Coeliac disease is caused by a genetically determined, specific immune response to antigens present in wheat gluten. This immune response may be focused on a limited region of the alpha gliadin component of gluten, and previous studies have suggested that the generation of epitopes for recognition by CD4+ T cells requires deamidation of the protein by tissue transglutaminase. However, it had not previously been shown that candidate epitope peptides could be generated from gluten in vivo, or that these epitopes were selective products of physiological digestion of gluten by tissue transglutaminase.

The sequencing of chromosome 21 and the use of models of Down's syndrome in mice have allowed us to relate genes and sets of genes to the neuropathogenesis of this syndrome, and to better understand its phenotype. Research in prenatal screening and diagnosis aims to find methods to identify fetuses with Down's syndrome, and reduce or eliminate the need for amniocentesis. Other areas of active research and clinical interest include the association of Down's syndrome with coeliac disease and Alzheimer's disease, and improved median age of death. Medical management of the syndrome requires an organised approach of assessment, monitoring, prevention, and vigilance. Improvements in quality of life of individuals with Down's syndrome have resulted from improvements in medical care, identification and treatment of psychiatric disorders (such as depression, disruptive behaviour disorders, and autism), and early educational interventions with support in typical educational settings. Approaches and outcomes differ throughout the world.

Body piercing is increasing in popularity around the world. In this review, I describe the history, origins, and peculiarities of various forms of body piercing, and procedures involved, variations in healing time, legal aspects and regulations, and complications and side-effects. I have also included a discussion of the motivation for and psychological background behind body piercing. In presenting research results, I aim to raise awareness of the many risks associated with body piercing. In presenting psychological data, I intend to create an understanding of the multifaceted and often intense motivations associated with body piercing, and, thus, to diminish any prejudices held by health professionals against people with piercings.

Recent breakthroughs in the treatment of psoriasis have led to improved understanding of the pathogenesis of this disease. Activation of T lymphocytes leading to release of cytokines results in proliferation of keratinocytes. Several new biological therapies have been developed, which target specific steps in the pathogenesis of psoriasis. With these new treatments, variable degrees of clearing occur. Initial data suggest improved safety over older agents such as methotrexate and ciclosporin, but long-term data are necessary. Enhancements in topical therapy and phototherapy have also increased the armamentarium of treatments available for this disorder.

Human papillomavirus (HPV) is believed to be the most important cause of cervical cancer. Recent studies suggest that long duration use of oral contraceptives increases the risk of cervical cancer in HPV positive women.

Epidemiologically, screening is justified by the importance of the disease and the lack of prospects for primary prevention, but evidence from natural history is unhelpful since men are more likely to die with, rather than from, prostate cancer. The available screening tests do not always detect men whose lesions could result in future morbidity or mortality. Evidence is limited for the benefits of treatment for localised cancers detected through screening, whereas the evidence for harm is clear. Observational evidence for the effect of population screening programmes is mixed, with no clear association between intensity of screening and reduced prostate cancer mortality. Screening for prostate cancer cannot be justified in low-risk populations, but the balance of benefit and harm will be more favourable after risk stratification. Prostate cancer screening can be justified only in research programmes designed to assess its effectiveness and help identify the groups who may benefit.

Gastro-oesophageal reflux disease (GORD) is a common chronic disorder that has severe impact on quality of life and often requires continuous acid-suppression therapy. Proton-pump inhibitors (PPIs) are extremely effective but expensive, and do not restore the normal antireflux barrier at the gastro-oesophageal junction. Antireflux surgery, even with the laparoscopic approach, has not proven more cost-effective than maintenance therapy with PPIs. Postoperative morbidity is substantial, especially when procedures are done outside expert centres. In the past few years several endoscopic techniques have been developed to treat chronic GORD on an outpatient basis. These techniques include radiofrequency-energy delivery and endoscopic suturing, although other approaches are now under development. STARING POINT: Two prospective open-label studies have recently reported 1-year follow-up of GORD patients treated either by radiofrequency-energy delivery (G Triadafilopoulos and colleagues Gastrointest Endosc 2002; 55:149-56) or endoscopic suturing (Z Mahmood and colleagues Gut 2003; 52:34-39). In a US multicentre trial, Triadafilopoulos and colleagues delivered radiofrequency energy to the cardia and distal oesophagus in patients with chronic heartburn, regurgitation or both (the Stretta procedure). All patients were on continuous acid-suppression therapy, but none had severe oesophagitis or hiatus hernia of more than 2 cm. At 12 months, 94 patients available for follow-up showed significant improvement in GORD symptoms, quality of life, and oesophageal acid-exposure. The need for PPI therapy fell from 98% to 30% of patients. In the Mahmood study, 26 similar patients had endoscopic suturing in a single centre. After 1 year, symptoms and quality of life improved and the need for PPIs was reduced to 36% from 100%. In both studies, only minor complications occurred, none of which required specific therapeutic intervention. WHERE NEXT? An effective outpatient procedure to treat chronic GORD would represent a major step forward. However, further studies are needed before an endoscopic approach can be adopted, as none of the published trials are well-controlled studies. Longer follow-up is needed to ensure that relapses do not occur rapidly, complications do not occur more frequently with less skilled operators, or that endoscopic-induced changes do not complicate or compromise subsequent antireflux surgery. Comparative studies of the cost-effectiveness of endoscopic therapy should also include medical strategies such as intermittent or on-demand PPI therapy.

