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Biomedical subjects

Michael J G Farthing

Publications and source records attributed to Michael J G Farthing.

At least 19 recordsLinked to original sources
PubMed2006

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.

Authorship↗
PubMed2006

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.

Antiprotozoal Agents↗
PubMed2006

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.

Adolescent↗
PubMed2006

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.

Antidiarrheals↗
PubMed2005

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.

Clinical Trials as Topic↗
PubMed2005

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.

Animals↗
PubMed2005

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.

Adenocarcinoma↗
PubMed2005

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.

Antioxidants↗
PubMed2005

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.

Adenomatous Polyposis Coli Protein↗
PubMed2004

Prognostic value of TP53 codon 72 polymorphism in advanced gastric adenocarcinoma.

PURPOSE: A common polymorphism of the tumor suppressor gene TP53 at codon 72 has been associated with human cancer susceptibility. The prognostic role of the polymorphism was assessed in 102 patients with advanced gastric adenocarcinoma. EXPERIMENTAL DESIGN: We followed up 102 consecutive Caucasian patients with advanced gastric adenocarcinoma for >5 years and determined the status of the TP53 codon 72 polymorphism in DNA samples extracted from archived gastric tissues. RESULTS: The frequency of the arginine homozygous allele was positively correlated to patient age at baseline (P = 0.002). However, the age-related increase in the percentage of codon 72 arginine p53 was not correlated to the prognosis for gastric cancer patients. Multivariable analysis in patients who had surgery showed that baseline age may be inversely associated with patient survival (odds ratio, 1.1; 95% confidence interval, 1.0-1.2; P = 0.02). Furthermore, alcohol consumption may be associated with reduced survival (P = 0.06). CONCLUSIONS: These findings indicate that codon 72 arginine p53 may not be associated with a prolonged survival in patients with advanced gastric adenocarcinoma, but further study is needed to assess whether this polymorphism is associated with a late onset or slow progress of early gastric adenocarcinoma.

Adenocarcinoma↗
PubMed2004

Bugs and the gut: an unstable marriage.

There is a symbiotic relationship between the gastrointestinal microflora and the human host. Commensal bacteria provide essential nutrients to the epithelium and promote healthy immune responses in the gut. Commensal bacteria such as Escherichia coli can, however, transform into pathogens when they acquire genetic material encoding virulence factors such as adhesins, enterotoxins, invasins and cytotoxins. Enterovirulent organisms 'communicate' with the host by a variety of diverse mechanisms; these underpin the pathogenic processes that are essential for the expression of diarrhoeal disease. Many of these mechanisms involve the activation of signal transduction pathways in epithelial cells. Classical pathways include activation of adenylate or guanylate cyclases to produce chloride secretion, and subversion of cytoskeletal functions to effect intimate attachment with or without invasion of epithelial cells. Other systems are also involved, including inflammatory cells and local neuroendocrine networks. Understanding the complex interactions between the human gastrointestinal tract and the commensals and pathogens which it encounters will hopefully help us to exploit further the beneficial effects of the 'marriage' and to find new ways of preventing and treating microbial disease of the intestine which occurs when the symbiotic arrangement breaks down.

Biological Evolution↗
PubMed2004

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.

Anti-Inflammatory Agents↗
PubMed2004

A comparison study of gastric cancer risk in patients with duodenal and gastric ulcer: roles of gastric mucosal histology and p53 codon 72 polymorphism.

Gastric ulcer is positively, and duodenal ulcer negatively, associated with the risk of gastric cancer. The relationship between a common p53 polymorphism at codon 72 and gastric cancer risk in patients with gastric and duodenal ulcer was examined in 397 Caucasian patients using PCR-RFLP. Noncardiac cancer patients had a distribution pattern of codon 72 genotypes similar to that of other non-cancer patient groups, though the frequency of the Pro/Pro genotype looks higher in duodenal ulcer. However, patients with cancer of the cardiac region had a significantly higher frequency of the Arg/Arg genotype than patients with chronic gastritis, duodenal ulcer, and noncardiac cancer. There was no significant difference in the distribution patterns between gastric ulcer and noncardiac or cardiac cancer or between gastric and duodenal ulcer. These findings may be a reflection of differences in the interaction between p53 codon 72 polymorphism and local factors in the stomach.

Adult↗
PubMed2004

Traveler's diarrhea.

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Diagnosis, Differential↗
PubMed2004

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.

Animals↗
PubMed2003

Fascin, an actin-bundling protein, modulates colonic epithelial cell invasiveness and differentiation in vitro.

In epithelial tissue, cell-matrix and cell-cell adhesive interactions have important roles in the normal organization and stabilization of the cell layer. The malignant conversion of epithelial cells involves alterations in the expression and function of these adhesion systems that enable a switch to a migratory phenotype in tumor invasion and metastasis. Fascin is an actin-crosslinking protein that is found in the core actin bundles of cell-surface spikes and projections that are implicated in cell motility. We demonstrate that fascin is not detectable in normal colonic epithelium, but is dramatically up-regulated in colorectal adenocarcinoma. To test the hypothesis that fascin could participate in tumor invasive behavior, we developed a cell culture model to examine the effect of fascin expression on the adhesive interactions, invasiveness, and differentiation of colonic epithelial cells. We report marked effects on the organization of cell-surface protrusions, actin cytoskeleton, and focal adhesions in the absence of alterations in the protein levels of the major components of these structures. These effects correlate with alterations in cell movements on two-dimensional matrix, and increased invasiveness in three-dimensional matrix. The cells also show increased proliferation and decreased capacity for normal glandular differentiation in collagen gels. We propose that up-regulation of fascin, by promoting the formation of protrusive, actin-based, cell-motility structures, could be a significant component in the acquisition of invasive phenotype in colonic carcinoma.

Actins↗