30 years of UEG: What has been achieved and what does the future hold?

The 30th UEG Week took place in Vienna at the Messe Wien Exhibition and Congress Center between 8 and 11 October 2022. It was the first face to face meeting of UEG for 3 years, the previous two UEG Weeks having been delivered in the virtual format. The participants were delighted to return to the vibrant, friendly, family atmosphere they had come to love, with the total number of attendees returning almost to pre-Covid levels. It was a triumph. There were frequent reminders that this was a significant anniversary meeting which included clinical topic based 30 year reviews and teatime treats in the social spaces, culminating in an anniversary scientific session which reviewed the outstanding progress that had be made during the last 3 decades in managing four of the most challenging diseases in gastroenterology and hepatology; hepatitis C, pancreatic cancer, gastric cancer, and inflammatory bowel disease. Following these high-quality scientific papers, I gave a brief account of UEG's history, focusing predominantly on progress made during the last 3 years which is described below. The session closed with a short musical interlude and a firework display!.

Nicholas Culpeper (1616-1654): London's first general practitioner?

Nicholas Culpeper is often regarded as an ill-disciplined, maverick, mid-17th century herbalist and the father of contemporary alternative medicine. There are elements of this statement that have some truth but to dismiss his contribution to the development of health provision in London at the time would be a great injustice. Culpeper did not complete his apprenticeship as an apothecary and was not a formally trained physician, but he developed a clinical practice for the poor of London, indistinguishable from the role of the present day general practitioner. Observers at the time recognised his concern and compassion and his commitment to treat the whole patient and not just the disease. His enduring contribution was his translation from Latin of the physicians' Pharmacopoeia Londinensis which could be regarded as the first major step towards the demystification of medicine. Culpeper's London Dispensatory and the many other medical treatises that followed were affordable and widely available to the common man. Culpeper antagonised both apothecaries and physicians because he breached the regulations of the day by accepting patients directly. So perhaps Culpeper was, de facto, London's first general practitioner, at least 150 years before the role was formally recognised in the Apothecaries Act 1815.

Research misconduct: a grand global challenge for the 21st Century.

Research misconduct is now acknowledged to be an important global issue for both researchers and the wider community. Guidance on the responsible conduct of research is now widespread, but many are still concerned by the apparent rising tide of serious cases of research misconduct, and perhaps the more worrying widespread presence of questionable research practices. I would suggest that guidance and training, while essential, are not sufficient. Additional interventions, including enhanced monitoring of research outputs and random audit using the available technology should be considered, as should the desirability of having a register of "licensed researchers." In addition, I would support a culture change in the research community in which researchers are encouraged to admit their mistakes; this should be accompanied by a spirit of forgiveness and programmed rehabilitation for the individual concerned. For multiple "premier league" offenders who are reluctant to face their misdemeanors, it is difficult to see how they could continue in the role of a researcher, and their "registration" should be revoked. Research is increasingly undertaken by researchers who cross national boundaries. The globalization of research demands greater collaboration between organizations that are responsible for ensuring standards of research integrity; the need for international standards and guidance has never been greater.

Gastro 2013 APDW/WCOG Shanghai working party report: chronic diarrhea: definition, classification, diagnosis.

