Since the 1990s, opportunistic fungal infections have emerged as a substantial cause of morbidity and mortality in profoundly immunocompromised patients. Hypercortisolaemic patients, both those with endogenous Cushing's syndrome and, much more frequently, those receiving exogenous glucocorticoid therapy, are especially at risk of such infections. This vulnerability is attributed to the complex dysregulation of immunity caused by glucocorticoids. We critically review the spectrum and presentation of invasive fungal infections that arise in the setting of hypercortisolism, and the ways in which glucocorticoids contribute to their pathogenesis. A better knowledge of the interplay between glucocorticoid-induced immunosuppression and invasive fungal infections should assist in earlier recognition and treatment of such infections. Efforts to decrease the intensity of glucocorticoid therapy should help to improve outcomes of opportunistic fungal infections.

Hepatorenal syndrome (HRS) is a common complication of advanced cirrhosis, characterised by renal failure and major disturbances in circulatory function. Renal failure is caused by intense vasoconstriction of the renal circulation. The syndrome is probably the final consequence of extreme underfilling of the arterial circulation secondary to arterial vasodilatation in the splanchnic vascular bed. As well as the renal circulation, most extrasplanchnic vascular beds are vasoconstricted. The diagnosis of HRS is currently based on the exclusion of other causes of renal failure. The prognosis is very poor, particularly when there is rapidly progressive renal failure (type 1). Liver transplantation is the best option in patients without contraindications to the procedure, but it is not always possible owing to the short survival expectancy. Therapies introduced during the past few years, such as vasoconstrictor drugs (vasopressin analogues, alpha-adrenergic agonists) or the transjugular intrahepatic portosystemic shunt, are effective in improving renal function. Nevertheless, liver transplantation should still be done in suitable patients even after improvement of renal function because the outcome of HRS is poor. Finally, recent findings suggest that the risk of developing HRS in the setting of spontaneous bacterial peritonitis may be reduced by the administration of albumin together with antibiotic therapy, and that of HRS occurring in severe alcoholic hepatitis can be lowered by administration of pentoxifylline. Although these findings need to be confirmed, these two strategies represent innovative approaches to lower the frequency of HRS in clinical practice.

Proteinuria is a major cause of progression in renal disease. The glomerular ultrafiltration barrier, containing highly differentiated podocytes, normally restricts protein access to the urine. Patients with urinary protein in the nephrotic range (>3.5 g daily) often have effaced podocyte foot-processes. Slit diaphragms span the gaps between foot processes as a barrier to macromolecules. Nephrin and podocin are slit-diaphragm proteins identified in families with congenital nephrotic syndromes. CD2-associated protein (CD2AP) is an adapter protein originally identified as a novel ligand interacting with the T-cell-adhesion protein CD2. CD2AP knockout (-/-) mice develop a congenital nephrotic syndrome with podocyte foot-process effacements and die at 6 weeks of age from renal failure. CD2AP localises to the slit diaphragm and links nephrin and podocin to phosphoinositide 3-OH kinase; this complex has cell-signalling properties.

Although most influenza infections are self-limited, few other diseases exert such a huge toll of suffering and economic loss. Despite the importance of influenza, there had been, until recently, little advance in its control since amantadine was licensed almost 40 years ago. During the past decade, evidence has accrued on the protection afforded by inactivated vaccines and the safety and efficacy in children of live influenza-virus vaccines. There have been many new developments in vaccine technology. Moreover, work on viral neuraminidase has led to the licensing of potent selective antiviral drugs, and economic decision modelling provides further justification for annual vaccination and a framework for the use of neuraminidase inhibitors. Progress has also been made on developing near-patient testing for influenza that may assist individual diagnosis or the recognition of widespread virus circulation, and so optimise clinical management. Despite these advances, the occurrence of avian H5N1, H9N2, and H7N7 influenza in human beings and the rapid global spread of severe acute respiratory syndrome are reminders of our vulnerability to an emerging pandemic. The contrast between recent cases of H5N1 infection, associated with high mortality, and the typically mild, self-limiting nature of human infections with avian H7N7 and H9N2 influenza shows the gaps in our understanding of molecular correlates of pathogenicity and underlines the need for continuing international research into pandemic influenza. Improvements in animal and human surveillance, new approaches to vaccination, and increasing use of vaccines and antiviral drugs to combat annual influenza outbreaks are essential to reduce the global toll of pandemic and interpandemic influenza.

