Seven different porphyrias form a group of inherited metabolic disorders, each resulting from a partial deficiency of a specific enzyme in the haem biosynthesis pathway. Clinically, the three most important entities are an acute porphyric attack and acute and chronic skin symptoms. Porphyrias are rare and sometimes misdiagnosed, because various symptoms and signs mimic other diseases. Once porphyria is suspected, biochemical analyses easily detect porphyrins and their precursors from blood, urine, or faeces. Mutation screening can be done at the quiescent phase of the disease. Pathogenetic mechanisms and clinical manifestations differ in individual porphyrias and most of them require a specific treatment. Early diagnosis and information about precipitating factors can diminish mortality and prevent subsequent attacks among patients with acute porphyrias, so mutation screening is recommended for family members.

Septic shock, the most severe complication of sepsis, is a deadly disease. In recent years, exciting advances have been made in the understanding of its pathophysiology and treatment. Pathogens, via their microbial-associated molecular patterns, trigger sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. Proinflammatory mediators that contribute to eradication of invading microorganisms are produced, and anti-inflammatory mediators control this response. The inflammatory response leads to damage to host tissue, and the anti-inflammatory response causes leucocyte reprogramming and changes in immune status. The time-window for interventions is short, and treatment must promptly control the source of infection and restore haemodynamic homoeostasis. Further research is needed to establish which fluids and vasopressors are best. Some patients with septic shock might benefit from drugs such as corticosteroids or activated protein C. Other therapeutic strategies are under investigation, including those that target late proinflammatory mediators, endothelium, or the neuroendocrine system.

Inhibitors of phosphodiesterase type 4 (PDE4) act by increasing intracellular concentrations of cyclic AMP, which has a broad range of anti-inflammatory effects on various key effector cells involved in asthma and chronic obstructive pulmonary disease (COPD). The therapeutic ratio for PDE4 inhibitors is thought to be determined by selectivity on receptor subtypes for relative effects on PDE4B (anti-inflammatory) and PDE4D (emesis). The two main orally active PDE4 inhibitors in the late phase III of clinical development are cilomilast and roflumilast; the latter (and its active metabolite N-oxide) is more selective and potent with a superior therapeutic ratio. Studies on cilomilast in COPD based on bronchial biopsy material have shown a broad range of anti-inflammatory activity, and the available evidence on clinical outcomes for up to 6 months with cilomilast 15 mg twice daily and roflumilast 500 mug once daily have shown variable but significant effects on exacerbations and quality of life, with small improvements in measures of pulmonary function. Roflumilast has a better safety and tolerability profile than cilomilast, with the main adverse effects being nausea, diarrhoea, and abdominal pain. Roflumilast also has activity in asthma as assessed by its attenuation of allergen and exercise challenges, and it shows clinical efficacy equivalent to that of beclomethasone dipropionate 400 mug daily. The emerging results of clinical trials on PDE4 inhibitors in asthma and COPD should be interpreted with cautious optimism since much of the evidence has been published only in abstract form to date. The next few years should resolve important issues about the potential role of these drugs as oral non-steroidal anti-inflammatory therapy for asthma and COPD and their place in management guidelines. Ultimately, clinicians will want to know whether PDE4 inhibitors are anything more than expensive "designer" theophylline, the archetypal non-selective phosphodiesterase inhibitor.

Every year, more than 945000 people develop colorectal cancer worldwide, and around 492000 patients die. This form of cancer develops sporadically, in the setting of hereditary cancer syndromes, or on the basis of inflammatory bowel diseases. Screening and prevention programmes are available for all these causes and should be more widely publicised. The adenoma-carcinoma sequence is the basis for development of colorectal cancer, and the underlying molecular changes have largely been identified. Prognosis depends on factors related to the patient, treatment, and tumour, and the expertise of the treatment team is one of the major determinants of outcome. New information on the molecular basis of this cancer have led to the development of targeted therapeutic options, which are being tested in clinical trials. Further clinical progress will largely depend on the broader implementation of multidisciplinary treatment strategies following the principles of evidence-based medicine.

Systemic inflammatory diseases commonly affect the sclera, cornea, retina, and orbit, and can pose a serious threat to sight. They encompass both primary and secondary vasculitic disorders and specific granulomatous inflammatory conditions. As well as direct eye involvement from the systemic inflammatory process, there can be signs of ocular ischaemia due to carotid or ophthalmic arteritis, hypertensive retinopathy, and ocular complications such as chloroquine maculopathy related to anti-inflammatory drug treatment. Additionally, systemic infection relating to the eye, either as the result of primary infective disease processes or infection secondary to immunosuppression, might be mistaken as endogenous intraocular inflammation. Infection can closely mimic the ocular signs of endogenous inflammation, and in selected patients (such as those who have been immunosuppressed to treat vasculitis and who additionally have had invasive surgery, indwelling intravenous catheters, or systemic sepsis), it might be necessary to specifically exclude infection by the sampling and culturing of intraocular fluids and tissue.

Collagenous colitis and lymphocytic colitis, collectively designated microscopic colitis, have until recently been considered as rare gastrointestinal disorders. New data suggest, however, that these disorders are relatively common, and to reach the correct diagnosis both the gastroenterologist and the pathologist must be aware of these diagnoses when evaluating patients with persistent watery non-bloody diarrhoea.