Diarrhea is best defined as passage of loose stools often with more frequent bowel movements. For clinical purposes, the Bristol Stool Form Scale works well to distinguish stool form and to identify loose stools. Laboratory testing of stool consistency has lagged behind. Acute diarrhea is likely to be due to infection and to be self-limited. As diarrhea becomes chronic, it is less likely to be due to infection; duration of 1 month seems to work well as a cut-off for chronic diarrhea, but detailed scientific knowledge is missing about the utility of this definition. In addition to duration of diarrhea, classifications by presenting scenario, by pathophysiology, and by stool characteristics (e.g. watery, fatty, or inflammatory) may help the canny clinician refine the differential diagnosis of chronic diarrhea. In this regard, a careful history remains the essential part of the evaluation of a patient with diarrhea. Imaging the intestine with endoscopy and radiographic techniques is useful, and biopsy of the small intestine and colon for histological assessment provides key diagnostic information. Endomicroscopy and molecular pathology are only now being explored for the diagnosis of chronic diarrhea. Interest in the microbiome of the gut is increasing; aside from a handful of well-described infections because of pathogens, little is known about alterations in the microbiome in chronic diarrhea. Serological tests have well-defined roles in the diagnosis of celiac disease but have less clearly defined application in autoimmune enteropathies and inflammatory bowel disease. Measurement of peptide hormones is of value in the diagnosis and management of endocrine tumors causing diarrhea, but these are so rare that these tests are of little value in screening because there will be many more false-positives than true-positive results. Chemical analysis of stools is of use in classifying chronic diarrhea and may limit the differential diagnosis that must be considered, but interpretation of the results is still evolving. Breath tests for assessment of carbohydrate malabsorption, small bowel bacterial overgrowth, and intestinal transit are fraught with technical limitations that decrease sensitivity and specificity. Likewise, tests of bile acid malabsorption have had limited utility beyond empirical trials of bile acid sequestrants.

Expert review of the evidence base for prevention of travelers' diarrhea.

The most frequent illness among persons traveling from developed to developing countries is travelers' diarrhea. Travelers to high-risk regions traditionally have been educated to exercise care in food and beverage selection. Innovative research is needed to identify ways to motivate people to exercise this care and to determine its value. Chemoprophylaxis can be recommended for certain groups while monitoring for safety, drug resistance, and efficacy against all forms of bacterial diarrhea. Research to evaluate the value of immunoprophylaxis is recommended. In the following document, the authors used an evidence base when available to determine strength and quality of evidence and when data were lacking, the panel experts provided consensus opinion.

The patient with refractory diarrhoea.

Persistent diarrhoea continues to present a management challenge to clinicians around the world. The investigation of persistent diarrhoea requires a logical hierarchical approach to ensure that resources are used appropriately and patients are not put at unnecessary risks during the investigative process. A 5-step process is described in which functional diarrhoea is excluded early in the workup, which might include a measurement of 24h faecal weight. Once infection, drugs and laxatives have been excluded more invasive tests such as endoscopy are sequentially introduced to exclude inflammatory disease and small bowel and pancreatic malabsorption. When the common causes have been excluded there remains a group of patients with high volume watery diarrhoea due to a variety of causes include the neuroendocrine diarrhoeas. A case of fictitious diarrhoea is described which illustrates the value of complete fluid balance studies, faecal osmolality and other biochemical faecal analyses. The management of some selected causes of refractory diarrhoea is discussed including functional diarrhoea, diabetic diarrhoea, diarrhoea dues to protozoal infections, microscopic colitis and antibiotic associated diarrhoea.

Treatment options for the eradication of intestinal protozoa.

Pathogenic intestinal protozoa are responsible for clinically important infections in both the developed and the developing world. These organisms are responsible for both acute and chronic diarrhea, and Entamoeba histolytica, which affects the colon, can spread to involve the liver. Many of these pathogens, particularly the intracellular protozoa that predominantly affect the small intestine, produce their most devastating effects in patients with HIV/AIDS and other forms of immune deficiency. There are also various intestinal protozoa that do not seem to have any adverse effects on humans and can, therefore, be regarded as harmless commensal organisms. Although treatment has been available for several decades for giardiasis, isosporiasis and amoebiasis, until recently there have been no effective remedies for infection with intestinal coccidia--Cryptosporidium, Microsporidium and Cyclospora species. Cyclospora respond well to co-trimoxazole, microsporidia respond variably to albendazole, and cryptosporidia can often be eradicated by nitazoxanide. In chronically infected HIV-positive patients, treatment with multidrug regimens usually results in rapid resolution of the diarrhea and, in many instances, eradication of the parasite.

Investigating vomiting and/or bloody diarrhoea in Campylobacter jejuni infection.

