Sepsis is a systemic inflammatory response to the presence of infection, mediated via the production of many cytokines, including tumour necrosis factor (TNF-), interleukin (IL)-6, and IL-1, which cause changes in the circulation and in the coagulation cascade. There is stagnation of blood flow and poor oxygenation, subclinical coagulopathy with elevated D-dimers, and increased production of superoxide from nitric oxide synthase. All of these changes favour endothelial apoptosis and necrosis as well as increased oxidant stress. Reduced levels of activated protein C, which is normally anti-inflammatory and antiapoptotic, can lead to further tissue injury. Cirrhotic patients are particularly susceptible to bacterial infections because of increased bacterial translocation, possibly related to liver dysfunction and reduced reticuloendothelial function. Sepsis ensues when there is overactivation of pathways involved in the development of the sepsis syndrome, associated with complications such as renal failure, encephalopathy, gastrointestinal bleed, and shock with decreased survival. Thus the treating physician needs to be vigilant in diagnosing and treating bacterial infections in cirrhosis early, in order to prevent the development and downward spiral of the sepsis syndrome. Recent advances in management strategies of infections in cirrhosis have helped to improve the prognosis of these patients. These include the use of prophylactic antibiotics in patients with gastrointestinal bleed to prevent infection and the use of albumin in patients with spontaneous bacterial peritonitis to reduce the incidence of renal impairment. The use of antibiotics has to be judicious, as their indiscriminate use can lead to antibiotic resistance with potentially disastrous consequences.

A systematic review of the epidemiology of gastro-oesophageal reflux disease (GORD) has been performed, applying strict criteria for quality of studies and the disease definition used. The prevalence and incidence of GORD was estimated from 15 studies which defined GORD as at least weekly heartburn and/or acid regurgitation and met criteria concerning sample size, response rate, and recall period. Data on factors associated with GORD were also evaluated. An approximate prevalence of 10-20% was identified for GORD, defined by at least weekly heartburn and/or acid regurgitation in the Western world while in Asia this was lower, at less than 5%. The incidence in the Western world was approximately 5 per 1000 person years. A number of potential risk factors (for example, an immediate family history and obesity) and comorbidities (for example, respiratory diseases and chest pain) associated with GORD were identified. Data reported in this systematic review can be interpreted with confidence as reflecting the epidemiology of "true" GORD. The disease is more common in the Western world than in Asia, and the low rate of incidence relative to prevalence reflects its chronicity. The small number of studies eligible for inclusion in this review highlights the need for global consensus on a symptom based definition of GORD.

Barrett's oesophagus is a premalignant condition that predisposes to the development of oesophageal adenocarcinoma. It is detected on endoscopy and confirmed histologically by the presence in the lower oesophagus of a metaplastic mucosa, the so-called specialised epithelium, which resembles incomplete intestinal metaplasia in the stomach. These similarities with incomplete intestinal metaplasia are present on histology, mucin histochemistry, and immunohistochemistry with various differentiation markers (cytokeratins and MUC antigens). On morphology, the carcinogenetic process of Barrett's mucosa progresses through increasing grades of epithelial dysplasia. Dysplasia, a synonym of intraepithelial neoplasia, is the only marker that can be used at the present time to delineate a population of patients at high risk of cancer. Among the numerous molecular events that have been shown to play a role in the neoplastic transformation of Barrett's mucosa, only changes in DNA ploidy, increased proliferation, and alterations of the p53 gene have been suggested to be of potential help in the surveillance of patients.

Patients with a Barrett's oesophagus are at risk for developing an adenocarcinoma of the distal oesophagus. Therefore, many patients undergo endoscopic surveillance to detect dysplasia and/or cancer at an early and curable stage. However, early neoplastic lesions are difficult to identify with standard endoscopy. In addition, the low incidence of these lesions, currently estimated at 0.5% per year, reduces the cost effectiveness of the surveillance strategy. New developments, aimed at improving the efficacy of Barrett's surveillance, focus on two areas: 1) improvement of the endoscopic detection of early neoplastic lesions; and 2) the use of alternative techniques for tissue sampling combined with molecular markers to identify patients at risk for malignant degeneration.