Neurological disease can involve the eye in many ways. Every structure--the conjunctiva, cornea, anterior chamber, iris, lens, vitreous humour, retina, choroid, and optic nerve--can be affected. In many cases, ocular involvement is the first manifestation of the underlying disease. In such cases, the ability of the physician to recognise the nature and significance of the ocular abnormality can lead to early diagnosis and successful treatment of the underlying condition. In other cases, recognition of the ocular abnormality can prevent permanent visual dysfunction.

Effective management of insomnia begins with recognition and adequate assessment. Family doctors and other health care providers such as practice nurses and psychologists should routinely enquire about sleep habits as a component of overall health assessment. Identification and treatment of primary psychiatric disorders, medical conditions, circadian disorders, or specific physiological sleep disorders--eg, sleep apnoea and periodic limb movement disorder--are essential steps in management of insomnia. Conditioned aspects of insomnia can be primary (psychophysiological insomnia) or may complicate sleep disturbance owing to other causes. Approved hypnotic drugs have clearly been shown to improve subjective and objective sleep measures in various short-term situations. Despite widespread use of standard hypnotics and sedating antidepressants for chronic insomnia, their role for this indication still remains to be further defined by research evidence. Non-pharmacological treatments, particularly stimulus control and sleep restriction, are effective for conditioned aspects of insomnia and are associated with durable long-term improvement in sleep.

Public nutrition is a broad-based, problem-solving approach to addressing malnutrition in complex emergencies that combines analysis of nutritional risk and vulnerability with action-oriented strategies, including policies, programmes, and capacity development. This paper focuses on six broad areas: nutritional assessment, distribution of a general food ration, prevention and treatment of moderate malnutrition, treatment of severe malnutrition in children and adults, prevention and treatment of micronutrient deficiency diseases, and nutritional support for at-risk groups, including infants, pregnant and lactating women, elderly people, and people living with HIV. Learning and documenting good practice from previous emergencies, the promotion of good practice in current emergencies, and adherence to international standards and guidelines have contributed to establishing the field of public nutrition. However, many practical challenges reduce the effectiveness of nutritional interventions in complex emergencies, and important research and programmatic questions remain.

Spina bifida results from failure of fusion of the caudal neural tube, and is one of the most common malformations of human structure. The causes of this disorder are heterogeneous and include chromosome abnormalities, single gene disorders, and teratogenic exposures. However, the cause is not known in most cases. Up to 70% of spina bifida cases can be prevented by maternal, periconceptional folic acid supplementation. The mechanism underlying this protective effect is unknown, but it is likely to include genes that regulate folate transport and metabolism. Individuals with spina bifida need both surgical and medical management. Although surgical closure of the malformation is generally done in the neonatal period, a randomised clinical trial to assess in utero closure of spina bifida has been initiated in the USA. Medical management is a lifelong necessity for individuals with spina bifida, and should be provided by a multidisciplinary team.

Delayed graft function is a form of acute renal failure resulting in post-transplantation oliguria, increased allograft immunogenicity and risk of acute rejection episodes, and decreased long-term survival. Factors related to the donor and prerenal, renal, or postrenal transplant factors related to the recipient can contribute to this condition. From experimental studies, we have learnt that both ischaemia and reinstitution of blood flow in ischaemically damaged kidneys after hypothermic preservation activate a complex sequence of events that sustain renal injury and play a pivotal part in the development of delayed graft function. Elucidation of the pathophysiology of renal ischaemia and reperfusion injury has contributed to the development of strategies to decrease the rate of delayed graft function, focusing on donor management, organ procurement and preservation techniques, recipient fluid management, and pharmacological agents (vasodilators, antioxidants, anti-inflammatory agents). Several new drugs show promise in animal studies in preventing or ameliorating ischaemia-reperfusion injury and possibly delayed graft function, but definitive clinical trials are lacking. The goal of monotherapy for the prevention or treatment of is perhaps unattainable, and multidrug approaches or single drug targeting multiple signals will be the next step to reduce post-transplantation injury and delayed graft function.

Endometriosis is an oestrogen-dependent disorder that can result in substantial morbidity, including pelvic pain, multiple operations, and infertility. New findings on the genetics, the possible roles of the environment and the immune system, and intrinsic abnormalities in the endometrium of affected women and secreted products of endometriotic lesions have given insight into the pathogenesis of this disorder and serve as the background for new treatments for disease-associated pain and infertility. Affected women are at higher risk than the general female population of developing ovarian cancer, and they also may be at increased risk of breast and other cancers as well as autoimmune and atopic disorders. Clinicians should assess and follow up affected women for these and other associated disorders. There will probably be a new repertoire of approaches for treatment and perhaps cure of this enigmatic disorder in the near future.

1-2% of children have vesicoureteric reflux (VUR). VUR occurs in 25-40% of children with acute pyelonephritis. VUR can lead to renal scarring, hypertension, and end-stage renal disease. The best form of treatment for children with VUR is debated: no treatment, long-term antibiotic prophylaxis, surgery, or a combination of antibiotic prophylaxis and surgery. In children with recurrent urinary tract infections (UTIs) and progressive renal damage, despite antibiotic prophylaxis, surgical correction of VUR, especially high-grade VUR, is generally recommended.

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.

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.