Campylobacter jejuni infection frequently presents as acute enteritis with diarrhoea, malaise, fever and abdominal pain. Vomiting and bloody diarrhoea are reported less frequently. To investigate potential host, micro-organism or environmental factors that might explain the different clinical presentations, the features of laboratory-confirmed Campylobacter jejuni cases presenting with vomiting and/or bloody diarrhoea were compared with cases who did not report either clinical manifestation. Single variable analysis and logistic regression were employed. Explanatory variables included food, water and environmental risks. Cases who reported vomiting and/or bloody diarrhoea tended to suffer a longer illness and were more likely to require hospital admission. Independent risks identified were being a child, female gender, consumption of poultry other than chicken, pre-packed sandwiches and sausages, and reported engineering work or problems with drinking-water supply. A dose-response relationship with vomiting and/or bloody diarrhoea and increasing daily consumption of unboiled tap water was observed also. Vomiting and/or bloody diarrhoea characterized the more severe end of the disease spectrum and might relate to host susceptibility and/or infective dose. The role of unboiled tap water as a potential source of C. jejuni infection in England and Wales requires further investigation.

Antisecretory drugs for diarrheal disease.

Acute diarrhea is a major cause of morbidity and mortality worldwide. Infants and pre-school children are the most vulnerable in whom there are 2-3 million deaths each year as a result of the associated dehydration and acidosis. Although oral rehydration therapy has reduced mortality during the past 30 years ago, the search for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce faecal losses in patients with high-volume watery diarrhea has continued for more than 20 years. A variety of potential targets for antisecretory agents have been explored which include loci within the enterocyte (the chloride channel, calcium-calmodulin) and other sites such as enteric nerves and endogenous mediators (such as 5-HT, prostaglandins). Although the potential of calcium-calmodulin inhibition has as yet not been realised, preliminary studies suggest that there are chloride channel blockers under development that will find a place in the management of secretory diarrheas. Recent work has highlighted the importance of neurohumoral mechanisms in the pathogenesis of acute diarrhea. Potentiation of the effects of endogenous enkephalin activity by enkephalinase inhibition has already produced a safe, effective anti-secretory drug, racecadotril. Speculative early work indicates that there may be a role for antagonists of 5-HT, substance P, and VIP receptors. There now seems to be a real possibility that antisecretory therapy will become more widely available in the future.

Authors and publication practices.

Although authors are usually considered to be the main perpetrators of research and publication misconduct, any person involved in the process has the potential to offend. Editors may breach ethical standards particularly with respect to conflicts of interest. In the same way that authors are now required to declare competing interests, notably commercial affiliations, financial interests and personal connections, so must editors. Editors can influence the chances of acceptance or rejection of a paper by reviewer selection. Reviewers should also be ready to disclose conflicts of interest. They must ensure that their reviews are evidence based and free from destructive criticism driven by self interest. It seems likely that ultimately we will progressively move towards 'open' peer review in which both the authors and the reviewers are known to each other. There is an urgent need for increased transparency of the relationship between editors and owners. The events of the last few years indicate that unless this interface is fully understood by all parties, conflicts may arise. There is also a need for a radical overhaul in the relationship between journals, journal editors and the biomedical industry. It is now increasingly accepted that all clinical trials should be registered in a centrally held database and that protocols should include the primary and secondary outcome measures and the intended approach to data analysis thereby avoiding opportunistic post hoc analyses. However, the even more radical proposal that journals should cease to publish clinical trials sponsored by industry deserves wider debate.

Functional diarrhea.

Functional diarrhea occurs as part of the irritable bowel syndrome (IBS) and as an isolated symptom as functional (painless) diarrhea. Progress has been made in defining these disorders and in identifying new mechanisms involved in symptom production. A strong link exists between intestinal infection and IBS, as is the role of 5-hydroxytryptamine (5-HT). The importance of persistent subclinical inflammation is also emerging as a potential etiologic factor, particularly in post-infectious IBS. Although changes in the bacterial flora and bacterial overgrowth have been put forward as additional new contributors to symptom production, the case is not strong. These developments in pathogenesis have facilitated the introduction of new therapies. 5-HT(3) antagonists reduce bowel frequency and pain in women with diarrhea-predominant IBS, but their use is limited because of ischemic colitis. Prednisolone lacks efficacy, and early results with probiotics and herbal remedies are encouraging but require confirmation by larger trials.

