clinical trials in children has been increasingly recognised by the scientific community and broader public, leading to new legislation in some countries making trials of interventions mandatory in children as well as adults before drug approval is given. Trials in children are more challenging than those in adults. The pool of eligible children entering trials is often small because many conditions are uncommon in children, and the threshold for gaining consent is often higher and more complex because parents have to make decisions about trial participation on behalf of their child. Uncertain about what is best, despite supporting the notion of trials in principle, parents and paediatricians generally opt for the new intervention or for standard care rather than trial participation. In this review, we explore issues relating to trial participation for children and suggest some strategies for improving the conduct of clinical trials involving children.

Chronic obstructive pulmonary disease (COPD) is a readily diagnosable disorder that responds to treatment. Smoking cessation can reduce symptoms and prevent progression of disease. Bronchodilator therapy is key in improvement of lung function. Three classes of bronchodilators-beta agonists, anticholinergics, and theophylline-are available and can be used individually or in combination. Inhaled glucocorticoids can also improve airflow and can be combined with bronchodilators. Inhaled glucocorticoids, in addition, might reduce exacerbation frequency and severity as might some bronchodilators. Effective use of pharmacotherapy in COPD needs integration with a rehabilitation programme and successful treatment of co-morbidities, including depression and anxiety. Treatment for stable COPD can improve the function and quality of life of many patients, could reduce admissions to hospital, and has been suggested to improve survival.

The cause and pathogenesis of Parkinson's disease remain unknown; mitochondrial dysfunction, oxidative damage, environmental factors, and genetic predisposition might all be involved. Identification of the causative genes for familial Parkinson's diseases allow study of the pathogenesis of the disease at the molecular level.

The airflow limitation that defines chronic obstructive pulmonary disease (COPD) is the result of a prolonged time constant for lung emptying, caused by increased resistance of the small conducting airways and increased compliance of the lung as a result of emphysematous destruction. These lesions are associated with a chronic innate and adaptive inflammatory immune response of the host to a lifetime exposure to inhaled toxic gases and particles. Processes contributing to obstruction in the small conducting airways include disruption of the epithelial barrier, interference with mucociliary clearance apparatus that results in accumulation of inflammatory mucous exudates in the small airway lumen, infiltration of the airway walls by inflammatory cells, and deposition of connective tissue in the airway wall. This remodelling and repair thickens the airway walls, reduces lumen calibre, and restricts the normal increase in calibre produced by lung inflation. Emphysematous lung destruction is associated with an infiltration of the same type of inflammatory cells found in the airways. The centrilobular pattern of emphysematous destruction is most closely associated with cigarette smoking, and although it is initially focused on respiratory bronchioles, separate lesions coalesce to destroy large volumes of lung tissue. The panacinar pattern of emphysema is characterised by a more even involvement of the acinus and is associated with alpha1 antitrypsin deficiency. The technology needed to diagnose and quantitate the individual small airway and emphysema phenotypes present in people with COPD is being developed, and should prove helpful in the assessment of therapeutic interventions designed to modify the progress of either phenotype.