Barrett's oesophagus is defined as the replacement of squamous oesophageal epithelium by intestinal metaplasia in the distal oesophagus. It is a fairly frequent complication of gastro-oesophageal reflux disease (GORD): 5-10% of patients with GORD suffer from Barrett's oesophagus. GORD is essential for the development of Barrett's oesophagus.1 Intestinal metaplasia is a premalignant lesion that may further develop into dysplasia and lead to adenocarcinoma of the oesophagus. The latter now accounts for almost 50% of oesophageal cancer cases in western countries, and the largest increase in its incidence was recorded during the past two decades. Patients with Barrett's oesophagus have a 2-25% risk of developing mild to severe dysplasia and a 2-5% risk of having adenocarcinoma: 30-150 times higher than the risk in the general population. Forty to fifty per cent of Barrett's oesophagus patients with severe dysplasia would present adenocarcinoma within 5 years.

Oesophageal adenocarcinoma has a low incidence and still remains an uncommon cancer; however, it has been on the rise over the past 20 years. Barrett's oesophagus, a complication of gastro-oesophageal reflux disease, is the only known precursor of this adenocarcinoma. It can often be asymptomatic and probably goes undiagnosed in the majority of the population. There are no direct data supporting the practice of screening for Barrett's oesophagus and oesophageal adenocarcinoma among the general population or even in patients with chronic reflux symptoms. However, many argue that the detection of neoplasms at a curable state in a high risk population can perhaps justify screening endoscopy. No prospective, controlled trials have been conducted to support the effectiveness of surveillance, but some indirect evidence does exist. The cost effectiveness of surveillance programmes needs to be further assessed in prospective studies. Ultimately, the use of better tools to diagnose Barrett's oesophagus and dysplasia and the identification of high risk groups for progression to oesophageal adenocarcinoma could potentially make screening and surveillance a cost effective practice.

Acid, a principal component of gastro-oesophageal refluxate, may contribute to the development and malignant progression of Barrett's oesophagus. Oesophageal pH monitoring studies have demonstrated that patients with Barrett's oesophagus have severe and chronic acid reflux. However, there is overlap between the amount of acid exposure in patients with oesophagitis compared with patients with Barrett's oesophagus. This suggests that factors other than acid may be important in the aberrant oesophageal cell differentiation process that leads to the development of the metaplastic Barrett's mucosa. The other factors important in the aetiology of Barrett's oesophagus are poorly understood but probably include both genetic and environmental factors.

Helicobacter pylori infection and gastro-oesophageal reflux disease (GERD) account for most upper gastrointestinal pathologies with a wide spectrum of clinical manifestations. The interplay of both conditions is complex, in part intriguing, and has become a matter of debate because of conflicting results. The cardia is an area where both H pylori and abnormal GERD exert their damaging potential, inducing inflammation and its consequences, such as intestinal metaplasia. While the role of intestinal metaplasia within columnar lined epithelium (Barrett's oesophagus) in the context of GERD is well established as a risk for neoplasia development, the role of intestinal metaplasia at the cardia in the context of H pylori infection is unclear. A particular challenge is the distinction of intestinal metaplasia as a consequence of GERD or H pylori if both conditions are concomitant. Available data on this issue, including follow up of a small patient series, are presented, but more studies are required to shed light on this issue because they will help to identify those patients that need surveillance.

The incidence of oesophageal adenocarcinoma is increasing and the prognosis is poor. There is a strong predominance of white males, and heredity plays a minor role. The established risk factors are Barrett's oesophagus, gastro-oesophageal reflux, and obesity. Infection with Helicobacter pylori and use of non-steroidal anti-inflammatory drugs might reduce the risk. Medications that relax the lower oesophageal sphincter might contribute to increasing the risk. Among dietary factors, low intake of fruit, vegetables, and cereal fibres seem to increase the risk of oesophageal adenocarcinoma. The role of tobacco smoking is probably limited and alcohol consumption is not a risk factor. It is uncertain which factors cause the increasing incidence. Increasing prevalences of reflux and obesity, and decreasing prevalence of H pylori infection may contribute to this development; however, the sex distributions of these factors do not match the incidence trends well. Endoscopic surveillance for oesophageal adenocarcinoma among persons with reflux and obesity is discussed, but presently there is no evidence that strongly supports such a strategy.

Two distinct, but rapidly converging, areas of research (the hygiene hypothesis and the study of probiotic/prebiotic effects) have emphasised the need to understand, and ultimately to manipulate, our physiological interactions with commensal flora, and with other transient but harmless organisms from the environment that affect immunoregulatory circuits. The story began with allergic disorders but now inflammatory bowel disease is increasingly involved.