The roles of vitamin C in Helicobacter pylori associated gastric carcinogenesis.

Ascorbic acid, as one of the important water-soluble vitamins, is essential for a range of physiological functions, including the syntheses of collagen, carnitine and neurotransmitters. It is also an important dietary antioxidant against oxidative stress. Current information suggests that vitamin C might be protective against the development of gastric cancer. Chronic infection with Helicobacter pylori is recognized to be a significant cause of gastric adenocarcinoma. Inflammation induced by H. pylori infection in the stomach not only causes significantly enhanced consumption of vitamin C, but also reduces secretion of the vitamin into the gastric lumen. Most of the evidence relating to vitamin C and H. pylori infection derives from clinical studies and experiments directly examining the effect of vitamin C on H. pylori-associated gastric carcinogenesis and remains limited. Furthermore, results from recent studies suggest that vitamin C might also increase the risk of cancer through its pro-oxidant activity and protect against oxidative stress in cancer cells through its antioxidant action. In this article we review recent publications on vitamin C research and assess the potential roles of vitamin C in H. pylori associated gastric carcinogenesis. The possible adverse effects of the vitamin C are also discussed.

Antisecretory actions of a novel vasoactive intestinal polypeptide (VIP) antagonist in human and rat small intestine.

Vasoactive intestinal peptide (VIP) has been demonstrated in intestinal mucosal neurones and elicits chloride secretion from enterocytes. These findings have led to the proposal that VIP is a secretomotor neurotransmitter. Confirmation of such a role may now be possible with the development of PG 97-269, a high-affinity, selective antagonist of VIP type 1 (VPAC1) receptor, which is expressed by gut epithelial cells. We have evaluated the VIP antagonism and antisecretory potential of this novel compound using in vitro and in vivo models of intestinal secretion. Monolayers of the human colonic cell line (T84) and muscle-stripped preparations of rat jejunum and human ileum were set up in Ussing chambers for recording of transepithelial resistance and short-circuit current. Ussing chambers were modified to allow electrical stimulation of mucosal neurones. Effects of PG 97-269 on enterotoxin-induced secretion were investigated in perfused rat jejunum in vivo. PG 97-269 competitively antagonised VIP in T84 monolayers. In rat jejunum and human ileum, responses to VIP were inhibited as were responses of rat jejunum to electrical stimulation of mucosal neurons. In perfused rat jejunum, PG 97-269 abolished the effects of VIP on fluid and electrolyte transport and attenuated cholera toxin and Escherichia coli heat labile toxin-induced net fluid and electrolyte secretion. PG 97-269 is a competitive antagonist of enterocyte VIP receptors and effectively inhibits responses of rat and human intestinal mucosa to VIP. Antagonism of secretory responses to electrical stimulation of mucosal neurons and lumenal application of enterotoxins imply a secretory role for VIP in these processes.

The effect of ascorbic acid on Helicobacter pylori induced cyclooxygenase 2 expression and prostaglandin E2 production by gastric epithelial cells in vitro.

BACKGROUND: Cyclooxygenase 2 (COX-2) is induced by the presence of Helicobacter pylori (H. pylori) on the gastric mucosa as part of the inflammatory response; this results in the synthesis of prostaglandins that amplify the local inflammatory response. The presence of H. pylori inhibits the secretion of ascorbate into the gastric lumen. Interestingly, ascorbate inhibits the growth of H. pylori and low dietary levels are associated with an increased risk of gastric adenocarcinoma. We therefore investigated the effect of ascorbate on H. pylori mediated COX-2 induction and prostaglandin production in vitro. METHODS: H. pylori was cocultured with gastric epithelial cells in the presence of ascorbate at physiological concentrations. The expression of COX-2 was assessed by Western blotting and prostaglandin E(2) (PGE(2)) was assessed by ELISA. RESULTS: Ascorbate inhibited gastric cell PGE(2) synthesis but not in COX-2 expression in response to H. pylori. In the absence of the organism, ascorbate also reduced PGE(2) expression in cells that constitutively express COX-2, again with no reduction of COX-2 protein expression. CONCLUSIONS: Physiological concentrations of ascorbate inhibit PGE(2) but not COX-2 expression in response to H. pylori in gastric epithelial cells.