There have been several new insights into the cause and treatment of sarcoidosis. Studies of genetic variation have shown that specific genetic polymorphisms are associated with increased risk of disease or affect disease presentation. These polymorphisms include variation of MHC and cytokines such as tumour necrosis factor (TNF). Not all investigators have come to the same conclusion, suggesting an interaction of various factors, including the patient's ethnic origin. Treatment of sarcoidosis varies considerably. Patients with symptomatic disease for more than 2-5 years have been of particular interest. Corticosteroids remain the standard of care in such cases, but immunosuppressive drugs have proved steroid-sparing in many patients. New agents, including pentoxifylline, thalidomide, and infliximab have proved useful in selected cases. The effectiveness of these agents seems to lie in their ability to block TNF, especially in the treatment of chronic disease.

Prostate cancer is one of the most common malignant diseases for which health-care intervention is sought worldwide, and in many developed countries it is the most common. Some patients with early-stage prostate cancer, especially those who are elderly and have comorbidities, can be observed without treatment. Surgery (radical prostatectomy) and radiotherapy (external-beam radiotherapy, brachytherapy, or both) are the most widely accepted curative options for patients with early-stage disease who need intervention. All these local treatments have been refined, resulting in comparable cure rates; however, they all have different side-effect profiles. Adjuvant systemic treatments (hormones or chemotherapy), which are effective for advanced-stage disease, might have a greater role in early-stage disease. Selecting the best option for individuals from the available options is challenging--the decision on whether and how to treat is based on many disease and patient factors. Here, we review the major treatment options, discuss their relative advantages and disadvantages, and provide a general approach to management of patients with early-stage prostate cancer.

We describe recent trends in the HIV epidemic and the differences between eastern and central Europe, using surveillance data, and published and unpublished reports. During the past 5 years, most countries of the former Soviet Union have been severely affected by HIV epidemics that continue to spread as a result of injecting drug use. With an estimated 1 million individuals already infected--mostly injecting drug users--and high rates of syphilis, the region may soon also face a large-scale epidemic of sexually-transmitted HIV infection. Indeed, data indicate that an HIV epidemic, fuelled by heterosexual transmission, is emerging; its expansion will depend on the size of so-called bridge populations that link high-risk groups with the general population. The lack of evidence to indicate increased rates of HIV as a result of homosexual transmission could indicate the social vulnerability of homosexual and bisexual men in the region rather than the true epidemiological picture. In view of the current levels of HIV prevalence, eastern Europe will soon be confronted with a major AIDS epidemic. By contrast, rates of HIV in central Europe remain low at present, but behaviours that promote HIV transmission are present in all countries. Improved measures to prevent further HIV spread are urgently needed.

Amoebiasis is the second leading cause of death from parasitic disease worldwide. The causative protozoan parasite, Entamoeba histolytica, is a potent pathogen. Secreting proteinases that dissolve host tissues, killing host cells on contact, and engulfing red blood cells, E histolytica trophozoites invade the intestinal mucosa, causing amoebic colitis. In some cases amoebas breach the mucosal barrier and travel through the portal circulation to the liver, where they cause abscesses consisting of a few E histolytica trophozoites surrounding dead and dying hepatocytes and liquefied cellular debris. Amoebic liver abscesses grow inexorably and, at one time, were almost always fatal, but now even large abscesses can be cured by one dose of antibiotic. Evidence that what we thought was a single species based on morphology is, in fact, two genetically distinct species--now termed Entamoeba histolytica (the pathogen) and Entamoeba dispar (a commensal)--has turned conventional wisdom about the epidemiology and diagnosis of amoebiasis upside down. New models of disease have linked E histolytica induction of intestinal inflammation and hepatocyte programmed cell death to the pathogenesis of amoebic colitis and amoebic liver abscess.

This review focuses on new findings and controversial issues in the the pathology and molecular biology of adenocarcinoma of the prostate. Since management of high-grade prostatic intraepithelial neoplasia on needle biopsy--the most common precursor lesion to prostate cancer--is the crucial issue with this lesion, we discuss the risk of cancer subsequent to this histological diagnosis and the issue of whether such neoplasia should be regarded as carcinoma-in-situ. We also look at prostate cancer itself, starting with its diagnosis, reporting on needle biopsy, and reviewing how the most frequently used grading system, the Gleason grading system, affects treatment. The molecular basis of prostate cancer includes inheritable and somatic genetic changes (tumour suppressor genes, loss of heterozygosity, gene targets and regions of chromosomal gain, CpG island promoter methylation, invasion and metastasis suppressor genes, telomere shortening, and genetic instability). Changed gene expression (eg, proliferation-related genes, changes in the androgen receptor, apoptosis and stress-response genes) have potential as biomarkers and therapeutic targets in prostate cancer.