Although anaesthetic and surgical procedures should be individualised for every patient, in practice many preoperative protocols and routines are used generally. In this article, we aim to emphasise: why preoperative assessment is important; how it should be done, and by whom; what can be expected; and the importance of test selection based on patients' needs and on scientific evidence of effectiveness. We outline the roles of preoperative medical assessment in otherwise healthy patients. Clinical history, preoperative questionnaires, physical examination, routine tests, individual risk-assessment, and fasting policies are investigated by review of published work. Cost of routine preoperative assessment, the anaesthetist's legal responsibility, and patients'views in the preoperative process are also considered. A thorough clinical preoperative assessment of the patient is more important than routine preoperative tests, which should be requested only when justified by clinical indications. Moreover, this practice eliminates unnecessary cost without compromising the safety and quality of care. Education and training of medical doctors should be more scientifically guided, emphasising the relevance of effectiveness, and cost-effectiveness in clinical decision-making and complemented by audit.

As many as one in 20 people in Europe and North America have some form of autoimmune disease. These diseases arise in genetically predisposed individuals but require an environmental trigger. Of the many potential environmental factors, infections are the most likely cause. Microbial antigens can induce cross-reactive immune responses against self-antigens, whereas infections can non-specifically enhance their presentation to the immune system. The immune system uses fail-safe mechanisms to suppress infection-associated tissue damage and thus limits autoimmune responses. The association between infection and autoimmune disease has, however, stimulated a debate as to whether such diseases might also be triggered by vaccines. Indeed there are numerous claims and counter claims relating to such a risk. Here we review the mechanisms involved in the induction of autoimmunity and assess the implications for vaccination in human beings.

Patients scheduled for surgical procedures continue to express concerns about their safety, outcome, and comfort. All medical interventions carry risks, but the patient often considers anaesthesia as the intervention with the greatest risk. Many still worry that they will not wake up after their surgery, or that they will be awake during the operation. Such events have received attention from the media, but are very rare. Challenges to improve the comfort of patients continue, especially with regard to the almost universal problems of nausea, vomiting, and pain after surgery. A newer concern is that patients will develop some degree of mental impairment that may delay return to a full work and social lifestyle for days and weeks. Developments in technology, education, and training have had a major effect on anaesthetic practice, so that anaesthesia is increasingly regarded as safe for the patient. This article explores patients' concerns, and considers whether science and technology help to provide solutions to these complex difficulties.

Lyme borreliosis is the most common tick-transmitted disease in the northern hemisphere and is caused by spirochaetes of the Borrelia burgdorferi species complex. A complete presentation of the disease is an extremely unusual observation in which a skin lesion results from a tick bite and is followed by heart and nervous system involvement, and later on by arthritis. Late involvement of eye, nervous system, joints, and skin can also occur. The only sign that enables a reliable clinical diagnosis of Lyme borreliosis is erythema migrans. Other features of some diagnostic value are earlobe lymphocytoma, meningoradiculoneuritis (Garin-Bujadoux-Bannwarth syndrome), and acrodermatitis chronica atrophicans. The many other symptoms and signs have little diagnostic value. Microbial or serological confirmation of borrelial infection is needed for all manifestations of the disease except for typical early skin lesions. However, even erythema migrans might not be pathognomonic for Lyme borreliosis, especially in the southern part of the USA where there is no microbiological evidence for infection with the agent. Treatment with antibiotics is beneficial for all stages of Lyme borreliosis, but is most successful early in the course of the illness. Prevention relies mainly on avoiding exposure to tick bites but there is some interest in chemoprophylaxis and also in vaccine development following initial disappointments.

Leptin was initially proposed to be the antiobesity hormone. Now it is realised that leptin is more a signal molecule that communicates nutritional status to the brain, and that it is involved in bone formation by having an antiosteogenic action.

In the past decade hernia surgery has been challenged by two new technologies: by laparoscopy, which has attempted to change the traditional open operative techniques, and by prosthetic mesh, which has achieved much lower recurrence rates. The demand by health care providers for increasingly efficient and cost-effective surgery has resulted in modifications to pathways of care to encourage more widespread adoption of day case, outpatient surgery, and local anaesthesia. In addition, the UK National Institute for Clinical Excellence has recommended strategies for bilateral and recurrent hernias. Here, we discuss these strategies and review some neglected aspects of hernia management such as trusses, antibiotic cover, return to work and activity, and emergency surgery. Many of the principles of management apply equally to inguinal and incisional hernias. We recommend that the more difficult and complex of the procedures be referred to specialists.

El Niño Southern Oscillation (ENSO) is a climate event that originates in the Pacific Ocean but has wide-ranging consequences for weather around the world, and is especially associated with droughts and floods. The irregular occurrence of El Niño and La Niña events has implications for public health. On a global scale, the human effect of natural disasters increases during El Niño. The effect of ENSO on cholera risk in Bangladesh, and malaria epidemics in parts of South Asia and South America has been well established. The strongest evidence for an association between ENSO and disease is provided by time-series analysis with data series that include more than one event. Evidence for ENSO's effect on other mosquito-borne and rodent-borne diseases is weaker than that for malaria and cholera. Health planners are used to dealing with spatial risk concepts but have little experience with temporal risk management. ENSO and seasonal climate forecasts might offer the opportunity to target scarce resources for epidemic control and disaster preparedness.

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.