Cyclooxygenase 2, p53, beta-catenin, and APC protein expression in gastric adenomatous polyps.

Gastric adenomatous polyps are rare findings in upper gastrointestinal endoscopy; however, they are associated strongly with malignant transformation. Few series describe the oncogenic characteristics of gastric adenomas. In the present study, we immunohisto-chemically assessed the expression of cyclooxygenase (COX)-2, beta-catenin, p53, and adenomatous polyposis coli (APC) in paraffin-embedded specimens of 14 gastric adenomas. Control samples of normal gastric tissue and gastric adenocarcinoma also were analyzed. Of the adenomas, 7 demonstrated overexpression of COX-2, and all demonstrated nuclear p53 accumulation. Accumulation of beta-catenin in the nucleus and cytoplasm was detected in 38% (3/8) of specimens. Loss of APC staining was observed in 50% (4/8). Similar alterations in oncoprotein expression were seen in gastric cancers but not in normal control sections. Gastric adenomas display alterations in the expression of COX-2, beta-catenin, and APC similar to those seen in adenocarcinomas; however, accumulation of p53 was significantly more common in adenomas than in cancers.

Treatment options in irritable bowel syndrome.

The irritable bowel syndrome (IBS) is part of the spectrum of functional bowel disorders characterised by a diverse consortium of abdominal symptoms including abdominal pain, altered bowel function (bowel frequency and/or constipation), bloating, abdominal distension, the sensation of incomplete evacuation and the increased passage of mucus. It is not surprising therefore that no single, unifying mechanism has as yet been put forward to explain symptom production in IBS. The currently favoured model includes both central and end-organ components which may be combined to create an integrated hypothesis incorporating psychological factors (stress, distress, affective disorder) with end-organ dysfunction (motility disorder, visceral hypersensitivity) possibly aggravated by sub-clinical inflammation as a residuum of an intestinal infection. There is currently no universally effective therapy for IBS. Standard therapy generally involves a symptom-directed approach; anti-diarrhoeal agents for bowel frequency, soluble fibre or laxatives for constipation and smooth muscle relaxants and anti-spasmodics for pain. New drug development has focused predominantly on agents that modify the effects of 5-hydroxytryptamine (5-HT) in the gut, principally the 5-HT(3) receptor antagonists for painful diarrhoea predominant IBS and 5-HT(4) agonists for constipation predominant IBS. More speculative new therapeutic approaches include anti-inflammatory agents, antibiotics, probiotics, antagonists of CCK1 receptors, tachykinins and other novel neuronal receptors.

Novel agents for the control of secretory diarrhoea.

Acute infectious diarrhoea continues to cause high morbidity and mortality worldwide. Although oral rehydration therapy has reduced the mortality associated with acute diarrhoea, stool volume often increases during the rehydration process. Therefore, for > 20 years there has been a search for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce stool volume. The most obvious target for antisecretory therapy has been the chloride channel and second messengers within the enterocyte. So far, this search has been largely unrewarding, although recent evidence suggests that a new class of chloride channel blocker is effective in vitro but further evaluation in humans is required. In addition, research during the past decade has highlighted the importance of neurohumoral mechanisms in the pathogenesis of diarrhoea, notably the role of 5-hydroxtryptamine, substance P, vasoactive intestinal polypeptide and neural reflexes within the enteric nervous system. This new dimension of intestinal pathophysiology has already exposed possible novel targets for antisecretory therapy; namely, 5-hydroxytryptamine receptor antagonists, substance P antagonists and sigma-receptor agonists. There is also the possibility for potentiating the proabsorptive effects of endogenous enkephalins by using enkephalinase inhibitors. There now seems to be a real possibility that antisecretory therapy will become more widely available in the future.