Variceal bleeding is the most frequent severe complication of portal hypertension and a leading cause of death and liver transplantation in patients with cirrhosis. Patients surviving a variceal bleed are at high risk of rebleeding (over 60% at 1 year). Portacaval shunts and transjugular intrahepatic portasystemic shunts (TIPS) are effective for prevention of rebleeding but carry a high risk of hepatic encephalopathy. Endoscopic techniques include band ligation (EBL) and injection sclerotherapy (EIS). Drug approaches are based on non-selective beta blocker with or without isosorbide-5-mononitrate (ISMN).

Hodgkin's lymphoma was first described in 1832, but the nature of the pathognomic Reed-Sternberg cell, on which diagnosis of the disease is based, has only been elucidated in the past few years. Radiotherapy has been used to treat localised disease since the 1940s, and in the 1960s, effective combination chemotherapy regimens were introduced for anatomically advanced disease. The past three decades have witnessed continued improvement in outcome to such an extent that Hodgkin's lymphoma is now one of the most curable of all non-cutaneous malignancies. With improved survival and extended follow-up, relevance of treatment-induced late effects has become apparent, and modern therapeutic strategies must fully account for these effects. We review the pathology of Hodgkin's lymphoma, and its clinical presentation, investigation, present management, and natural history, including late effects of treatment.

Inability to replicate many results has led to increasing scepticism about the value of simple association study designs for detection of genetic variants contributing to common complex traits. Much attention has been drawn to the problems that might, in theory, bedevil this approach, including confounding from population structure, misclassification of outcome, and allelic heterogeneity. Other researchers have argued that absence of replication may indicate true heterogeneity in gene-disease associations. We suggest that the most important factors underlying inability to replicate these associations are publication bias, failure to attribute results to chance, and inadequate sample sizes, problems that are all rectifiable. Without changes to present practice, we risk wastage of scientific effort and rejection of a potentially useful research strategy.

Because more and more men are being diagnosed with prostate cancer worldwide, knowledge about and prevention of this disease is important. Epidemiological studies have provided some insight about the cause of prostate cancer in terms of diet and genetic factors. However, compared with other common cancers such as breast and lung cancer, the causes remain poorly understood. Several important issues could help in our understanding of this disease-the variation in incidence of prostate cancer between ethnic populations and the factors leading to familial clustering of the diseases.

Acute myocardial infarction is a common disease with serious consequences in mortality, morbidity, and cost to the society. Coronary atherosclerosis plays a pivotal part as the underlying substrate in many patients. In addition, a new definition of myocardial infarction has recently been introduced that has major implications from the epidemiological, societal, and patient points of view. The advent of coronary-care units and the results of randomised clinical trials on reperfusion therapy, lytic or percutaneous coronary intervention, and chronic medical treatment with various pharmacological agents have substantially changed the therapeutic approach, decreased in-hospital mortality, and improved the long-term outlook in survivors of the acute phase. New treatments will continue to emerge, but the greatest challenge will be to effectively implement preventive actions in all high-risk individuals and to expand delivery of acute treatment in a timely fashion for all eligible patients.

We aimed to review published work for the efficacy and safety of electroconvulsive therapy (ECT) with simulated ECT, ECT versus pharmacotherapy, and different forms of ECT for patients with depressive illness.

Measles is the most frequent cause of vaccine-preventable childhood deaths. Infants younger than the recommended age for vaccination are susceptible to the disease, and in developing countries they have a high risk of complications and mortality. Vaccine coverage in excess of 95% interrupts endemic transmission of measles in many countries, but achievement of such coverage almost always requires coordinated supplementary mass vaccination campaigns. There are substantial health gains if countries improve measles vaccine coverage, irrespective of whether or not high coverage is achieved; these gains include much lower measles complication and case fatality rates, long-term interepidemic duration, and possibly non-specific improvements in survival of children. Investigation into the cost-effectiveness of different strategies for measles control, including mass campaigns, two-dose schedules, and young-infant doses, would help countries to formulate control policies appropriate to their setting. Pneumonia is the most common fatal complication associated with measles, and at least 50% of measles-related pneumonias are due to bacterial superinfection. WHO has developed standard case management programmes for measles, but there are several unresolved clinical issues, including optimum indications for antibiotic treatment, the importance of intravenous immunoglobulin, the role of viral coinfection, and the risk of tuberculosis after measles. The priority in worldwide efforts to control measles is to lend support to poor countries, helping them to increase vaccine coverage and sustain improvements to vaccination infrastructure, and to address technical issues with respect to optimum vaccination schedules. Measles represents a specific challenge, whereby partnerships between high-income and developing nations would reduce child mortality in developing countries; such partnerships are not without incentive for high-income countries, since without them imported measles cannot be prevented.